The Measurement of Pain in the Laboratory Rodent
Abstract and Keywords
The current translational crisis, in which apparently rapidly expanding genetic, molecular, and cellular knowledge has not resulted in novel clinical therapies, has forced preclinical pain researchers to question the algesiometric status quo. One hypothesized cause of poor translation is the limited external validity of the reflexive withdrawals to evoking stimuli that represent the ubiquitous dependent measures of pain at the present time. As a response, new techniques have been developed and are increasingly being incorporated into pain studies. This comprehensive review examines the subjects, assays, and measures used in preclinical pain research, as well as the need for and implementation of newly described measures of spontaneous, ongoing chronic pain.
Algesiometry and the Translational Crisis
It is almost axiomatic now, in the late 2010s, that biomedical science—in particular, neuroscience—is in the midst of a translational crisis in which apparently rapidly expanding genetic, molecular, and cellular knowledge has not resulted in novel clinical therapies. Pain is no exception, with failures to observe efficacy in Phase 2 and Phase 3 clinical trials of at least 14 different therapeutic targets in the past few decades (see Table 1 in Yezierski & Hansson, 2018). The degree to which this truly represents a crisis is debated because (a) some trials have failed due to issues of tolerability/side effects, not efficacy; (b) few trials have demonstrated appropriate levels of drug exposure in humans accompanying efficacy failure; and (c) a few apparent success stories can be pointed to (e.g., ziconitide, CGRP [calcitonin gene-related peptide] antibodies for migraine, tanezumab).
Among those who think a serious problem exists, some place the blame largely on preclinical pain science, whereas others have pointed to the changing nature of clinical trials making it ever harder to separate drug from placebo effects (Dworkin et al., 2012; Katz, Finnerup, & Dworkin, 2008; Tuttle et al., 2015). There exist two fundamentally different critiques of the preclinical pain research status quo, one related to internal validity and the other to external validity. Pain research, of course, is not exempt from the “replication/reproducibility crisis” continuing to convulse science (Baker, 2016), and the quality of reporting and statistical practices appears to be as low in the pain field as elsewhere (Currie et al., 2013; Rice et al., 2009). Others, myself included, have instead criticized the external validity (i.e., generalizability) of the animal models representing the mainstay of preclinical pain research for many decades and of their relevance to clinical and epidemiological reality. This critique has become increasingly strident, with a number of recent reviews questioning the very foundations of pain modeling in animals and calling for major reform (Blackburn-Munro, 2004; J. D. Clark, 2016; Mao, 2002; Mogil & Crager, 2004; Nagakura, 2017; Percie du Sert & Rice, 2014; Vierck, Hansson, & Yezierski, 2008; Yezierski & Hansson, 2018).
As I have argued previously (Mogil, 2009), an “animal model” of pain has three separate facets: (a) the subject (who is in pain?), (b) the assay (how is pain generated?), and (c) the measure (how is the pain of the subject undergoing the assay quantified?). Each can be separately considered in terms of best practices, challenges to external validity, relevant considerations, and recent developments.
Animal Models of Pain: Subjects
Unlike for some disease states like Alzheimer’s disease, there is no widely accepted transgenic “model” of pain in any species. There do exist, however, animal models of diseases featuring pain as a primary symptom, which may therefore be appropriate as the subjects of preclinical pain studies. For example, one might study painful diabetic neuropathy in spontaneously developing diabetes models such as the C57BL/6-ob/ob (B6.V-Lepob/J), BKS-db/db (BKS.Cg‑m+/+Leprdb/J), NOD, or Akita (C57BL/6-Ins2Akita/J) mouse lines (Bierhaus & Nawroth, 2012; Sullivan, Lentz, Roberts, & Feldman, 2008). Single-gene mutant mice developing behavioral symptoms of familial hemiplegic migraine are available (Chanda et al., 2013), as is a rat line developed from a single individual with spontaneous trigeminal allodynia (Oshinsky et al., 2012). Sickle cell pain can be studied in transgenic HbSS-BERK sickle mice (Mittal, Gupta, Lamarre, Jahagirdar, & Gupta, 2016). Mice with a null mutation of the Sparc (secreted protein, acidic, and rich in cysteine) may develop low back and radicular pain caused by degenerative disk disease (Millecamps, Tajerian, Sage, & Stone, 2011).
As a practical matter, the default subjects of preclinical pain experiments are rats and mice. This choice has been made for practical reasons, as rats and mice are among the smallest rodents and therefore the cheapest to house and feed. They are limited as proxies for humans in a number of ways, however, including the fact that they are prey species with strong motivation to hide their pain from potential predators such as ourselves. (This fact is not cited because although it is commonly asserted, and perfectly reasonable, I am aware of no actual data demonstrating differential willingness to display overt pain-related behaviors in prey versus predator species.) The role of companion animals as research subjects is engendering increased interest (Klinck et al., 2017; Lascelles, Brown, Maixner, & Mogil, 2018), as is the use of nontraditional rodents like the naked mole rat (Smith et al., 2011) and submammalian species such as Drosophila melanogaster (Leung, Wilson, Khuong, & Neely, 2013).
Within rats and mice, the lion’s share of preclinical pain studies are performed in particular strains: outbred Sprague Dawley rats and inbred C57BL/6 mice (see Mogil, 2009). The choice matters because robust and even extreme differences in pain sensitivity, chronic pain susceptibility, and analgesic response have been demonstrated among panels of mouse strains (Lariviere et al., 2002; Mogil et al., 1999; Sorge et al., 2012; Wilson, Bryant, et al., 2003; Wilson, Smith, et al., 2003) and rat strains (Carr, Best, Mackinnon, & Evans, 1992; Fecho, Nackley, Wu, & Maixner, 2005; Lovell, Stuesse, Cruce, & Crisp, 2000; Schaap et al., 2014; Shir et al., 2001; Yoon, Lee, Lee, Chung, & Chung, 1999). For example, the concentration of formalin required to produce equivalent amounts of licking behavior in A/J and C57BL/6J mice differs by a factor of 100 (Mogil, Lichtensteiger, & Wilson, 1998), the amount of intracerebroventricularly injected morphine required to produce half-maximal analgesia in C57BL/6J mice is almost six-fold higher than that required in 129P3/J mice (Kest, Wilson, & Mogil, 1999), and male C3H/HeJ mice do not develop mechanical allodynia after nerve injury (Sorge et al., 2011; Tanga, Nutile-McMenemy, & DeLeo, 2005). Unfortunately, the ubiquitous C57BL/6 strain may be somewhat of an outlier among available mouse strains with respect to its pain phenotype (Lariviere, Chesler, & Mogil, 2001). In addition to quantitative strain differences, there are a number of reports of qualitative differences in pain-processing biology between rodent strains (Mogil et al., 2005) and even substrains (F. M. Clark & Proudfit, 1992), raising the specter that some of what we think we know may only be true in certain genotypes and not others. Finally, meta-analysis suggested that the regulation of gene expression by chronic pain is disturbingly species specific (LaCroix-Fralish et al., 2010).
Raising similar issues, the default subjects of preclinical pain experiments up to the present time have been male rats and mice. Pain studies exclusively featuring male rodent subjects represented 79% of studies published in the journal Pain from 1996 to 2005 (Mogil & Chanda, 2005) and 79% again in 2015 (Mogil, 2016). Given increasing evidence of robust, qualitative sex differences in pain processing (e.g., Sorge et al., 2015; see Mogil, 2012, for review), the inclusion of female subjects in preclinical pain experiments, as recently mandated by the US National Institutes of Health (Clayton & Collins, 2014), seems utterly warranted. The use of female rodents as 50% of experimental subjects in pain experiments (Mogil, 2016) will allow the detection of large sex differences without increasing cost, as female rodents do not feature increased variability compared to males, either in pain assays (Mogil & Chanda, 2005) or more generally (Becker, Prendergast, & Liang, 2016; Prendergast, Onishi, & Zucker, 2014).
One facet of subject choice that has received very little attention is that of age, as the default subjects of preclinical pain experiments are young adult (6- to 12-week-old) rodents. Given the epidemiological realities of chronic pain in humans (Institute of Medicine, 2011), it would seem advisable to routinely use far older animals. Only a handful of experiments have ever evaluated the pain phenotype of older rodents (see Gagliese & Melzack, 2000). Some recent studies have pointed to considerably altered analgesic responsivity of aged rodents (Mecklenburg, Patil, Koek, & Akopian, 2017; Morgan, Mitzelfelt, Koerper, & Carter, 2012; Samir, Yllanes, Lallemand, Brewer, & Clemens, 2017). Unlike the inclusion of females, however, such a change would greatly increase costs, as it would require housing and feeding animals for many months or even years before testing commenced.
Animal Models of Pain: Assays
Preclinical pain research features a rapidly expanding collection of assays, suggesting that the field is nowhere close to solving its “lumping-versus-splitting” problem. In general, existing assays—which as previously described (Mogil, 2009) have been developed in several waves over the past hundred years—share the following features: Assays of acute pain simply expose a body part (generally the hind paw) to a noxious stimulus–heat, cold, mechanical, or electrical–or a series of graded stimuli, including those in the noxious range. These exposures lead (or do not, depending on the intensity) to reflexive withdrawals of the body part from the stimulus and, in some cases, recuperative and avoidance behaviors. Note that these acute assays also serve as the measures of chronic pain assays (at multiple time points) described in the material that follows. An extremely comprehensive review of acute nociceptive assays was provided by Le Bars, Gozariu, and Cadden (2001). Assays of tonic pain involve the injection into a body part (or into the nervous system directly) of a direct or indirect algogen/irritant or inflammogen; commonly used substances include capsaicin, substance P, N-methyl-d-aspartic acid, prostaglandin E2, acetic acid, hypo-/hypertonic saline, and formalin. Such injections produce so-called nocifensive behaviors (e.g., lifting, guarding, licking, shaking, abdominal constriction) that last for several minutes to an hour or two and may be either supraspinally mediated recuperative responses or brainstem reflexes (Matthies & Franklin, 1992; Woolf, 1984). Frustrated with the short duration of existing assays, the first widely used “chronic” pain assays were developed starting in the late 1980s (Bennett & Xie, 1988). These assays generally feature experimental nerve injuries designed to mimic the partial peripheral nerve injuries commonly causing chronic neuropathic pain in humans (see Sorkin & Yaksh, 2009) or injections of compounds (e.g., complete Freund’s adjuvant [CFA], carrageenan) producing longer lasting inflammatory states.
It should be noted that the word chronic is relative. Most neuropathic and inflammatory assays produce symptoms fully resolving in a matter of weeks, or even sooner. The relevance to human clinical pain, which can last for many years, is difficult to assess. On the one hand, rodents only live for 2–3 years instead of the 75–80 years typical of modern humans; thus, a 6-week pain episode in a 2-year life span might indeed be considered a chronic condition. On the other hand, the biochemical and structural processes thought to underlie pathological pain proceed at the same pace in rodents and humans. One neuropathic surgery, the spared nerve injury (Decosterd & Woolf, 2000), reliably produces pain symptoms lasting as long as anyone has thus far looked, but even so I was only able to identify 13 published studies ever testing rodents past the 3-month postsurgery time point.
A more modern approach to the development of preclinical pain assays is to pay more attention to etiology. Popular assays with realistic etiologies include assays of cancer pain (see Pacharinsak & Beitz, 2008); postoperative pain (see Bove, Flatters, Inglis, & Mantyh, 2009); and chemotherapy-induced neuropathy (see Hopkins, Duggett, & Flatters, 2016). In some cases, credible assays of hard-to-study pain states have been developed, but their widespread use has been limited by their highly labor-intensive nature. For example, we developed a mouse assay of vulvodynia based on repeated Candida infection and treatment (Farmer et al., 2011), a proposed human etiology of the disorder. Although the behavioral and immunohistochemical sequelae were highly reminiscent of human clinical observations, a single run of this paradigm takes at least 3 months to conduct. The tension between the clinical relevance and the practicality of animal pain assays is likely to continue, especially as regards the increasing desire for high-throughput screening methods.
Other clear trends in recent years include the more common use of “batteries” of assays in preclinical pain papers (Mogil et al., 2006) and the use of assays based on hypothesized pain chronification mechanisms, for example, “double-hit” or hyperalgesic priming assays (Reichling & Levine, 2009; K. A. Sluka, Kalra, & Moore, 2001). Our colleagues studying orofacial, visceral, or joint pain rightly bemoan the continued fixation on the hind paw as the anatomical target of most assays and have developed assays specific to other tissues and regions. Increasing attention is recently being paid as well to the problem of experimenter influences on behavior in pain experiments (Sorge et al., 2014), leading to automation efforts (see Jourdan, Ardid, & Eschalier, 2001).
Animal Models of Pain: Measures
The facet of animal models of pain receiving the most attention is that of the dependent measure being used to quantify the pain produced in assays of chronic pain. Here, the critiques are many and varied. Probably the most common criticism is that the measures in ubiquitous use are all reflexive withdrawals to evoking (heat, cold, or mechanical) stimuli delivered by an experimenter (see Vierck & Yezierski, 2015). Although pain reflexes may indeed change in clinical pain disorders, they are hardly the relevant clinical complaint.
Another recognized problem relates to the disconnect between the prevalence of symptoms of chronic pain in humans and the popularity of various dependent measures (see Mogil & Crager, 2004). Evoking stimuli leading to limb withdrawals measured hypersensitivity (i.e., allodynia and hyperalgesia), and mechanical or thermal hypersensitivity were measured exclusively in over 90% of preclinical pain studies published in the journal Pain from 2000 to 2003 (Mogil & Crager, 2004). Although hypersensitivity can be observed in some proportion of patients with chronic pain, it is certainly rarer than loss-of-function symptoms like numbness and completely overshadowed in terms of prevalence and bothersomeness by spontaneous, ongoing pain (Backonja & Stacey, 2004; Maier et al., 2010; Scholz et al., 2009). Spontaneous neuropathic pain is likely due to spontaneous firing of C fibers (Kleggetveit et al., 2012), and the technical challenge of measuring C-fiber excitability in humans (using microneurography) is likely to blame for our relatively poor understanding of the most common clinical pain symptom.
