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date: 10 December 2019

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.

Keywords: pain, algesiometry, rodents, validity, techniques

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

Category

Measure

Biomarker

Autonomic nervous system (blood flow, blood pressure, corticosterone, heart rate, heart rate variability, plasma norepinephrine, pupil dilation, respiration, skin conductance)

Body weight

Functional imaging

Pain-stimulated behavior

Asymmetric limb-associated behaviors (grooming, flinching, licking, lifting, scratching, shaking, turning)

Autotomy

Facial grimacing

Ultrasonic vocalization

Pain-depressed behavior

Burrowing

Locomotor activity

Nest building

Operant responding (for reward)

Sleep disruption/fragmentation

Wheel running

Functional disability

Grip strength

Locomotor activity

Weight bearing (dynamic weight bearing [gait], guarding, posture, static weight bearing)

Conditioning/motivational

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.

Pain-Stimulated Behaviors

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).

Pain-Depressed Behaviors

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?

Conditioning/Motivational Paradigms

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).

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