Of interest is a counterargument by Bennett (2012), who suggested that much pain considered spontaneous may actually be unrecognized, repeated episodes of stimulus-evoked pain, where the evoking stimuli are internal (e.g., gravity) or associated with activities of daily life. Some have pointed out that the status quo only addresses and quantifies the sensory-discriminative aspect of pain, but not the motivational–affective aspect (Melzack & Casey, 1968). Although measurement of more global concepts such as disability and quality of life has taken on increased importance in the clinical pain literature, some have argued we should attempt to do the same in animals. Finally, patients with clinical pain are bothered by more than just their pain; comorbid conditions accompanying or caused by the pain—most notably, sleep disruption and depression/anxiety—could also be measured in animals in the context of algesiometry.
Measures of Spontaneous Pain in Rodents
Given these criticisms, the last few decades have witnessed a flurry of innovative suggestions for the measurement of spontaneous, ongoing, or affective pain, which for simplicity I simply refer to here as spontaneous pain. These can be broadly categorized into five categories (see Table 1): (a) biomarkers, (b) pain-stimulated behaviors, (c) pain-depressed behaviors, (d) measures of pain-related disability, and (e) conditioning/motivational paradigms. In some cases, collections of different pain-stimulated and pain-depressed behaviors, most recently measured in a home cage context via automated video-based systems, have been used to compile “ethograms” (see Peters, Pothuizen, & Spruijt, 2015, for review; e.g., Roughan & Flecknell, 2001). Many attempts have been made to simultaneously measure pain comorbid conditions, using standard animal models of cognition (attention and memory), emotion (depression and anxiety), and social behavior (see Li, 2015; Liu & Chen, 2014, for reviews). These investigations are not considered here, except to say that although many studies have seen chronic pain-induced changes in these behavioral assays, many others have not; thus, the subfield likely suffers greatly from a “file-drawer problem.” At least some investigations have observed that comorbidities occur with some delay past the insult (Seminowicz et al., 2009; Sieberg et al., 2018), suggesting that many negative studies may not have been sufficiently patient.
Table 1. Categories of Proposed Measures of Spontaneous Pain in Laboratory Animals
Autonomic nervous system (blood flow, blood pressure, corticosterone, heart rate, heart rate variability, plasma norepinephrine, pupil dilation, respiration, skin conductance)
Asymmetric limb-associated behaviors (grooming, flinching, licking, lifting, scratching, shaking, turning)
Operant responding (for reward)
Weight bearing (dynamic weight bearing [gait], guarding, posture, static weight bearing)
Classical conditioning (conditioned place avoidance, conditioned place preference)
Operant conditioning (analgesic self-administration, motivational conflicts, place escape/avoidance)
Note. See text for further information.
Biomarkers of Pain
The holy grail of pain measurement in animals would be the discovery of an easily accessible and cheaply processed biomarker whose current state or level reliably predicted the existence of pain without the need for time- and labor-intensive behavioral measurements. The desire for a biomarker in humans is exceedingly high as well, mostly as a means of bypassing potentially unreliable subjective pain ratings. Unfortunately, no such biomarker has ever been validated; all contenders fail to show convincing enough evidence of specificity or sensitivity. Proposed biomarkers of pain include body weight decreases and autonomic nervous system measures such as pupil dilation, blood pressure, blood flow, respiration, heart rate, skin conductance, fecal corticosterone, plasma norepinephrine, and heart rate variability (HRV). Of these, only HRV measured via telemetry is still actively studied as a potential pain measure (Arras, Rettich, Cinelli, Kasermann, & Burki, 2007; Charlet, Rodeau, & Poisbeau, 2011; Goecke, Awad, Lawson, & Boivin, 2005) and only in the context of postoperative pain. Recent studies in humans have shown that autonomic responses to pain are closely related to the intensity of the noxious stimulus, but not to the resultant pain perception (Mischkowski, Palacios-Barrios, Banker, Dildine, & Atlas, 2018; Nickel et al., 2017).
Current best hopes for a pain biomarker in humans revolve around functional magnetic resonance imaging (fMRI) procedures and algorithms, which have achieved impressive accuracy at least for the prediction of acute pain (Wager et al., 2013). Although it is apparently possible to train rats to tolerate awake immobilization in a scanner (see Borsook & Becerra, 2011), it is difficult to envisage this method being used routinely for pain quantification. Although chronic pain causes, after a number of months, cortical volume loss in rats (as in people) detectable by structural MRI (Seminowicz et al., 2009), a true biomarker would need to display much better time resolution. Similarly, DNA variants are not useful as biomarkers because they are markers only of susceptibility to pain, not of whether pain exists at any particular time point. On the other hand, particular messenger RNA (mRNA) species could be biomarkers in theory, although in practice one might suspect that mRNA levels only in particular tissues would be relevant, and the labor required to extract this tissue and quantify the gene expression greatly exceeds that for behavioral measurement. The same is true for electrophysiological recordings and calcium imaging techniques, which are of great use in preclinical pain research but hardly practical as biomarkers.
The reflexive withdrawal behaviors measured in acute pain assays and nocifensive behaviors measured in tonic pain assays belong in the category of pain-stimulated behaviors, but this section focuses on behaviors proposed to be associated with chronic pain states. The fundamental problem, of course, is that the robust, easily quantified nocifensive behaviors seen in tonic pain models (e.g., licking and shaking of the affected hind paw) are simply not displayed with any useful frequency in chronic inflammatory or neuropathic pain states. The reasons for this absence are unclear and may have to do with conscious or unconscious inhibition of pain behavior in prey species, although again there is no extant evidence for this.
The most striking example of a chronic pain-stimulated behavior is autotomy (i.e., self-mutilation of the digits) following complete deafferentation, for example, after ligation of both the sciatic and saphenous nerves serving the hind paw. The scoring of autotomy is so simple—one simply counts missing hind paw phalanges every morning—that the behavior itself practically qualifies as a biomarker. Thought to represent deafferentation pain despite the fact that the limb is otherwise insensate (Wall et al., 1979), some have suggested that autotomy behavior is secondary to itch, nonpainful parasthesias, or the desire to rid oneself of a functionally impaired appendage (Rodin & Kruger, 1984). As a practical matter, the procedure has been almost completely abandoned, both due to its “aesthetic repugnancy” (much bleeding occurs) and because partial peripheral nerve injuries are thought to be better assays of most neuropathic pain syndromes in humans. Devor and colleagues (Koplovitch, Minert, & Devor, 2012) have demonstrated that partial injuries do not feature autotomy because the nociceptive “sensory cover” provided by the residual innervation would make autotomy painful to perform.
A number of reports have alleged that chronic assays are accompanied by increased frequency of asymmetric limb-associated behaviors on the side ipsilateral to the injury, such as lifting, licking/grooming, shaking/flinching/scratching of the hind paw, or turning the head to the side of the injury. As described in Mogil, Graham et al. (2010), a blinded evaluation of this hypothesis using both sham- and unoperated controls, over an extended time course, and with scoring of long (1-hour) time intervals revealed no evidence of an increase in any of these behaviors caused by chronic constriction injury. An analysis of the existing literature supporting the use of these end points revealed that the modal scored interval was a mere 300 seconds, and that the percentage of that interval featuring the behavior was often extremely small (Mogil, Graham, et al., 2010). For example, in a study introducing a new nerve injury model producing spontaneous hind paw lifting, the duration of such lifting was less than 10 seconds out of a total 600-second observation period in 16 of 25 rats tested (Djouhri, Koutsikou, Fang, McMullan, & Lawson, 2006). The statistical evidence for an increase in hind paw lifting was robust, but it is hard to understand what the true meaning of such a rare behavior might be. Do rats only lift their hind paws when the pain level is above a certain threshold? Do they do it only after a certain amount of time has passed since the last such lift? Such questions are a long way from being answered, although more attention is starting to be paid to the precise subsecond details of pain-related behavioral responses (Browne et al., 2017). In certain contexts, however, the evidence seems incontrovertible that particular behaviors are pain relevant, including grooming of a tumor-implanted limb (McCaffrey et al., 2014); postural changes after uterine inflammation (Wesselmann, Czakanski, Affaitati, & Giamberardino, 1998); and a suite of behaviors associated with postoperative pain (Roughan & Flecknell, 2000). None of these behaviors, however, is universally associated with pain regardless of type, etiology, and body part.
A pain-stimulated behavior that might well be universal, at least within a certain time range, is facial grimacing. Facial grimacing to pain has been shown to occur in at least 10 nonhuman species: mouse (Langford et al., 2010); rat (Sotocinal et al., 2011); rabbit (Keating, Thomas, Flecknell, & Leach, 2012); horse (Dalla Costa et al., 2014; Gleerup, Forkman, Lindegaard, & Andersen, 2015); cat (Holden et al., 2014); cattle (Gleerup, Andersen, Munksgaard, & Forkman, 2015); sheep (Guesgen et al., 2016; Hager et al., 2017; McLennan et al., 2016); pig (Gottardo et al., 2016); ferret (Reijgwart et al., 2017); and seal (MacRae, Makowska, & Fraser, 2018). Pain assays producing facial grimacing include (in this and all subsequent lists of this type, only the first such demonstration known to me is cited): abdominal inflammation (Langford et al., 2010); hind paw inflammation (Langford et al., 2010); joint inflammation (Langford et al., 2010); spontaneous headache (Langford et al., 2010); laparotomy (Langford et al., 2010); tattooing (Keating et al., 2012); castration (Dalla Costa et al., 2014); tooth movement (Liao et al., 2014); muscle inflammation (Asgar et al., 2015); myocardial infarction (Faller, McAndrew, Schneider, & Lygate, 2015); tourniquet application (Gleerup, Forkman, et al., 2015); follicular puncture (Diego et al., 2016); experimental autoimmune encephalomyelitis (Duffy et al., 2016); tail docking (Guesgen et al., 2016); maxillary sinus grafting (Hedenqvist et al., 2016); foot rot/mastitis (McLennan et al., 2016); sickle cell disease (Mittal et al., 2016); spinal cord injury (Wu et al., 2016); osteotomy (Hager et al., 2017); drug-induced headache (Harris, Carpenter, Black, Smitherman, & Sufka, 2017); and cervical radiculopathy (Philips, Weisshaar, & Winkelstein, 2017). Although the initial article describing the Mouse Grimace Scale did not observe grimacing in acute (<10-minute) and chronic (>1-day) contexts (Langford et al., 2010), many subsequent articles have reported seen changes in facial expression lasting only a few seconds to minutes or out to several months postinjury. It is possible that limitations in optical quality in the original study are to blame, as my laboratory is also now seeing evidence of facial grimacing 12 months after a spared nerve injury. The selectivity of facial grimacing has been questioned, however, as somewhat similar changes in facial musculature can be seen in aggressive and fearful contexts (Defensor, Corley, Blanchard, & Blanchard, 2012) and with nausea (Yamamoto, Tatsutani, & Ishida, 2017).
A seemingly ideal pain-stimulated behavior is ultrasonic vocalization (USV), which can be picked up with an inexpensive bat detector, recorded, and quantified. Rats especially are well known to emit “alarm” calls at approximately 22 kHz, and pain assays might produce such alarm. Given its advantages, the technique is not very commonly used, but pain-induced USVs have been observed in rats and mice in the following assays: electric shock (which, of course, also can produce audible vocalization) (Jourdan, Ardid, Chapuy, Eschalier, & Le Bars, 1995); adjuvant-induced arthritis (Calvino, Besson, Boehrer, & Depaulis, 1996); kaolin/carrageenan-induced arthritis (J. S. Han, Bird, Li, Jones, & Neugebauer, 2005); capsaicin (S. W. Ko, Chatila, & Zhuo, 2005); formalin (Oliveira & Barros, 2006); spared nerve injury (Kurejova et al., 2010); tumor implantation (Kurejova et al., 2010); CFA (Tsuzuki, Maekawa, Konno, & Hori, 2012); incision (Lim, Kim, Han, & Kim, 2014); and spinal cord injury (M. Y. Ko et al., 2018). There are critiques of the measure, largely based on the fact that alarm calls are not selective to pain, being elicited by human handling (Brudzynski & Ociepa, 1992); stress/anxiety (Naito, Nakamura, Inoue, & Suzuki, 2003); anticipation of negative events (Knutsen, Burgdorf, & Panksepp, 2002); and social interactions (Jourdan, Ardid, & Eschalier, 2002). Others have simply failed to observe any USVs (Wallace, Norbury, & Rice, 2005) or USVs only in a percentage of animals (Williams, Riskin, & Mott, 2008).
In contrast to pain-stimulated behaviors, the appearance of things that would otherwise not be there, pain-depressed behaviors are activities of daily living whose frequency is decreased in the presence of chronic pain. Feeding and drinking are not considered here, as there is no evidence in any modern chronic pain assay for long-term reductions in body weight. Advantages of the pain-depressed behavior concept include the clinical parallel, the required decision-making on the part of the animal, and the fact that although sedating or ataxic analgesics may suppress the ability to perform pain-stimulated behaviors, the reinstatement of pain-depressed behaviors by those analgesics would introduce no such confound (see Stevenson, Bilsky, & Negus, 2006). On the other hand, of course, a stimulant drug might increase pain-depressed behaviors nonselectively.
The first pain-depressed behavior suggested as a measure of chronic pain was locomotor activity (Harada, Takahashi, Kaya, & Inoki, 1979; Larsen & Arnt, 1985), both horizontal (walking) and vertical (rearing). Until the recent advent of home cage-monitoring systems, locomotor behavior was measured in novel open-field environments, rendering it unclear whether what was being measured was exploration versus anxiety versus disability. Apart from the interpretational problem, any number of health challenges might depress locomotion; thus, the measure features very little specificity. Our systematic study of behavioral changes after chronic constriction injury yielded no evidence whatsoever for deficits in horizontal or vertical locomotion compared to sham and unoperated mice (Mogil, Graham, et al., 2010). In contrast, as a measure of postoperative pain (Goecke et al., 2005; Roughan & Flecknell, 2000) or inflammatory pain (Matson et al., 2007; Zhu et al., 2012), the evidence for the utility of locomotor activity is considerably more convincing.
A somewhat related idea is the use of within-cage wheel-running devices (Cobos et al., 2012; Stevenson et al., 2011). The advantage is that instead of measuring locomotion in a stressful novel environment, wheel running represents a highly motivated behavior performed in the animal’s home cage, and data can be collected automatically, 24 hours a day. Depression of wheel running has been demonstrated after monosodium iodoacetate (MIA) (Stevenson et al., 2011); bilateral CFA (Cobos et al., 2012); intradural allyl isothiocyanate as an assay of migraine (Kandasamy, Lee, & Morgan, 2017); and paclitaxel-induced neuropathy (Griffiths, Duggett, Pitcher, & Flatters, 2018). However, Cobos and colleagues (2012) reported that unilateral injections of CFA did not produce depression of wheel running in mice, and Stevenson et al. (2011) only observed effects after unilateral MIA in a subset of rats, both suggesting that wheel-running depression is more a measure of functional disability (see next section) than a loss of motivation to participate in an activity of daily living. Grace and colleagues (2014) observed that CFA into the plantar surface of the hind paw decreased wheel running, but CFA into the dorsal surface did not, suggesting that reduction of wheel running actually reflects evoked pain from the act of running itself and not spontaneous pain. Some have observed depressed wheel running after CFA to be transient, normalizing far sooner than other measures (Pitzer, Kuner, & Tappe-Theodor, 2016; Sheahan et al., 2017). Critics have also suggested that wheel running as a dependent measure of pain might be confounded by the analgesic effects of exercise (K. A. Sluka, O’Donnell, Danielson, & Rasmussen, 1985).
An intriguing recent idea is to use species-specific behaviors like nest building (Jirkof, Fleischmann, et al., 2013; Rock et al., 2014) and burrowing (Deacon, 2006) as measures of overall quality of life, which pain might be expected to disrupt. Modern rodent husbandry protocols require that animals be provided with nesting material, which rodents of both sexes will use to build nests for protection and thermoregulation. Postoperative pain has been shown to decrease the complexity of the nests that are built (Jirkof, Fleischmann, et al., 2013) and the time taken to integrate the material into nests (Rock et al., 2014), as has CFA injection (Negus et al., 2015). Burrowing behavior is displayed by virtually all rodents and represents another very easy way to quantify quality of life, as one simply needs to measure the weight of the burrowing material (e.g., gravel) at the beginning and end of any desired time period. Burrowing behavior has been shown to be disrupted by laparotomy (Jirkof et al., 2010); CFA (Andrews et al., 2011); nerve injury (Andrews et al., 2011); colitis (Jirkof, Leucht, et al., 2013); chemotherapy-induced mucositis (Whittaker, Lymn, Nicholson, & Howarth, 2015); chemotherapeutic neuropathy (Griffiths et al., 2018); and disk injury (Shi et al., 2018). The disadvantage here, of course, is specificity, because any procedure that decreases welfare will likely decrease nest building and burrowing. As well, some have complained about large interindividual variability (Muralidharan et al., 2016) and extreme dependence on strain and precise test conditions (Shepherd, Cloud, Cao, & Mohapatra, 2018). Some studies have failed to see suppressions in burrowing in assays where they might be expected (Rutten et al., 2018; Shepherd et al., 2018). An extremely ambitious cross-center study of burrowing behavior in the rat looked at burrowing reductions after CFA in 11 different studies across eight laboratories (Wodarski et al., 2016). Overall, significant reduction of burrowing, compared to naïve and sham groups, was observed only on Day 1 postinjection. Extreme intersite variability was observed in both baseline burrowing and CFA-induced suppression, which was only observed in 7 of 11 studies. These observations reinforce the huge influence of subtle local environmental factors related to husbandry and testing on preclinical pain studies (e.g., Mogil, 2017).
Given that sleep disruption is among the most common pain-related comorbidities in humans (see Morin, Gibson, & Wade, 1998), it is not surprising that preclinical researchers have looked for evidence of same in rodents. Sleep fragmentation and disruption has been reported in arthritic rats (Landis, Robinson, & Levine, 1988); after nerve injury (D’Almeida et al., 1999); orofacial CFA (Schutz, Andersen, & Tufik, 2003); hypotonic saline into the muscle (Sutton & Opp, 2014); and reserpine-induced “fibromyalgia” (Hernandez-Leon, Fernandez-Guasti, Martinez, Pellicer, & Gonzalez-Trujano, 2018), although others have failed to observe any changes (Kontinen, Ahnaou, Drinkenburg, & Meert, 2003). Monassi, Bandler, and Keay (2003) reported that a subpopulation of nerve-injured rats displayed decreased slow-wave sleep. Disturbances were also observed in a more recent study in some but not other pain assays (Leys et al., 2013), in male but not female mice (Schutz, Andersen, Silva, & Tufik, 2009), and in one case only when nerve-injured rats were placed on sandpaper to sleep (Tokunaga et al., 2007). It is well known that sleep deprivation and fragmentation strongly affect pain sensitivity (e.g., Alexandre et al., 2017).
Finally, it has been proposed that pain may interfere with otherwise-rewarding behaviors; that is, pain may produce anhedonia. It was recently proposed that suppression of the normal rodent preference for sweet substances, including nonnutrient sweeteners like saccharine, might be used as a measure of pain (de la Puente et al., 2015; Refsgaard, Hoffmann-Petersen, Sahlholt, Pickering, & Andreasen, 2016). Like with locomotor activity, a potential confound here involves potential analgesic (or hyperalgesic) effects of the compounds themselves (e.g., Suri, Jain, & Mathur, 2010). A related concept is intracranial electrical self-stimulation, which taps directly into brain reward-processing systems, which has been shown to be depressed by lactic acid in rats (Negus, Morrissey, Rosenberg, Cheng, & Rice, 2010). There are also a number of demonstrations that pain can suppress operant responding (via lever pressing; see discussion that follows) for natural rewards, such as food pellets (e.g., LaGraize, Borzan, Rinker, Kopp, & Fuchs, 2004; Martin, Buechler, Kahn, Crews, & Eisenach, 2004).
Measures of Functional Disability
Low back pain is the condition causing the most years lived with disability of all diseases, disorders, or injuries, and neck pain, other musculoskeletal disorders, and migraine are also featured in the top ten (Vos et al., 2012). Pain disability is so critical in clinical pain research that multiple instruments have been developed to measure it (e.g., see Smeets, Koke, Lin, Ferreira, & Demoulin, 2011), and consensus-based recommendations advocate the measurement of physical function as a main outcome in analgesic clinical trials (Dworkin et al., 2008). In animals, the concept of “disability” has been interpreted very broadly. Some have asserted that the decreased locomotor activity exhibited by rodents with inflammatory or neuropathic conditions represents disability or functional impairment (Cain, Francis, Plone, Emerich, & Lindner, 1997; Keay, Monassi, Levison, & Bandler, 2004; Lopez-Munoz, Salazar, Castaneda-Hernandez, & Villarreal, 1993). Two other measures of functional disability have been proposed: grip strength and static or dynamic weight bearing.
Rodents pulled by the tail will attempt to resist and will do so tenaciously if provided a grid-like surface to hold on to. By attaching to the grid to a force transducer or strain gauge, the maximum force exerted by the forelimbs before the animal is moved by an experimenter pulling it caudally can be quantified Kehl, Trempe, & Hargreaves, 2000). Inflammation given to the forelimbs reduces this maximum grip force in an analgesic-reversible fashion (e.g., Kehl, Kovacs, & Larson, 2004; Kehl et al., 2000; Montilla-Garcia et al., 2017). It is more difficult to test hind paw grip strength, but it is possible (Montilla-Garcia et al., 2017).
The most popular measures of functional disability relate to weight bearing, more specifically to the avoidance of (usually) hind limb weight bearing on the side of the injury. Multiple terms are used here (including guarding, posture, weight bearing, and gait);in some cases, the animal is motionless (guarding, posture, static weight bearing), whereas in others locomoting animals (dynamic weight bearing) are monitored. Techniques to quantify weight-bearing changes range from low tech (e.g., simple observation, ink prints on paper) to high (load cells, scattering of internally reflected light, machine learning). Changes in one or more of these parameters have been documented for gallstones (Beynen et al., 1987); arthritis (Schott et al., 1994); nerve injury (Bennett & Xie, 1988); disk herniation (Olmarker, Iwabuchi, Larsson, & Rydevik, 1998); spinal cord injury (Hamers, Lankhorst, Van Laar, Veldhuis, & Gispen, 2001); cancer pain (Medhurst et al., 2002); chemotherapy-induced neuropathy (Huehnchen, Boehmerle, & Endres, 2013); and abdominal pain (Laux-Biehlmann et al., 2016). So ubiquitous are these changes that they have been proposed as confounds of other pain measures, including mechanical allodynia quantified with von Frey fibers (Kauppila, Kontinen, & Pertovaara, 1998). Although there is a huge literature supporting the use of these measures, criticisms abound as well. The standard static weight-bearing “incapacitance meter” test requires stressful restraint (although rats at least can be trained to voluntarily enter; Kim, Uchimoto, Duellman, & Yang, 2015); results may therefore be confounded by stress-induced analgesia (see Butler & Finn, 2009) or stress-induced hyperalgesia (see Jennings, Okine, Roche, & Finn, 2014). Although dynamic weight-bearing systems require no restraint and less handling, they are extremely labor intensive even when automated. Gait can be affected by joint deformation caused by cartilage or bone destruction accompanying some inflammatory states (Boettger et al., 2009). The use of gait analysis for the measurement of nerve injury pain has been especially questioned, as nerve damage itself produces changes in gait uncorrelated with apparent pain in terms of time course or response to analgesics (Mogil, Graham, et al., 2010; Piesla et al., 2009; Shepherd & Mohapatra, 2018), likely due to motor neuron damage (Daemen et al., 1998; Na, Yoon, & Chung, 1996) or tethering of the nerve to the adjacent muscle due to scar tissue formation (Tseng, Hsieh, & Hsieh, 2007). Finally, it remains unclear what guarding/gait/weight bearing actually measure. Is reluctance to bear weight a sign of ongoing pain? Does it reflect the inability to stand or walk without pain? Is it an attempt to avoid (and thus an indirect measure of) the allodynia that would result if the hind limb were placed on the ground?
Two forms of conditioning ultimately underlie all learning: classical (Pavlovian) and operant conditioning. Both are increasingly used in algesiometry, with the obvious practical disadvantage that, as conditioning paradigms, subject training is required, as are control experiments to rule out alternate explanations involving motivation, learning, and memory. The advantage, of course, is that animals are making decisions about their pain; thus, these assays are thought to be much more clinically relevant than mere reflexive withdrawals.
Classical conditioning can be used to measure pain either via conditioned place avoidance (CPA; to pain) or conditioned place preference (CPP; to analgesia). Place conditioning involves a training phase, wherein rodents are confined to one compartment of a two-compartment chamber (each distinctive from each other) and exposed to different experiences in each chamber and a test phase in which they are allowed to freely explore both chambers. The amount of time spent in each chamber is compared, and during testing, the animal is in a drug-free or pain-free state, so what is being measured in an entirely unconfounded manner is their learning about what happened in the chambers during training.
Conditioned place avoidance is the conceptually simpler of the two and simply posits that rodents will learn to avoid the chamber in which they experienced pain. The first direct demonstration using a nonacute noxious stimulus was by Johansen, Fields, and Manning (2001), who observed that rats developed a CPA to formalin that could be abolished with lesions of the rostral anterior cingulate cortex. Carrageenan (Hummel, Lu, Cummons, & Whiteside, 2008; van der Kam, de Vry, Schiene, & Tzschentke, 2008); nerve injury (Hummel et al., 2008); CFA (Zhang et al., 2011); colorectal distension (Yan et al., 2012); tendon ligation (Guo et al., 2016); cancer pain (Feng, Chen, Wang, Zhao, & Liu, 2016); and of course electric shock have also been shown to produce a CPA. Increasingly, the ability of pain to produce place avoidance even without conditioning has been shown in optogenetic stimulation paradigms (e.g., Daou et al., 2013).
The first demonstration of CPP to a chamber paired with analgesia, from which the presence of pain might be inferred, was by Sufka (1994), who demonstrated that rats injected with CFA would develop a CPP to several analgesics, including morphine. This observation was confounded by the inherently rewarding properties of morphine itself, and I am aware of no further investigation into analgesic CPP for another 15 years, at which point T. King et al. (2009) showed robust CPP to clonidine, lidocaine, and Ω-conotoxin in rats with nerve injury. Cleverly, these drugs were chosen as they have no rewarding properties by themselves and were injected intrathecally so that the analgesic action did not outlast the training period. CPP has become quite popular, with a number of pain states and analgesics having been investigated (see Navratilova, Xie, King, & Porreca, 2013, for review). Although it is possible to assess whether a novel, systemically administered drug is analgesic using CPP, it is more difficult. Another limitation of the technique is that it does not measure pain in real time; one must infer the existence of pain in the past by the presence of a CPP in the present.
Unlike classical conditioning, which simply requires the passive pairing of unconditioned stimuli like pain with originally neutral contextual stimuli, operant conditioning requires the direct reward or punishment of behaviors emitted by rodent subjects. In the earliest such paradigms, escape from noxious stimuli via lever pressing or some other instrumental response was measured (Babbini, Gaiardi, & Bartoletti, 1979; Berkley, Wood, Scofield, & Little, 1995; Bodnar, Kelly, Brutus, Mansour, & Glusman, 1978; Ross, Komisaruk, & O’Donnell, 1979). A clever but labor-intensive technique called the place escape/avoidance paradigm (LaBuda & Fuchs, 2000) requires an experimenter to stimulate the animal with mechanical stimuli on the hind paw ipsilateral to the injury every time it enters one half of an arena and to the contralateral hind paw every time it enters the other half. If the animal avoids the former half, it is exhibiting stimulus-related aversion, sometimes leading to a CPA. In some cases, the reward or punishment is automatic, not requiring experimenter intervention. For example, rodents will choose to escape or avoid chambers or surfaces that are too hot or cold, too bright, too steep, or too sharp. For example, systems tracking the location of an animal choosing among surfaces of contrasting (or smoothly graded) temperature have been used to measure heat and cold hypersensitivity (Baliki, Calvo, Chialvo, & Apkarian, 2005; Duraku et al., 2014; Mauderli, Acosta-Rua, & Vierck, 2000; Shimizu et al., 2005). If an animal is in pain, administration of an analgesic should be rewarding, and lever pressing for analgesics (i.e., self-administration) is another highly clinically relevant but very labor-intensive measure of pain (Colpaert et al., 2001).
Some of the most interesting operant paradigms involve trade-offs between competing motivational states, or operant conflicts. A clever example is a strategy developed by Neubert and colleagues (2005) to measure orofacial pain hypersensitivity. Rats with orofacial nerve damage and shaved cheeks are placed in a testing device in which a rewarding liquid solution can only be accessed by contacting a thermode with their face. If the thermode is heated, this will produce thermal allodynia on the cheek, which is quantified by measuring thermode contacts and liquid consumption. Another example is the “dolognawmeter” (Dolan, Lam, Achdjian, & Schmidt, 2010), in which, to escape restraint in a polyvinyl chloride tube, a mouse is required to gnaw through foam dowels. Gnawing time was affected by inflammation of the temporomandibular joint or the masticatory muscles or the introduction of a squamous cell carcinoma.
Should We All Switch?
In virtually every case, and even despite automation, newly developed assays and measures of pain are longer lasting or more labor intensive than the status quo model of preclinical pain in 2018: testing male, C57BL/6 mice for mechanical sensitivity using von Frey fibers before and at a few time points for a few weeks after an experimental nerve injury. The real question, therefore, is whether any newly proposed subject, assay, or measure of pain is superior than the status quo. Superiority could lie either in sensitivity or predictivity, and before either issue was addressed, it would first need to be demonstrated that the new technique gave different results than the techniques it purported to replace.
There is in fact plenty of evidence documenting that measures of spontaneous pain outlined previously give different answers than evoked measures. A common finding is that the time course of spontaneous pain and evoked hypersensitivity is different, with the latter usually outlasting the former (e.g., de Rantere, Schuster, Reimer, & Pang, 2016), as is true in humans (Gould, 2000). In some cases, qualitative differences in the underlying pathophysiology have been documented. For example, spontaneous inflammatory orofacial pain as measured by facial grimacing or face-wiping behaviors is TRPV1 (transient receptor potential vanilloid 1) dependent, being reduced in null mutants and reversed by antagonists, but evoked hypersensitivity from the same injury (measured via bite force) is TRPV1 independent (Wang et al., 2017). Vierck and Yezierski (2015) have reviewed studies comparing operant escape and reflex measures head to head. The techniques yield very different answers regarding the efficacy of low-dose aspirin (LaBuda & Fuchs, 2001) and morphine (van der Kam et al., 2008; Vierck, Acosta-Rua, Nelligan, Tester, & Mauderli, 2002); effects of cingulate lesions (LaGraize, Labuda, Rutledge, Jackson, & Fuchs, 2004) and restraint stress (C. D. King, Devine, Vierck, Mauderli, & Yezierski, 2007); sex differences (Vierck, Acosta-Rua, Rossi, & Neubert, 2008); and the involvement of SNAP25 interacting protein of 30 in neuropathic pain (M. Han et al., 2014). Classical conditioning techniques have also yielded different experimental results compared to reflex measures, including the efficacy of low-dose morphine (Harton, Richardson, Armendariz, & Nazarian, 2017) and vis-à-vis gabapentin (Hung, Wang, & Strichartz, 2015), the TRPV1 receptor antagonist AMG9810 (Okun et al., 2011), and the TRPA1 receptor antagonist C-5861528 (Wei, Viisanen, Amorim, Koivisto, & Pertovaara, 2013); effects of cingulate lesions (Qu et al., 2011); the role of protein kinase C isoforms (He & Wang, 2015) and dorsal column projection neurons to the nucleus gracilis (T. King et al., 2011); and the involvement of the P311 peptide in pain (Sun et al., 2008).
An extremely large literature documents that virtually every other measure of chronic pain is more sensitive to analgesics than is evoked hypersensitivity. This is important because one of the biggest reasons to doubt the predictivity of animal models is that efficacious doses in rodents appear to be much higher than clinically efficacious doses in humans, although this may be due to pharmacokinetics in addition to end points (Whiteside, Adedoyin, & Leventhal, 2008). A representative example is that of Cobos and colleagues (2012), who observed that the half-maximal effective dose of morphine to reduce voluntary wheel-running deficits produced by CFA in male C57BL/6 mice was 0.08 mg/kg; in this same study, 0.25 mg/kg of morphine had no detectable effect whatsoever on mechanical allodynia measured with von Frey fibers.
The proof that new techniques are superior to old ones would require evidence of better rodent-to-human predictivity. Such proof will be difficult to come by for some time. It has long been known that “backward translation” works very well in algesiometry. Drugs known to be efficacious in humans can be easily demonstrated to work in standard preclinical neuropathic pain assays (Kontinen & Meert, 2002; Whiteside et al., 2008). If anything, backward translation works too well because analgesics like gabapentin are generally fully effective in, say, reversing nerve injury–induced mechanical allodynia (at least at some doses), whereas its number needed to treat in humans is 5.5 (Finnerup, Sindrup, & Jensen, 2010) and falling. Furthermore, there are compounds such as adenosine that are perfectly able to reverse mechanical allodynia (e.g., T. King et al., 2009) but are inefficacious in relieving ongoing pain in humans (Eisenach, Rauck, & Curry, 2003). Ultimately, though, it is forward translation that is the problem, and it remains unclear what the appropriate metric is to evaluate the success of forward translation other than simply counting successful versus failed clinical trials.
As a practical matter, the experiment has already begun, as large subsets of current preclinical pain studies are using, exclusively or in addition to older methods, the measures of spontaneous pain described herein. I remain optimistic that the current translation crisis in pain research is a temporary situation, and that novel analgesic strategies will be forthcoming. I also believe as strongly as ever that animal models will remain indispensable to this effort (Mogil, Davis, & Derbyshire, 2010).
Alexandre, C., Latremoliere, A., Ferreira, A., Miracca, G., Yamamoto, M., Scammell, T. E., & Woolf, C. J. (2017). Decreased alertness due to sleep loss increases pain sensitivity in mice. Nature Medicine, 23(6), 768–774.Find this resource:
Andrews, N., Legg, E., Lisak, D., Issop, Y., Richardson, D., Harper, S., … Rice, A. S. C. (2011). Spontaneous burrowing behaviour in the rat is reduced by peripheral nerve injury or inflammation associated pain. European Journal of Pain, 16(4), 485–495.Find this resource:
Arras, M., Rettich, A., Cinelli, P., Kasermann, H. P., & Burki, K. (2007). Assessment of post-laparotomy pain in laboratory mice by telemetric recording of heart rate and heart rate variability. BMC Veterinary Research, 3, 16.Find this resource:
Asgar, J., Zhang, Y., Saloman, J. L., Wang, S., Chung, M.-K., & Ro, J. Y. (2015). The role of TRPA1 in muscle pain and mechanical hypersensitivity under inflammatory conditions in rats. Neuroscience, 310, 206–215.Find this resource:
Babbini, M., Gaiardi, M., & Bartoletti, M. (1979). Stimulus-response relationships in a quickly learned escape from shock: Effects of morphine. Pharmacology Biochemistry and Behavior, 11, 155–158.Find this resource:
Backonja, M.-M., & Stacey, B. (2004). Neuropathic pain symptoms relation to overall pain rating. Journal of Pain, 5(9), 491–497.Find this resource:
Baker, M. (2016). Is there a reproducibility crisis? Nature, 533, 452–454.Find this resource:
Baliki, M., Calvo, O., Chialvo, D. R., & Apkarian, A. V. (2005). Spared nerve injury rats exhibit thermal hyperalgesia on an automated operant dynamic thermal escape task. Molecular Pain, 1, 18.Find this resource:
Becker, J. B., Prendergast, B. J., & Liang, J. W. (2016). Female rats are not more variable than male rats: A meta-analysis of neuroscience studies. Biology of Sex Differences, 7, 34.Find this resource:
Bennett, G. J. (2012). What is spontaneous pain and who has it? Journal of Pain, 13(10), 921–929.Find this resource:
Bennett, G. J., & Xie, Y.-K. (1988). A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain, 33, 87–107.Find this resource:
Berkley, K. J., Wood, E., Scofield, S. L., & Little, M. (1995). Behavioral responses to uterine or vaginal distension in the rat. Pain, 61(1), 121–131.Find this resource:
Beynen, A. C., Baumans, V., Bertens, A. P. M. G., Havenaar, R., Hesp, A. P. M., & van Zutphen, L. F. M. (1987). Assessment of discomfort in gallstone-bearing mice: A practical example of the problems encountered in an attempt to recognize discomfort in laboratory animals. Lab Animal, 21, 35–42.Find this resource:
Bierhaus, A., & Nawroth, P. P. (2012). Critical evaluation of mouse models used to study pain and loss of pain perception in diabetic neruopathy. Experimental and Clinical Endocrinology & Diabetes, 120(4), 188–190.Find this resource:
Blackburn-Munro, G. (2004). Pain-like behaviours in animals—How human are they? Trends in Pharmacological Science, 25(6), 299–305.Find this resource:
Bodnar, R. J., Kelly, D. D., Brutus, M., Mansour, A., & Glusman, M. (1978). 2-Deoxy-D-glucose-induced decrements in operant and reflex pain thresholds. Pharmacology Biochemistry and Behavior, 9, 543–549.Find this resource:
Boettger, M. K., Weber, K., Schmidt, M., Gajda, M., Brauer, R., & Schaible, H.-G. (2009). Gait abnormalities differentially indicate pain or structural joint damage in monoarticular antigen-induced arthritis. Pain, 145(1–2), 142–150.Find this resource:
Borsook, D., & Becerra, L. (2011). CNS animal fMRI in pain and analgesia. Neuroscience and Biobehavioral Reviews, 35, 1125–1143.Find this resource:
Bove, S. E., Flatters, S. J. L., Inglis, J. J., & Mantyh, P. W. (2009). New advances in musculoskeletal pain. Brain Research Reviews, 60(1), 187–201.Find this resource:
Browne, L. E., Latremoliere, A., Lehnert, B. P., Grantham, A., Ward, C., Alexandre, C., … Woolf, C. J. (2017). Time-resolved fast mammalian behavior reveals the complexity of protective pain responses. Cell Reports, 20, 89–98.Find this resource:
Brudzynski, S. M., & Ociepa, D. (1992). Ultrasonic vocalization of laboratory rats in response to handling and touch. Physiology & Behavior, 52, 655–660.Find this resource:
Butler, R. K., & Finn, D. P. (2009). Stress-induced analgesia. Progress in Neurobiology, 88, 184–202.Find this resource:
Cain, C. K., Francis, J. M., Plone, M. A., Emerich, D. F., & Lindner, M. D. (1997). Pain-related disability and effects of chronic morphine in the adjuvant-induced arthritis model of chronic pain. Physiology & Behavior, 62(1), 199–205.Find this resource:
Calvino, B., Besson, J. M., Boehrer, A., & Depaulis, A. (1996). Ultrasonic vocalization (22–28 kHz) in a model of chronic pain, the arthritic rat: Effects of analgesic drugs. Neuroreport, 7(2), 581–584.Find this resource:
Carr, M. M., Best, T. J., Mackinnon, S. E., & Evans, P. J. (1992). Strain differences in autotomy in rats undergoing sciatic nerve transection or repair. Annals of Plastic Surgery, 28, 538–544.Find this resource:
Chanda, M. L., Tuttle, A. H., Baran, I., Atlin, C., Guindi, D., Hathaway, G., … Mogil, J. S. (2013). Behavioral evidence for photophobia and stress-related ipsilateral head pain in transgenic Cacna1a mutant mice. Pain, 154(8), 1254–1262.Find this resource:
Charlet, A., Rodeau, J.-L., & Poisbeau, P. (2011). Radiotelemetric and symptomatic evaluation of pain in the rat after laparotomy: Long-term benefits of perioperative ropivacaine care. Journal of Pain, 12(2), 246–256.Find this resource:
Clark, F. M., & Proudfit, H. K. (1992). Anatomical evidence for genetic differences in the innervation of the rat spinal cord by noradrenergic locus coeruleus neurons. Brain Research, 591, 44–53.Find this resource:
Clark, J. D. (2016). Preclinical pain research: Can we do better? Anesthesiology, 125, 846–849.Find this resource:
Clayton, J. A., & Collins, F. S. (2014). Policy: NIH to balance sex in cell and animal studies. Nature, 509(7500), 282–283.Find this resource:
Cobos, E. J., Ghasemlou, N., Araldi, D., Segal, D., Duong, K., & Woolf, C. J. (2012). Inflammation-induced decrease in voluntary wheel running in mice: A nonreflexive test for evaluating inflammatory pain and analgesia. Pain, 153, 876–884.Find this resource:
Colpaert, F. C., Tarayre, J. P., Alliaga, M., Bruins Slot, L. A., Attal, N., & Koek, W. (2001). Opiate self-administration as a measure of chronic nociceptive pain in arthritic rats. Pain, 91, 33–45.Find this resource:
Currie, G. L., Delaney, A., Bennett, M. I., Dickenson, A. H., Egan, K. J., Vesterinen, H. M., … Fallon, M. T. (2013). Animal models of bone cancer pain: Systematic review and meta-analyses. Pain, 154(6), 917–926.Find this resource:
Daemen, M. A. R. C., Kurvers, H. A. J. M., Bullens, P. H. J., Slaaf, D. W., Freling, G., Kitslaar, P. J. E. H. M., & van den Wildenberg, F. A. J. M. (1998). Motor denervation induces altered muscle fiber type densities and atrophy in a rat model of neuropathic pain. Neuroscience Letters, 247, 204–208.Find this resource:
Dalla Costa, E., Minero, M., Lebelt, D., Stucke, D., Canali, E., & Leach, M. C. (2014). Development of the Horse Grimace Scale (HGS) as a pain assessment tool in horses undergoing routine castration. PLoS One, 9(3), e92281.Find this resource:
D’Almeida, J. A. C., de Castro-Costa, C. M., Frota, C. H., Severo, J. F., Rocha, T. D. S., & Nogueira, T. F. (1999). Behavioral changes of Wistar rats with experimentally-induced painful diabetic neuropathy. Arquivos de Neuro-Psiquiatria, 57(3-B), 746–752.Find this resource:
Daou, I., Tuttle, A. H., Longo, G., Wieskopf, J. S., Bonin, R. P., Ase, A. R., … Seguela, P. (2013). Remote optogenetic activation and sensitization of pain pathways in freely moving mice. Journal of Neuroscience, 33(47), 18631–18640.Find this resource:
Deacon, R. M. J. (2006). Burrowing in rodents: A sensitive method for detecting behavioral dysfunction. Nature Protocols, 1(1), 118–121.Find this resource:
Decosterd, I., & Woolf, C. J. (2000). Spared nerve injury: An animal model of persistent peripheral neuropathic pain. Pain, 87, 149–158.Find this resource:
Defensor, E. B., Corley, M. J., Blanchard, R. J., & Blanchard, D. C. (2012). Facial expressions of mice in aggressive and fearful contexts. Physiology & Behavior, 107, 680–685.Find this resource:
de la Puente, B., Romero-Alejo, E., Vela, J. M., Merlos, M., Zamanillo, D., & Portillo-Salido, E. (2015). Changes in saccharin preference behavior as a primary outcome to evaluate pain and analgesia in acetic acid-induced visceral pain in mice. Journal of Pain Research, 8, 663–673.Find this resource:
de Rantere, D., Schuster, C. J., Reimer, J. N., & Pang, D. S. J. (2016). The relationship between the Rat Grimace Scale and mechanical hypersensitivity testing in three experimental pain models. European Journal of Pain, 20, 417–426.Find this resource:
Diego, R., Douet, C., Reigner, F., Blard, T., Cognie, J., Deleuze, S., & Goudet, G. (2016). Influence of transvaginal ultrasound-guided follicular punctures in the mare on heart rate, respiratory rate, facial expression changes, and salivary cortisol as pain scoring. Theriogenology, 86, 1757–1763.Find this resource:
Djouhri, L., Koutsikou, S., Fang, X., McMullan, S., & Lawson, S. N. (2006). Spontaneous pain, both neuropathic and inflammatory, is related to frequency of spontaneous firing in intact C-fiber nociceptors. Journal of Neuroscience, 26(4), 1281–1292.Find this resource:
Dolan, J. C., Lam, D. K., Achdjian, S. H., & Schmidt, B. L. (2010). The dolognawmeter: A novel instrument and assay to quantify nociception in rodent models of orofacial pain. Journal of Neuroscience Methods, 187, 207–215.Find this resource:
Duffy, S. S., Perera, C. J., Makker, P. G. S., Lees, J. G., Carrive, P., & Moalem-Taylor, G. (2016). Peripheral and central neuroinflammatory changes and pain behaviors in an animal model of multiple sclerosis. Frontiers in Immunology, 7, 369.Find this resource:
Duraku, L. S., Niehof, S. P., Misirli, Y., Everaers, M., Hoendervangers, S., Holstege, J., … Walbeehm, E. T. (2014). Rotterdam Advanced Multiple Plate: A novel method to measure cold hyperalgesia and allodynia in freely behaving rodents. Journal of Neuroscience Meth., 224, 1–12.Find this resource:
Dworkin, R. H., Turk, D. C., Peirce-Sandner, S., Burke, L. B., Farrar, J. T., Gilron, I., … Ziegler, D. (2012). Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations. Pain, 153(6), 1148–1158.Find this resource:
Dworkin, R. H., Turk, D. C., Wyrwich, K. W., Beaton, D., Cleeland, C. S., Farrar, J. T., … Zavisic, S. (2008). Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. Journal of Pain, 9(2), 105–121.Find this resource:
Eisenach, J. C., Rauck, R. L., & Curry, R. (2003). Intrathecal, but not intravenous adenosine reduces allodynia in patients with neuropathic pain. Pain, 105, 65–70.Find this resource:
Faller, K. M. E., McAndrew, D. J., Schneider, J. E., & Lygate, C. A. (2015). Refinement of analgesia following thoracotomy and experimental myocardial infarction using the Mouse Grimace Scale. Experimental Physiology, 100.2, 164–172.Find this resource:
Farmer, M. A., Taylor, A. M., Bailey, A. L., Tuttle, A. H., MacIntyre, L. C., Milagrosa, Z. E., … Mogil, J. S. (2011). Repeated vulvovaginal fungal infections cause persistent pain in a mouse model of vulvodynia. Science Translational Medicine, 3(101), 101ra191.Find this resource:
Fecho, K., Nackley, A. G., Wu, Y., & Maixner, W. (2005). Basal and carrageenan-induced pain behavior in Sprague-Dawley, Lewis and Fischer rats. Physiology & Behavior, 85, 177–186.Find this resource:
Feng, H., Chen, Z., Wang, G., Zhao, X., & Liu, Z. (2016). Effect of the ifenprodil administered into rostral anterior cingulate cortex on pain-related aversion in rats with bone cancer pain. BMC Anesthesiology, 16(1), 117.Find this resource:
Finnerup, N. B., Sindrup, S. H., & Jensen, T. S. (2010). The evidence for pharmacological treatment of neuropathic pain. Pain, 150, 573–581.Find this resource:
Gagliese, L., & Melzack, R. (2000). Age differences in nociception and pain behaviours in the rat. Neuroscience and Biobehavioral Reviews, 24, 843–854.Find this resource:
Gleerup, K. B., Andersen, P. H., Munksgaard, L., & Forkman, B. (2015). Pain evaluation in dairy cattle. Applied Animal Behaviour Science, 171, 25–32.Find this resource:
Gleerup, K. B., Forkman, B., Lindegaard, C., & Andersen, P. H. (2015). An equine pain face. Veterinary Anaesthesia and Analgesia, 42, 103–114.Find this resource:
Goecke, J. C., Awad, H., Lawson, J. C., & Boivin, G. P. (2005). Evaluating postoperative analgesics in mice using telemetry. Comparative Medicine, 55(1), 37–44.Find this resource:
Gottardo, F., Scollo, A., Contiero, B., Ravagnani, A., Tavella, G., Bernardini, D., … Edwards, S. A. (2016). Pain alleviation during castration of piglets: A comparative study of different farm options. Journal of Animal Science, 94, 5077–5088.Find this resource:
Gould, H. J., III. (2000). Complete Freund’s adjuvant-induced hyperalgesia: A human perception. Pain, 85, 301–303.Find this resource:
Grace, P. M., Strand, K. A., Maier, S. F., & Watkins, L. R. (2014). Suppression of voluntary wheel running in rats is dependent on the site of inflammation: Evidence for voluntary running as a measure of hind paw-evoked pain. Journal of Pain, 15(2), 121–128.Find this resource:
Griffiths, L. A., Duggett, N. A., Pitcher, A. L., & Flatters, S. J. L. (2018). Evoked and ongoing pain-like behaviours in a rat model of paclitaxel-induced peripheral neuropathy. Pain Research and Management, 2018, 8217613.Find this resource:
Guesgen, M. J., Beausoleil, N. J., Minot, E. O., Stewart, M., Stafford, K. J., & Morel, P. C. H. (2016). Lambs show changes in ear posture when experiencing pain. Animal Welfare, 25, 171–177.Find this resource:
Guo, W., Chu, Y. X., Imai, S., Yang, J. L., Zou, S., Mohammad, Z., … Ren, K. (2016). Further observations on the behavioral and neural effects of bone marrow stromal cells in rodent pain models. Molecular Pain, 12, 1–12.Find this resource:
Hager, C., Biernot, S., Buettner, M., Glage, S., Keubler, L. M., Held, N., … Bleich, A. (2017). The Sheep Grimace Scale as an indicator of post-operative distress and pain in laboratory sheep. PLoS One, 12(4), e0175839.Find this resource:
Hamers, F. P. T., Lankhorst, A. J., Van Laar, T.-J., Veldhuis, W. B., & Gispen, W. H. (2001). Automated quantitative gait analysis during overground locomotion in the rat: Its application to spinal cord contusion and transection injuries. Journal of Neurotrauma, 18, 187–201.Find this resource:
Han, J. S., Bird, G. C., Li, W., Jones, J., & Neugebauer, V. (2005). Computerized analysis of audible and ultrasonic vocalizations of rats as a standardized measure of pain-related behavior. Journal of Neuroscience Methods, 141, 261–269.Find this resource:
Han, M., Xiao, X., Yang, Y., Huang, R.-Y., Cao, H., Zhao, Z.-Q., & Zhang, Y.-Q. (2014). SIP30 is required for neuropathic pain-evoked aversion in rats. Journal of Neuroscience, 34(2), 346–355.Find this resource:
Harada, T., Takahashi, H., Kaya, H., & Inoki, R. (1979). A test for analgesics as an indicator of locomotor activity in writhing mice. Archives internationales Pharmacodynamie et de Therapie, 242(2), 273–284.Find this resource:
Harris, H. M., Carpenter, J. M., Black, J. R., Smitherman, T. A., & Sufka, K. J. (2017). The effects of repeated nitroglycerin administrations in rats; modeling migraine-related endpoints and chronification. Journal of Neuroscience Methods, 284, 63–70.Find this resource:
Harton, L. R., Richardson, J. R., Armendariz, A., & Nazarian, A. (2017). Dissociation of morphine analgesic effects in the sensory and affective components of formalin-induced spontaneous pain in male and female rats. Brain Research, 1658, 36–41.Find this resource:
He, Y., & Wang, Z. J. (2015). Nociceptor beta II, delta, and epsilon isoforms of PKC differentially mediate paclitaxel-induced spontaneous and evoked pain. Journal of Neuroscience, 35(11), 4614–4625.Find this resource:
Hedenqvist, P., Trbakovic, A., Thor, A., Ley, C., Ekman, S., & Jensen-Waern, M. (2016). Carprofen neither reduces postoperative facial expression scores in rabbits treated with buprenorphine nor alters long term bone formation after maxillary sinus grafting. Research in Veterinary Science, 107, 123–131.Find this resource:
Hernandez-Leon, A., Fernandez-Guasti, A., Martinez, A., Pellicer, F., & Gonzalez-Trujano, M. E. (2018). Sleep architecture is altered in the reserpine-induced fibromyalgia model in ovariectomized rats. Behavioural Brain Research. doi:10.1016/j.bbr.2018.01.005. [Epub ahead of print]Find this resource:
Holden, E., Calvo, G., Collins, M., Bell, A., Reid, J., Scott, E. M., & Nolan, A. M. (2014). Evaluation of facial expression in acute pain in cats. Journal of Small Animal Practice, 55, 615–621.Find this resource:
Hopkins, H. L., Duggett, N. A., & Flatters, S. J. L. (2016). Chemotherapy-induced painful neuropathy: Pain-like behaviours in rodent models and their response to commonly used analgesics. Current Opinion in Supportive and Palliative Care, 10, 119–128.Find this resource:
Huehnchen, P., Boehmerle, W., & Endres, M. (2013). Assessment of paclitaxel induced sensory polyneuropathy with “Catwalk” automated gait analysis in mice. PLoS One, 8(10), e76772.Find this resource:
Hummel, M., Lu, P., Cummons, T. A., & Whiteside, G. T. (2008). The persistence of a long-term negative affective state following the induction of either acute or chronic pain. Pain, 140, 436–445.Find this resource:
Hung, C.-H., Wang, J. C.-F., & Strichartz, G. R. (2015). Spontaneous chronic pain after experimental thoracotomy revealed by conditioned place preference: Morphine differentiates tactile evoked pain from spontaneous pain. Journal of Pain, 16(9), 903–912.Find this resource:
Institute of Medicine. (2011). Relieving pain in America: A blueprint for transforming prevention, care, education, and research. Washington, DC: National Academies Press.Find this resource:
Jennings, E. M., Okine, B. N., Roche, M., & Finn, D. P. (2014). Stress-induced hyperalgesia. Progress in Neurobiology, 121, 1–18.Find this resource:
Jirkof, P., Cesarovic, N., Rettich, A., Nicholls, F., Seifert, B., & Arras, M. (2010). Burrowing behavior as an indicator of post-laparotomy pain in mice. Frontiers in Behavioral Neuroscience, 4, 165.Find this resource:
Jirkof, P., Fleischmann, T., Cesarovic, N., Rettich, A., Vogel, J., & Arras, M. (2013). Assessment of postsurgical distress and pain in laboratory mice by nest complexity scoring. Lab Animal, 47(3), 153–161.Find this resource:
Jirkof, P., Leucht, K., Cesarovic, N., Caj, M., Nicholls, F., Rogler, G., & Arras, M. H., M. (2013). Burrowing is a sensitive behavioural assay for monitoring general wellbeing during dextran sulfate sodium colitis in laboratory mice. Lab Animal, 47(4), 274–283.Find this resource:
Johansen, J. P., Fields, H. L., & Manning, B. H. (2001). The affective component of pain in rodents: Direct evidence for a contribution of the anterior cingulate cortex. Proceedings of the National Academies of Science of the United States of America, 98(14), 8077–8082.Find this resource:
Jourdan, D., Ardid, D., Chapuy, E., Eschalier, A., & Le Bars, D. (1995). Audible and ultrasonic vocalization elicited by single electrical nociceptive stimuli to the tail in the rat. Pain, 63, 237–249.Find this resource:
Jourdan, D., Ardid, D., & Eschalier, A. (2001). Automated behavioural analysis in animal pain studies. Pharmacological Research, 43(2), 103–110.Find this resource:
Jourdan, D., Ardid, D., & Eschalier, A. (2002). Analysis of ultrasonic vocalisation does not allow chronic pain to be evaluated in rats. Pain, 95, 165–173.Find this resource:
Kandasamy, R., Lee, A. T., & Morgan, M. M. (2017). Depression of home cage wheel running: A reliable and clinically relevant method to assess migraine pain in rats. Journal of Headache Pain, 18, 5.Find this resource:
Katz, J., Finnerup, N. B., & Dworkin, R. H. (2008). Clinical trial outcome in neuropathic pain: Relationship to study characteristics. Neurology, 70(4), 263–272.Find this resource:
Kauppila, T., Kontinen, V. K., & Pertovaara, A. (1998). Weight bearing of the limb as a confounding factor in assessment of mechanical allodynia in the rat. Pain, 74, 55–59.Find this resource:
Keating, S. C. J., Thomas, A. A., Flecknell, P. A., & Leach, M. C. (2012). Evaluation of EMLA cream for preventing pain during tattooing of rabbits: Changes in physiological, behavioural and facial expression responses. PLoS One, 7(9), e44437.Find this resource:
Keay, K. A., Monassi, C. R., Levison, D. B., & Bandler, R. (2004). Peripheral nerve injury evokes disabilities and sensory dysfunction in a subpopulation of rats: A closer model to human chronic neuropathic pain? Neuroscience Letters, 361, 188–191.Find this resource:
Kehl, L. J., Kovacs, K. J., & Larson, A. A. (2004). Tolerance develops to the effect of lipopolysaccharides on movement-evoked hyperalgesia when administered chronically by a systemic but not an intrathecal route. Pain, 111(1–2), 104–115.Find this resource:
Kehl, L. J., Trempe, T. M., & Hargreaves, K. M. (2000). A new animal model for assessing mechanisms and management of muscle hyperalgesia. Pain, 85, 333–343.Find this resource:
Kest, B., Wilson, S. G., & Mogil, J. S. (1999). Sex differences in supraspinal morphine analgesia are dependent on genotype. Journal of Pharmacology and Experimental Therapeutics, 289(3), 1370–1375.Find this resource:
Kim, H. T., Uchimoto, K., Duellman, T., & Yang, J. (2015). Automated assessment of pain in rats using a voluntarily accessed static weight-bearing test. Physiology & Behavior, 151, 139–146.Find this resource:
King, C. D., Devine, D. P., Vierck, C. J., Mauderli, A., & Yezierski, R. P. (2007). Opioid modulation of reflex versus operant responses following stress in the rat. Neuroscience, 147, 174–182.Find this resource:
King, T., Qu, C., Okun, A., Mercado, R., Ren, J., Brion, T., … Porreca, F. (2011). Contribution of afferent pathways to nerve injury-induced spontaneous pain and evoked hypersensitivity. Pain, 152, 1997–2005.Find this resource:
King, T., Vera-Portocarrero, L., Gutierrez, T., Vanderah, T. W., Dussor, G., Lai, J., … Porreca, F. (2009). Unmasking the tonic-aversive state in neuropathic pain. Nature Neuroscience, 12(11), 1361–1363.Find this resource:
Kleggetveit, I. P., Namer, B., Schmidt, R., Helas, T., Ruckel, M., Orstavik, K., … Jorum, E. (2012). High spontaneous activity of C-nociceptors in painful polyneuropathy. Pain, 153, 2040–2047.Find this resource:
Klinck, M. P., Mogil, J. S., Moreau, M., Lascelles, B. D. X., Flecknell, P. A., Poitte, T., & Troncy, E. (2017). Translational pain assessment: Could natural animal models be the missing link? Pain, 158(9), 1633–1646.Find this resource:
Knutsen, B., Burgdorf, J., & Panksepp, J. (2002). Ultrasonic vocalizations as indices of affective states in rats. Psychological Bulletin, 128(6), 961–977.Find this resource:
Ko, M. Y., Jang, E. Y., Lee, J. Y., Kim, S. P., Whang, S. H., Lee, B. H., … Gwak, Y. S. (2018). The role of ventral tegmental area gamma-aminobutyric acid in chronic neuropathic pain after spinal cord injury in rats. Journal of Neurotrauma, 35(15), 1755–1764.Find this resource:
Ko, S. W., Chatila, T., & Zhuo, M. (2005). Contribution of CaMKIV to injury and fear-induced ultrasonic vocalizations in adult mice. Molecular Pain, 1, 10.Find this resource:
Kontinen, V. K., Ahnaou, A., Drinkenburg, W. H., & Meert, T. F. (2003). Sleep and EEG patterns in the chronic constriction injury model of neuropathic pain. Physiology & Behavior, 78(2), 241–246.Find this resource:
Kontinen, V. K., & Meert, T. F. (2002). Predictive validity of neuropathic pain models in pharmacological studies with a behavioral outcome in the rat: A systematic review. In J. O. Dostrovsky, D. B. Carr, & M. Koltzenburg (Eds.), Proceedings of the 10th World Congress on Pain (pp. 489–498). Seattle, WA: IASP Press.Find this resource:
Koplovitch, P., Minert, A., & Devor, M. (2012). Spontaneous pain in partial nerve injury models of neuropathy and the role of nociceptive sensory cover. Experimental Neurology, 236, 103–111.Find this resource:
Kurejova, M., Nattenmuller, U., Hildebrandt, U., Selvaraj, D., Stosser, S., & Kuner, R. (2010). An improved behavioural assay demonstrates that ultrasound vocalizations constitute a reliable indicator of chronic cancer pain and neuropathic pain. Molecular Pain, 6, 18.Find this resource:
LaBuda, C. J., & Fuchs, P. N. (2000). A behavioral test paradigm to measure the aversive quality of inflammatory and neuropathic pain in rats. Experimental Neurology, 163, 490–494.Find this resource:
LaBuda, C. J., & Fuchs, P. N. (2001). Low dose aspirin attenuates escape/avoidance behavior, but does not reduce mechanical hyperalgesia in a rodent model of inflammatory pain. Neuroscience Letters, 304, 137–140.Find this resource:
LaCroix-Fralish, M. L., Austin, J.-S., Liu, G., Zheng, F., Levitin, D. J., & Mogil, J. S. (2010). Patterns of pain: Meta-analysis of microarray studies of pain. Pain, 152(8), 1888–1898.Find this resource:
LaGraize, S. C., Borzan, J., Rinker, M. M., Kopp, J. L., & Fuchs, P. N. (2004). Behavioral evidence for competing motivational drives of nociception and hunger. Neuroscience Letters, 372, 30–34.Find this resource:
LaGraize, S. C., Labuda, C. J., Rutledge, M. A., Jackson, R. J., & Fuchs, P. N. (2004). Differential effect of anterior cingulate cortex lesion on mechanical hypersensitivity and escape/avoidance behavior in an animal model of neuropathic pain. Experimental Neurology, 188, 139–148.Find this resource:
Landis, C. A., Robinson, C. R., & Levine, J. D. (1988). Sleep fragmentation in the arthritic rat. Pain, 34(1), 93–99.Find this resource:
Langford, D. L., Bailey, A. L., Chanda, M. L., Clarke, S. E., Drummond, T. E., Echols, S., … Mogil, J. S. (2010). Coding of facial expressions of pain in the laboratory mouse. Nature Methods, 7(6), 447–449.Find this resource:
Lariviere, W. R., Chesler, E. J., & Mogil, J. S. (2001). Transgenic studies of pain and analgesia: Mutation or background phenotype? Journal of Pharmacology and Experimental Therapeutics, 297(2), 467–473.Find this resource:
Lariviere, W. R., Wilson, S. G., Laughlin, T. M., Kokayeff, A., West, E. E., Adhikari, S. M., … Mogil, J. S. (2002). Heritability of nociception. III. Genetic relationships among commonly used assays of nociception and hypersensitivity. Pain, 97(1–2), 75–86.Find this resource:
Larsen, J. J., & Arnt, J. (1985). Reduction in locomotor activity of arthritic rats as parameter for chronic pain: Effect of morphine, acetylsalicylic acid and citalopram. Acta Pharmacologica et Toxicologica, 57(5), 345–351.Find this resource:
Lascelles, B. D. X., Brown, D. C., Maixner, W., & Mogil, J. S. (2018). Spontaneous painful disease in companion animals can facilitate the development of chronic pain therapies for humans: Osteoarthritis as a leading example. Osteoarthritis and Cartilage, 26, 175–183.Find this resource:
Laux-Biehlmann, A., Boyken, J., Dahllof, H., Schmidt, N., Zollner, T. M., & Nagel, J. (2016). Dynamic weight bearing as a non-reflexive method for the measurement of abdominal pain in mice. European Journal of Pain, 20, 742–752.Find this resource:
Le Bars, D., Gozariu, M., & Cadden, S. W. (2001). Animal models of nociception. Pharmacological Reviews, 53, 597–652.Find this resource:
Leung, C., Wilson, Y., Khuong, T. M., & Neely, G. G. (2013). Fruit flies as a powerful model to drive or validate pain genomics efforts. Pharmacogenomics, 14(15), 1879–1887.Find this resource:
Leys, L. J., Chu, K. L., Xu, J., Pai, M., Yang, H. S., Robb, H. M., … McGaraughty, S. (2013). Disturbances in slow-wave sleep are induced by models of bilateral inflammation, neuropathic, and postoperative pain, but not osteoarthritic pain in rats. Pain, 154, 1092–1102.Find this resource:
Li, J.-X. (2015). Pain and depression comorbidity: A preclinical perspective. Behav. Brain Research, 276, 92–98.Find this resource:
Liao, L., Long, H., Zhang, L., Chen, H., Zhou, Y., Ye, N., & Lai, W. (2014). Evaluation of pain in rats through facial expression following experimental tooth movement. European Journal of Oral Sciences, 122, 122–124.Find this resource:
Lim, D. W., Kim, J. G., Han, D., & Kim, Y. T. (2014). Analgesic effect of Harpagophytum procumbens on postoperative and neuropathic pain in rats. Molecules, 19, 1060–1068.Find this resource:
Liu, M.-G., & Chen, J. (2014). Preclinical research on pain comorbidity with affective disorders and cognitive deficits: Challenges and perspectives. Progress in Neurobiology, 116, 13–32.Find this resource:
Lopez-Munoz, F. J., Salazar, L. A., Castaneda-Hernandez, G., & Villarreal, J. E. (1993). A new model to assess analgesic activity: Pain-induced functional impairment in the rat (PIFIR). Drug Development and Research, 28, 169–175.Find this resource:
Lovell, J. A., Stuesse, S. L., Cruce, W. L. R., & Crisp, T. (2000). Strain differences in neuropathic hyperalgesia. Pharmacology Biochemistry and Behavior, 65(1), 141–144.Find this resource:
MacRae, A. M., Makowska, I. J., & Fraser, D. (2018). Initial evaluation of facial expressions and behaviours of harbour seal pups (Phoca vitulina) in response to tagging and microchipping. Applied Animal Behaviour Science, 205, 167–174.Find this resource:
Maier, C., Baron, R., Tolle, T. R., Binder, A., Birbaumer, N., Birklein, F., … Treede, R.-D. (2010). Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain, 150, 439–450.Find this resource:
Mao, J. (2002). Translational pain research: Bridging the gap between basic and clinical research. Pain, 97, 183–187.Find this resource:
Martin, T. J., Buechler, N. L., Kahn, W., Crews, J. C., & Eisenach, J. C. (2004). Effects of laparotomy on spontaneous exploratory activity and conditioned operant responding in the rat: A model for postoperative pain. Anesthesiology, 101(1), 191–203.Find this resource:
Matson, D. J., Broom, D. C., Carson, S. R., Baldassari, J., Kehne, J., & Cortright, D. N. (2007). Inflammation-induced reduction of spontaneous activitity by adjuvant: A novel model to study the effect of analgesics in rats. Journal of Pharmacology and Experimental Therapeutics, 320, 194–201.Find this resource:
Matthies, B. K., & Franklin, K. B. J. (1992). Formalin pain is expressed in decerebrate rats but not attenuated by morphine. Pain, 51, 199–206.Find this resource:
Mauderli, A. P., Acosta-Rua, A., & Vierck, C. J. (2000). An operant assay of thermal pain in conscious, unrestrained rats. Journal of Neuroscience Methods, 97, 19–29.Find this resource:
McCaffrey, G., Thompson, M. L., Majuta, L., Fealk, M. N., Chartier, S., Longo, G., & Mantyh, P. W. (2014). NGF blockade at early times during bone cancer development attenuates bone destruction and increases limb use. Cancer Research, 74(23), 7014–7023.Find this resource:
McLennan, K. M., Rebelo, C. J. B., Corke, M. J., Holmes, M. A., Leach, M. C., & Constantino-Casas, F. (2016). Development of a facial expression scale using footrot and mastitis as models of pain in sheep. Applied Animal Behaviour Science, 176, 19–26.Find this resource:
Mecklenburg, J., Patil, M. J., Koek, W., & Akopian, A. N. (2017). Effects of local and spinal administrations of mu-opioids on postoperative pain in aged versus adult mice. Pain Reports, 2, e584.Find this resource:
Medhurst, S. J., Walker, K., Bowes, M., Kidd, B. L., Glatt, M., Muller, M., … Urban, L. (2002). A rat model of bone cancer pain. Pain, 96, 129–140.Find this resource:
Melzack, R., & Casey, K. L. (1968). Sensory, motivational, and central control determinants of pain: A new conceptual model. In D. R. Kenshalo (Ed.), The skin senses (pp. 423–439). Springfield, IL: Thomas.Find this resource:
Millecamps, M., Tajerian, M., Sage, E. H., & Stone, L. S. (2011). Behavioral signs of chronic back pain in the SPARC-null mouse. Spine, 36(2), 95–102.Find this resource:
Mischkowski, D., Palacios-Barrios, E. E., Banker, L., Dildine, T. C., & Atlas, L. Y. (2018). Pain or nociception? Subjective experience mediates the effects of acute noxious heat on autonomic responses. Pain, 159(4), 699–711.Find this resource:
Mittal, A., Gupta, M., Lamarre, Y., Jahagirdar, B., & Gupta, K. (2016). Quantification of pain in sickle mice using facial expressions and body measurements. Blood Cells, Molecules and Diseases, 57, 58–66.Find this resource:
Mogil, J. S. (2009). Animal models of pain: Progress and challenges. Nature Reviews Neuroscience, 10(4), 283–294.Find this resource:
Mogil, J. S. (2012). Sex differences in pain and pain inhibition: Multiple explanations of a controversial phenomenon. Nature Reviews Neuroscience, 13, 859–866.Find this resource:
Mogil, J. S. (2016). Equality need not be painful. Nature, 535, S7.Find this resource:
Mogil, J. S. (2017). Laboratory environmental factors and pain behavior: The relevance of unknown unknowns to reproducibility and translation. Lab Animal, 46(4), 136–141.Find this resource:
Mogil, J. S., & Chanda, M. L. (2005). The case for the inclusion of female subjects in basic science studies of pain. Pain, 117(1–2), 1–5.Find this resource:
Mogil, J. S., & Crager, S. E. (2004). What should we be measuring in behavioral studies of chronic pain in animals? Pain, 112(1–2), 12–15.Find this resource:
Mogil, J. S., Davis, K. D., & Derbyshire, S. W. (2010). The necessity of animal models in pain research. Pain, 151, 12–17.Find this resource:
Mogil, J. S., Graham, A. C., Ritchie, J., Hughes, S. F., Austin, J.-S., Schorscher-Petcu, A., … Bennett, G. J. (2010). Hypolocomotion, asymmetrically directed behaviors (licking, lifting, flinching, and shaking) and dynamic weight bearing (gait) changes are not measures of neuropathic pain in mice. Molecular Pain, 6(1), 34.Find this resource:
Mogil, J. S., Lichtensteiger, C. A., & Wilson, S. G. (1998). The effect of genotype on sensitivity to inflammatory nociception: Characterization of resistant (A/J) and sensitive (C57BL/6) inbred mouse strains. Pain, 76, 115–125.Find this resource:
Mogil, J. S., Meirmeister, F., Seifert, F., Strasburg, K., Zimmermann, K., Reinold, H., … Reeh, P. W. (2005). Variable sensitivity to noxious heat is mediated by differential expression of the CGRP gene. Proceedings of the National Academies of Science of the United States of America, 102, 12938–12943.Find this resource:
Mogil, J. S., Ritchie, J., Sotocinal, S. G., Smith, S. B., Croteau, S., Levitin, D. J., & Naumova, A. K. (2006). Screening for pain phenotypes: Analysis of three congenic mouse strains on a battery of nine nociceptive assays. Pain, 126(1–2), 24–34.Find this resource:
Mogil, J. S., Wilson, S. G., Bon, K., Lee, S. E., Chung, K., Raber, P., … Devor, M. (1999). Heritability of nociception. I. Responses of eleven inbred mouse strains on twelve measures of nociception. Pain, 80(1–2), 67–82.Find this resource:
Monassi, C. R., Bandler, R., & Keay, K. A. (2003). A subpopulation of rats show social and sleep-waking changes typical of chronic neuropathic pain following peripheral nerve injury. European Journal of Neuroscience, 17, 1907–1920.Find this resource:
Montilla-Garcia, A., Tejada, M. A., Perazzoli, G., Entrena, J. M., Portillo-Salido, E., Fernandez-Segura, E., … Cobos, E. J. (2017). Grip strength in mice with joint inflammation: A rheumatology function test sensitive to pain and analgesia. Neuropharmacology, 125, 231–242.Find this resource:
Morgan, D., Mitzelfelt, J. D., Koerper, L. M., & Carter, C. S. (2012). Effects of morphine on thermal sensitivity in adult and aged rats. Journals of Gerontology, Series A, Biological Sciences and Medical Sciences, 67(7), 705–713.Find this resource:
Morin, C. M., Gibson, D., & Wade, J. (1998). Self-reported sleep and mood disturbance in chronic pain patients. Clinical Journal of Pain, 14, 311–314.Find this resource:
Muralidharan, A., Kuo, A., Jacob, M., Lourdesamy, J. S., De Carvalho, L. M. S. P., Nicholson, J. R., … Smith, M. T. (2016). Comparison of burrowing and stimuli-evoked pain behaviors as end-points in rat models of inflammatory pain and peripheral neuropathic pain. Frontiers in Behavioral Neuroscience, 10, 88.Find this resource:
Na, H. S., Yoon, Y. W., & Chung, J. M. (1996). Both motor and sensory abnormalities contribute to changes in foot posture in an experimental rat neuropathic model. Pain, 67, 173–178.Find this resource:
Nagakura, Y. (2017). The need for fundamental reforms in the pain research field to develop innovative drugs. Expert Opinion on Drug Discovery, 12(1), 39–46.Find this resource:
Naito, H., Nakamura, A., Inoue, M., & Suzuki, Y. (2003). Effect of anxiolytic drugs on air-puff-elicited ultrasonic vocalizations in adult rats. Experimental Animals, 52(5), 409–414.Find this resource:
Navratilova, E., Xie, J. Y., King, T., & Porreca, F. (2013). Evaluation of reward from pain relief. Annals of the New York Academy of Science, 11282, 1–11.Find this resource:
Negus, S. S., Morrissey, E. M., Rosenberg, M., Cheng, K., & Rice, K. C. (2010). Effects of kappa opioids in an assay of pain-depressed intracranial self-stimulation in rats. Psychopharmacology, 210, 149–159.Find this resource:
Negus, S. S., Neddenriep, B., Altarifi, A. A., Carroll, F. I., Leitl, M. D., & Miller, L. L. (2015). Effects of ketoprofen, morphine, and kappa opioids on pain-related depression of nesting in mice. Pain, 156(6), 1153–1160.Find this resource:
Neubert, J. K., Widmer, C. G., Malphurs, W., Rossi, H. L., Vierck, C. J., Jr., & Caudle, R. M. (2005). Use of a novel thermal operant behavioral assay for characterization of orofacial pain sensitivity. Pain, 116, 386–395.Find this resource:
Nickel, M. M., May, E. S., Tiemann, L., Postorino, M., Dinh, S. T., & Ploner, M. (2017). Autonomic responses to tonic pain are more closely related to stimulus intensity than to pain intensity. Pain, 158, 2129–2136.Find this resource:
Okun, A., DeFelice, M., Eyde, N., Ren, J., Mercado, R., King, T., & Porreca, F. (2011). Transient inflammation-induced ongoing pain is driven by TRPV1 sensitive afferents. Molecular Pain, 7, 4.Find this resource:
Oliveira, A. R., & Barros, H. M. T. (2006). Ultrasonic rat vocalizations during the formalin test: A measure of the affective dimension of pain? Anesthesia & Analgesia, 102, 832–839.Find this resource:
Olmarker, K., Iwabuchi, M., Larsson, K., & Rydevik, B. (1998). Walking analysis of rats subjected to experimental disc herniation. European Spine Journal, 7(5), 394–399.Find this resource:
Oshinsky, M. L., Sanghvi, M. M., Maxwell, C. R., Gonzalez, D., Spangenberg, R. J., Cooper, M., & Silberstein, S. D. (2012). Spontaneous trigeminal allodynia in rats: A model of primary headache. Headache, 52(9), 1336–1449.Find this resource:
Pacharinsak, C., & Beitz, A. (2008). Animal models of cancer pain. Comparative Medicine, 58(3), 220–233.Find this resource:
Percie du Sert, N., & Rice, A. S. C. (2014). Improving the translation of analgesic drugs to the clinic: Animal models of neuropathic pain. British Journal of Pharmacology, 171, 2951–2963.Find this resource:
Peters, S. Z., Pothuizen, H. H. J., & Spruijt, B. M. (2015). Ethological concepts enhance the translational value of animal models. European Journal of Pharmacology, 759, 42–50.Find this resource:
Philips, B. H., Weisshaar, C. L., & Winkelstein, B. A. (2017). Use of the Rat Grimace Scale to evaluate neuropathic pain in a model of cervical radiculopathy. Comparative Medicine, 67(1), 1–9.Find this resource:
Piesla, M. J., Leventhal, L., Strassle, B. W., Harrison, J. E., Cummons, T. A., Lu, P., & Whiteside, G. T. (2009). Abnormal gait, due to inflammation but not nerve injury, reflects enhanced nociception in preclinical pain models. Brain Research, 1295, 89–98.Find this resource:
Pitzer, C., Kuner, R., & Tappe-Theodor, A. (2016). Voluntary and evoked behavioral correlates in inflammatory pain conditions under different social housing conditions. Pain Reports, 1, e564.Find this resource:
Prendergast, B. J., Onishi, K. G., & Zucker, I. (2014). Female mice liberated for inclusion in neuroscience and biomedical research. Neuroscience and Biobehavioral Reviews, 40, 1–5.Find this resource:
Qu, C., King, T., Okun, A., Lai, J., Fields, H. L., & Porreca, F. (2011). Lesion of the rostral anterior cingulate cortex eliminates the aversiveness of spontaneous neuropathic pain following partial or complete axotomy. Pain, 152, 1641–1648.Find this resource:
Refsgaard, L. K., Hoffmann-Petersen, J., Sahlholt, M., Pickering, D. S., & Andreasen, J. T. (2016). Modelling affective pain in mice: Effects of inflammatory hypersensitivity on place escape/avoidance behaviour, anxiety and hedonic state. Journal of Neuroscience Methods, 262, 85–92.Find this resource:
Reichling, D. B., & Levine, J. D. (2009). Critical role of nociceptor plasticity in chronic pain. Trends in Neurosciences, 32(12), 611–618.Find this resource:
Reijgwart, M. L., Schoemaker, N. J., Pascuzzo, R., Leach, M. C., Stodel, M., de Nies, L., … van Zeeland, Y. R. A. (2017). The composition and initial evaluation of a grimace scale in ferrets after surgical implantation of a telemetry probe. PLoS One, 12(11), e0187986.Find this resource:
Rice, A. S. C., Cimino-Brown, D., Eisenach, J. C., Kontinen, V. K., LaCroix-Fralish, M. L., Machin, I., … Stohr, T. (2009). Animal models and the prediction of efficacy in clinical trials of analgesic drugs: A critical appraisal and call for uniform reporting standards. Pain, 139, 241–245.Find this resource:
Rock, M. L., Karas, A. Z., Gartrell Rodriguez, K. B., Gallo, M. S., Pritchett-Corning, K., Karas, R. H., … Gaskill, B. N. (2014). The time-to-integrate-to-nest test as an indicator of wellbeing in laboratory mice. Journal of the American Association for Laboratory Animal Science, 53(1), 24–28.Find this resource:
Rodin, B. E., & Kruger, L. (1984). Deafferentation in animals as a model for the study of pain: An alternate hypothesis. Brain Research Reviews, 7, 213–228.Find this resource:
Ross, E. L., Komisaruk, B. R., & O’Donnell, D. (1979). Evidence that probing the vaginal cervix is analgesic in rats, using an operant paradigm. Journal of Comparative and Physiological Psychology, 93(2), 330–336.Find this resource:
Roughan, J. V., & Flecknell, P. A. (2000). Effects of surgery and analgesic administration on spontaneous behaviour in singly housed rats. Research in Veterinary Science, 69, 283–288.Find this resource:
Roughan, J. V., & Flecknell, P. A. (2001). Behavioural effects of laparotomy and analgesic effects of ketoprofen and carprofen in rats. Pain, 90, 65–74.Find this resource:
Rutten, K., Gould, S. A., Bryden, L., Doods, H., Christoph, T., & Pekcec, A. (2018). Standard analgesics reverse burrowing deficits in a rat CCI model of neuropathic pain, but not in models of type 1 and type 2 diabetes-induced neuropathic pain. Behavioral Brain Research, 350, 129–138.Find this resource:
Samir, S., Yllanes, A. P., Lallemand, P., Brewer, K. L., & Clemens, S. (2017). Morphine responsiveness to thermal pain stimuli is aging-associated and mediated by dopamine D1 and D3 receptor interactions. Neuroscience, 349, 87–97.Find this resource:
Schaap, M. W. H., Van Oostrom, H., Doornenbal, A., van’t Klooster, J., Baars, A. M., Arndt, S. S., & Hellebrekers, L. J. (2014). Nociception and conditioned fear in rats: Strains matter. PLoS One, 8(12), e83339.Find this resource:
Scholz, J., Mannion, R. J., Hord, D. E., Griffin, R. S., Rawal, B., Zheng, H., … Woolf, C. J. (2009). A novel tool for the assessment of pain: Validation in low back pain. PLoS Medicine, 6(4), e1000047.Find this resource:
Schott, E., Berge, O.-G., Angeby-Moller, K., Hammarstrom, G., Dalsgaard, C.-J., & Brodin, E. (1994). Weight bearing as an objective measure of arthritic pain in the rat. Journal of Pharmacological and Toxicological Methods, 31, 79–83.Find this resource:
Schutz, T. C. B., Andersen, M. L., Silva, A., & Tufik, S. (2009). Distinct gender-related sleep pattern in an acute model of TMJ pain. Journal of Dental Research, 88(5), 471–476.Find this resource:
Schutz, T. C. B., Andersen, M. L., & Tufik, S. (2003). Sleep alterations in an experimental orofacial pain model in rats. Brain Research, 993(1–2), 164–171.Find this resource:
Seminowicz, D. A., Laferriere, A. L., Millecamps, M., Yu, J. S. C., Coderre, T. J., & Bushnell, M. C. (2009). MRI structural brain changes associated with sensory and emotional function in a rat model of long-term neuropathic pain. Neuroimage, 47, 1007–1014.Find this resource:
Sheahan, T. D., Siuda, E. R., Bruchas, M. R., Shepherd, A. J., Mohapatra, D. P., Gereau, R. W., IV, & Golden, J. P. (2017). Inflammation and nerve injury minimally affect mouse voluntary behaviors proposed as indicators of pain. Neurobiology of Pain, 2, 1–12.Find this resource:
Shepherd, A. J., Cloud, M. E., Cao, Y.-Q., & Mohapatra, D. P. (2018). Deficits in burrowing behaviors are associated with mouse models of neuropathic but not inflammatory pain or migraine. Frontiers in Behavioral Neuroscience, 12, 124.Find this resource:
Shepherd, A. J., & Mohapatra, D. P. (2018). Pharmacological validation of voluntary gait and mechanical sensitivity assays associated with inflammatory and neuropathic pain in mice. Neuropharmacology, 130, 18–29.Find this resource:
Shi, C., Das, V., Li, X., Kc, R., Qiu, S., O’Sullivan, I., … Im, H.-J. (2018). Development of an in vivo mouse model of discogenic low back pain. Journal of Cell Physiology, 233, 6589–6602.Find this resource:
Shimizu, I., Iida, T., Guan, Y., Zhao, C., Raja, S. N., Jarvis, M. F., … Caterina, M. J. (2005). Enhanced thermal avoidance in mice lacking the ATP receptor P2X3. Pain, 116(1–2), 96–108.Find this resource:
Shir, Y., Zeltser, R., Vatine, J.-J., Carmi, G., Belfer, I., Zangen, A., … Seltzer, Z. (2001). Correlation of intact sensibility and neuropathic pain-related behaviors in eight inbred and outbred rat strains and selection lines. Pain, 90, 75–82.Find this resource:
Sieberg, C. B., Taras, C., Gomaa, A., Nickerson, C., Wong, C., Ward, C., … Costigan, M. (2018). Neuropathic pain drives anxiety behavior in mice, results consistent with anxiety levels in diabetic neuropathy patients. Pain Reports, 3, e651.Find this resource:
Sluka, K. A., Kalra, A., & Moore, S. A. (2001). Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia. Muscle & Nerve, 24, 37–46.Find this resource:
Sluka, K. A., O’Donnell, J. M., Danielson, J., & Rasmussen, L. A. (1985). Regular physical activity prevents development of chronic pain and activation of central neurons. Journal of Applied Physiology, 114(6), 725–733.Find this resource:
Smeets, R., Koke, A., Lin, C. W., Ferreira, M., & Demoulin, C. (2011). Measures of function in low back pain/disorders: Low Back Pain Rating Scale (LBPRS), Oswestry Disability Index (ODI), Progressive Isoinertial Lifting Evaluation (PILE), Quebec Back Pain Disability Scale (QBPDS), and Roland-Morris Disability Questionnaire (RDQ). Arthritis Care & Research, 63(Suppl. 11), S158–S173.Find this resource:
Smith, E. S. J., Omerbasic, D., Lechner, S. G., Anirudhan, G., Lapatsina, L., & Lewin, G. R. (2011). The molecular basis of acid insensitivity in the African naked mole-rat. Science, 334, 1557–1560.Find this resource:
Sorge, R. E., LaCroix-Fralish, M. L., Tuttle, A. H., Sotocinal, S. G., Austin, J.-S., Ritchie, J., … Mogil, J. S. (2011). Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice. Journal of Neuroscience, 31(43), 15450–15454.Find this resource:
Sorge, R. E., Mapplebeck, J. C. S., Rosen, S., Beggs, S., Taves, S., Alexander, J. K., … Mogil, J. S. (2015). Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nature Neuroscience, 18(8), 1081–1083.Find this resource:
Sorge, R. E., Martin, L. J., Isbester, K. A., Sotocinal, S. G., Rosen, S., Tuttle, A. H., … Mogil, J. S. (2014). Olfactory exposure to males, including human males, stresses rodents. Nature Methods, 11(6), 629–632.Find this resource:
Sorge, R. E., Trang, T., Dorfman, R., Smith, S. B., Beggs, S., Ritchie, J., … Mogil, J. S. (2012). Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nature Medicine, 18(4), 595–599.Find this resource:
Sorkin, L. S., & Yaksh, T. L. (2009). Behavioral models of pain states evoked by physical injury to the peripheral nerve. Neurotherapeutics, 6, 609–619.Find this resource:
Sotocinal, S. G., Sorge, R. E., Zaloum, A., Tuttle, A. H., Martin, L. J., Wieskopf, J. S., … Mogil, J. S. (2011). The Rat Grimace Scale: A partially automated method for quantifying pain in the laboratory rat via facial expressions. Molecular Pain, 7(1), 55.Find this resource:
Stevenson, G. W., Bilsky, E. J., & Negus, S. S. (2006). Targeting pain-suppressed behaviors in preclinical assays of pain and analgesia: Effects of morphine on acetic acid-suppressed feeding in C57BL/6J mice. Journal of Pain, 7(6), 408–416.Find this resource:
Stevenson, G. W., Mercer, H., Cormier, J., Dunbar, C., Benoit, L., Adams, C., … Bilsky, E. J. (2011). Monosodium iodoacetate-induced osteoarthritis produces pain-depressed wheel running in rats: Implications for preclinical behavioral assessment of chronic pain. Pharmacology Biochemistry and Behavior, 98, 35–42.Find this resource:
Sufka, K. J. (1994). Conditioned place preference paradigm: A novel approach for analgesic drug assessment against chronic pain. Pain, 58, 355–366.Find this resource:
Sullivan, K. A., Lentz, S. I., Roberts, J. L., Jr., & Feldman, E. L. (2008). Criteria for creating and assessing mouse models of diabetic neuropathy. Current Drug Targets, 9(1), 3–13.Find this resource:
Sun, Y.-G., Gao, Y.-J., Zhao, Z.-Q., Huang, B., Yin, J., Taylor, G. A., & Chen, Z.-F. (2008). Involvement of P311 in the affective, but not in the sensory component of pain. Molecular Pain, 4, 23.Find this resource:
Suri, M., Jain, S., & Mathur, R. (2010). Pattern of biphasic response to various noxious stimuli in rats ingesting sucrose ad libitum. Physiology & Behavior, 101(2), 224–231.Find this resource:
Sutton, B. C., & Opp, M. R. (2014). Musculoskeletal sensitization and sleep: Chronic muscle pain fragments sleep of mice without altering its duration. Sleep, 37(3), 505–513.Find this resource:
Tanga, F. Y., Nutile-McMenemy, N., & DeLeo, J. A. (2005). The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy. Proceedings of the National Academies of Science of the United States of America, 102(16), 5856–5861.Find this resource:
Tokunaga, S., Takeda, Y., Shinomiya, K., Yamamoto, W., Utsu, Y., Toide, K., & Kamei, C. (2007). Changes of sleep patterns in rats with chronic constriction injury under aversive conditions. Biological and Pharmaceutical Bulletin, 30(11), 2088–2090.Find this resource:
Tseng, T. J., Hsieh, Y. L., & Hsieh, S. T. (2007). Reversal of ERK activation in the dorsal horn after decompression in chronic constriction injury. Experimental Neurology, 206, 17–23.Find this resource:
Tsuzuki, H., Maekawa, M., Konno, R., & Hori, Y. (2012). Functional roles of endogenous D-serine in pain-induced ultrasonic vocalization. Neuroreport, 23, 937–941.Find this resource:
Tuttle, A. H., Tohyama, S., Ramsay, T., Kimmelman, J., Schweinhardt, P., Bennett, G. J., & Mogil, J. S. (2015). Increasing placebo responses over time in US clinical trials of neuropathic pain. Pain, 156, 2616–2626.Find this resource:
van der Kam, E. L., de Vry, J., Schiene, K., & Tzschentke, T. M. (2008). Differential effects of morphine on the affective and the sensory component of carrageenan-induced nociception in the rat. Pain, 136, 373–379.Find this resource:
Vierck, C. J., Acosta-Rua, A., Nelligan, R., Tester, N., & Mauderli, A. (2002). Low dose systemic morphine attenuates operant escape but facilitates innate reflex responses to thermal stimulation. Journal of Pain, 3(4), 309–319.Find this resource:
Vierck, C. J., Acosta-Rua, A. J., Rossi, H. L., & Neubert, J. K. (2008). Sex differences in thermal pain sensitivity and sympathetic reactivity for two strains of rat. Journal of Pain, 9(8), 739–749.Find this resource:
Vierck, C. J., Hansson, P. T., & Yezierski, R. P. (2008). Clinical and pre-clinical pain assessment: Are we measuring the same thing? Pain, 135, 7–10.Find this resource:
Vierck, C. J., & Yezierski, R. P. (2015). Comparison of operant escape and reflex tests of nociceptive sensitivity. Neuroscience and Biobehavioral Reviews, 51, 223–242.Find this resource:
Vos, T., Flaxman, A. D., Naghavi, M., Lozano, R., Michaud, C., Ezzati, M., … Memish, Z. A.. (2012). Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet, 380(9859), 2163–2196.Find this resource:
Wager, T. D., Atlas, L. Y., Lindquist, M. A., Roy, M., Woo, C.-W., & Kross, E. (2013). An fMRI-based neurologic signature of physical pain. New England Journal of Medicine, 368, 1388–1397.Find this resource:
Wall, P. D., Devor, M., Inbal, R., Scadding, J. W., Schonfeld, D., Seltzer, Z., & Tomkiewicz, M. M. (1979). Autotomy following peripheral nerve lesions: Experimental anaesthesia dolorosa. Pain, 7, 103–113.Find this resource:
Wallace, V. C. J., Norbury, T. A., & Rice, A. S. C. (2005). Ultrasound vocalisation by rodents does not correlate with behavioural measures of persistent pain. European Journal of Pain, 9, 445–452.Find this resource:
Wang, S., Lim, J., Joseph, J., Wang, S., Wei, F., Ro, J. Y., & Chung, M.-K. (2017). Spontaneous and bite-evoked muscle pain are mediated by a common nociceptive pathway with differential contribution by TRPV1. Journal of Pain, 18(11), 1333–1345.Find this resource:
Wei, H., Viisanen, H., Amorim, D., Koivisto, A., & Pertovaara, A. (2013). Dissociated modulation of conditioned place-preference and mechanical hypersensitivity by a TRPA1 channel antagonist in peripheral neuropathy. Pharmacology Biochemistry and Behavior, 104, 90–96.Find this resource:
Wesselmann, U., Czakanski, P. P., Affaitati, G., & Giamberardino, M. A. (1998). Uterine inflammation as a noxious visceral stimulus: Behavioral characterization in the rat. Neuroscience Letters, 246, 73–76.Find this resource:
Whiteside, G. T., Adedoyin, A., & Leventhal, L. (2008). Predictive validity of animal pain models? A comparison of the pharmacokinetic-pharmacodynamic relationship for pain drugs in rats and humans. Neuropharmacology, 54, 767–775.Find this resource:
Whittaker, A. L., Lymn, K. A., Nicholson, A., & Howarth, G. S. (2015). The assessment of general well-being using spontaneous burrowing behaviour in a short-term model of chemotherapy-induced mucositis in the rat. Lab Animal, 49(1), 30–39.Find this resource:
Williams, W. O., Riskin, D. K., & Mott, K. M. (2008). Ultrasonic sound as an indicator of acute pain in laboratory mice. Journal of the American Association of Laboratory Animal Science, 47(1), 8–10.Find this resource:
Wilson, S. G., Bryant, C. D., Lariviere, W. R., Olsen, M. S., Giles, B. E., Chesler, E. J., & Mogil, J. S. (2003). The heritability of antinociception II: Pharmacogenetic mediation of three over-the-counter analgesics in mice. Journal of Pharmacology and Experimental Therapeutics, 305, 755–764.Find this resource:
Wilson, S. G., Smith, S. B., Chesler, E. J., Melton, K. A., Haas, J. J., Mitton, B. A., … Mogil, J. S. (2003). The heritability of antinociception: Common pharmacogenetic mediation of five neurochemically distinct analgesics. Journal of Pharmacology and Experimental Therapeutics, 304(2), 547–559.Find this resource:
Wodarski, R., Delaney, A., Ultenius, C., Morland, C., Andrews, N., Baastrup, C., … Rice, A. S. C. (2016). Cross-centre replication of suppressed burrowing behaviour as an ethologically relevant pain outcome measure in the rat: A prospective multicentre study. Pain, 157, 2350–2365.Find this resource:
Woolf, C. J. (1984). Long term alterations in excitability of the flexion reflex produced by peripheral tissue injury in the chronic decerebrate rat. Pain, 18, 325–343.Find this resource:
Wu, J., Zhao, Z., Zhu, X., Renn, C. L., Dorsey, S. G., & Faden, A. I. (2016). Cell cycle inhibition limits development and maintenance of neuropathic pain following spinal cord injury. Pain, 157, 488–503.Find this resource:
Yamamoto, K., Tatsutani, S., & Ishida, T. (2017). Detection of nausea-like response in rats by monitoring facial expression. Frontiers in Pharmacology, 7, 534.Find this resource:
Yan, N., Cao, B., Xu, J., Hao, C., Zhang, X., & Li, Y. (2012). Glutamatergic activation of anterior cingulate cortex mediates the affective component of visceral pain memory in rats. Neurobiology of Learning and Memory, 97, 156–164.Find this resource:
Yezierski, R. P., & Hansson, P. (2018). Inflammatory and neuropathic pain from bench to bedside: What went wrong? Journal of Pain, 19(6), 571–588.Find this resource:
Yoon, Y. W., Lee, D. H., Lee, B. H., Chung, K., & Chung, J. M. (1999). Different strains and substrains of rats show different levels of neuropathic pain behaviors. Experimental Brain Research, 129, 167–171.Find this resource:
Zhang, Y., Meng, X., Li, A., Xin, J., Berman, B. M., Lao, L., … Zhang, R. X. (2011). Acupuncture alleviates the affective dimension of pain in a rat model of inflammatory hyperalgesia. Neurochemical Research, 36(11), 2104–21100.Find this resource:
Zhu, C. Z., Mills, C. D., Hsieh, G. C., Zhong, C., Mikusa, J., Lewis, L. G., … Joshi, S. K. (2012). Assessing carrageenan-induced locomotor activity impairment in rats: Comparison with evoked endpoint of acute inflammatory pain. European Journal of Pain, 16, 816–826.Find this resource: