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date: 17 June 2019

Heat Pain and Cold Pain

Abstract and Keywords

Noxious cold and noxious heat have detrimental effects on key biological macromolecules and thus on the integrity of cells, tissues, and organisms. Thanks to the action of a subset of somatosensory neurons, mammals can swiftly detect noxiously cold or hot objects or environments. These temperature-sensitive nociceptor neurons become activated when the temperature at their free endings in the skin or mucosae reaches noxious levels, provoking acute pain and rapid avoidance reflexes. Whereas acute temperature-induced pain is essential to prevent or limit burn injury, pathological conditions such as inflammation or tissue injury can deregulate the thermal sensitivity of the somatosensory system, resulting in painful dysesthesias such as heat and cold hypersensitivity. In recent years, important advances have been made in our understanding of the cellular and molecular mechanisms that underlie the detection of painful heat or cold. These research efforts not only provided key insights into an evolutionary conserved biological alarm system, but also revealed new avenues for the development of novel therapies to treat various forms of persistent pain.

Keywords: thermosensation, cold pain, heat pain, somatosensory neurons, burn injury, pain, TRP channels, thermal hypersensitivity

Introduction: Thermal Pain and Thermal Injury

In humans at rest, a skin temperature of around 33°C is experienced as thermoneutral, with lower temperatures felt as cool/cold and higher temperatures as warm/hot (Vriens, Nilius, & Voets, 2014). In particular, temperatures below about 15°C or above about 43°C evoke acute pain (Basbaum, Bautista, Scherrer, & Julius, 2009; Vriens et al., 2014). This pain signal represents an important protective warning system. Indeed, classical experiments on porcine and human skin have shown that exposure of the skin to a temperature as low as 44°C causes cutaneous burn injury when sustained for a period of approximately 6 hours (Henriques & Moritz, 1947; Moritz, 1947; Moritz & Henriques, 1947). Moreover, the rate of injury rises rapidly with increasing temperature, such that for each degree rise in surface temperature the time to produce such injury approximately halves (Moritz & Henriques, 1947) (Figure 1). As such, at temperatures above 50°C, burn injuries occur on the seconds timescale and above 60°C on the subseconds timescale, requiring rapid heat detection and withdrawal response to avoid serious tissue damage (Moritz & Henriques, 1947). On the other hand, exposure to cold temperatures can also result in severe, irreversible, and potentially fatal tissue damage. There are countless examples in history where cold was the prime cause of a large number of casualties during war and military campaigns. Notorious examples include the loss of about 50% of the troops of Hannibal (19,000 casualties) when crossing the Alps in 218 bc or the huge losses of Napoleon’s troops (>100,000) during his Russian campaign in 1812 (Whitaker, 2016). Napoleon’s surgeon Dominique Jean Larrey was the first to provide a detailed description of symptoms of freezing and nonfreezing cold injury in his Mémoirs de chirurgie militaire, et campagnes (Larrey, 1812). Nonfreezing cold injury, which was named trenchfoot during World War I (J. L. Smith, Ritchie, & Dawson, 1915), develops after sustained exposure to temperatures between 0°C and 15°C. This leads to vasoconstriction and tissue ischemia, which, when left untreated, can lead to irreversible tissue damage and necrosis (Eglin, Montgomery, & Tipton, 2018; Heil et al., 2016). Freezing injury or frostbite occurs when tissue temperature drops below the freezing point, which can cause severe tissue damage due to the formation of ice crystals, as well as via ischemia–reperfusion injury following rewarming (Mohr, Jenabzadeh, & Ahrenholz, 2009; Murphy, Banwell, Roberts, & McGrouther, 2000). Thus, overall, the thermal pain thresholds of intact, healthy skin are well tuned to signal temperatures that are capable of causing tissue damage. Psychophysically, even very large transient cooling steps evoke an immediate sensation of cold. The cold sensation only turns to pain after a considerable delay of many seconds (Wolf & Hardy, 1941).

Heat Pain and Cold PainClick to view larger

Figure 1. Temperature extremes lead to tissue damage and cause pain by activation of different thermosensitive TRP channels in nociceptors. (A) Brief or prolonged exposure of the skin to low and high temperatures can cause various forms of tissue injury. The rate of injury increases steeply with temperature deviations from the thermoneutral zone. (B) Temperature-dependent activity profile in different subclasses of primary sensory neurons and the putative TRP channels that support their thermosensitive activation. Cold and warm thermoreceptors convey nonpainful temperatures and show rapid adaptation. Cold and heat nociceptors convey noxious temperatures and mostly do not adapt.

Neurons of the Thermal Pain Pathway

The detection of painful thermal stimuli commences when peripheral terminals of nociceptive C fibers (nonmyelinated) and Aδ fibers (thinly myelinated) in the skin and mucosae become depolarized in response to noxious temperatures, leading to the initiation of trains of action potentials (Basbaum et al., 2009; Vriens et al., 2014). These neurons have a characteristic pseudounipolar morphology, with a single axon that bifurcates into a peripheral branch and a central branch. Via this axon, action potentials that originate in the periphery are transmitted toward the presynaptic terminal, where the detected information is relayed onto second-order sensory neurons and interneurons. The cell bodies of nociceptive and nonnociceptive primary sensory neurons are contained in the dorsal root ganglia (DRG), just lateral to the spinal cord, and in the trigeminal ganglia (TG), located in the middle cranial fossa adjacent to the brain (Basbaum et al., 2009; Vriens et al., 2014).

Nociceptive DRG neurons, including those that convey cold and heat pain, have their synaptic endings in lamina I, II, and V of the spinal cord dorsal horn. There, they release glutamate onto second-order sensory neurons, which cross the midline and project to the thalamus via the contralateral ascending spinothalamic tract. Signals that travel via the spinothalamic tract are decoded by the thalamus, sensorimotor cortex, insular cortex, and the anterior cingulate, resulting in the perception of an unpleasant sensation localized to a specific region of the body. Action potentials ascending the spinobulbar tract are decoded by the amygdala and hypothalamus to generate a sense of urgency and intensity (Basbaum et al., 2009; Mertens, Blond, David, & Rigoard, 2015; von Hehn, Baron, & Woolf, 2012). Our perception of pain reflects the integration of sensations, emotions, and cognition and involves multiple brain areas that can be monitored with different techniques (positron emission tomography [PET], functional magnetic resonance imaging [fMRI], magnetoencephalography). These studies suggested that the brain network for acute pain perception in normal subjects is partially distinct from that activated during chronic pain conditions (Apkarian, Bushnell, Treede, & Zubieta, 2005).

The Molecular Basis of the Detection of Noxious Temperature

The detection of painful temperatures at sensory nerve endings depends on specific molecular sensors that convert thermal stimuli into electrical activity. Research from the last two decades has clearly established that ion channels are the primary molecular sensors of noxious temperatures in the mammalian somatosensory system.

Molecular Sensors for Noxious Heat

The expression cloning of the receptor for capsaicin in 1997 represents a pivotal step in our understanding of the molecular basis of noxious heat sensing in mammals (Caterina et al., 1997). Already in the nineteenth century, capsaicin and related capsaicinoids had been isolated from Capsicum fruits (Thresh, 1876), and it was demonstrated that capsaicin is responsible for the burning feeling when “hot peppers” come in contact with mucous membranes (Buchheim, 1873). During the twentieth century, capsaicin was extensively used as an experimental tool compound to study its effects on C-type nociceptor neurons, revealing that it causes activation of a depolarizing current, provokes calcium entry, induces the release of neuropeptides such as substance P and calcitonin gene–related peptide (CGRP), and leads to C-fiber desensitization and degeneration (Fitzgerald, 1983). The last properties also lie at the basis of the use of capsaicin to locally treat different forms of neuropathic pain (H. Smith & Brooks, 2014). The molecular identification of the receptor for capsaicin revealed that capsaicin acts as a direct agonist of an ion channel of the transient receptor potential (TRP) superfamily, now known as TRPV1 (transient receptor potential channel vanilloid 1; Caterina et al., 1997). Since TRPV1 was found to be activated not only by capsaicin and other vanilloids (e.g., resiniferatoxin) but also by heat, it was immediately brought forward as a prime candidate molecular sensor for noxious heat in nociceptor neurons (Caterina et al., 1997).

However, the initial analysis of TRPV1 knockout (KO) mice did not fully support a central role for TRPV1 in acute heat-induced pain. Indeed, whereas TRPV1-deficient mice fully lacked the cellular and behavioral responses to capsaicin, they still exhibited robust pain responses to heat in the hot-plate and tail-immersion assays, albeit with an overall increased withdrawal latency compared to wild-type animals (Caterina et al., 2000; Davis et al., 2000). Strikingly, various strategies to eliminate or silence TRPV1-expressing neurons in mice resulted in much more severe deficits in acute heat sensing. For instance, Mishra et al. created mice in which all TRPV1-lineage neurons were eliminated by crossing mice in which the Cre recombinase was expressed under control of the TRPV1 promotor and mice with Cre-dependent expression of the diphtheria toxin fragment A (DTA; Mishra, Tisel, Orestes, Bhangoo, & Hoon, 2011). These TRPV1-DTA mice were found completely insensitive to both noxious heat and noxious cold, indicating that all sensory neurons involved in sensing noxious thermal stimuli express TRPV1 at some point during their development (Mishra et al., 2011). Cavanaugh et al. ablated the central terminals of TRPV1-positive nociceptors in adult mice by intrathecal injection of capsaicin and found that these mice showed a selective loss of heat pain, while cold- or mechanically induced pain remained fully intact, indicating that in adulthood TRPV1-positive neurons are specifically implicated in detecting noxious heat but not cold (Cavanaugh et al., 2009). Later, Binshtok, Bean, and Woolf (2007) found that silencing of TRPV1-positive neurons through TRPV1-dependent intracellular loading with the voltage-gated sodium channel blocker QX-314 also rendered animals temporarily insensitive to radiant heat. Taken together, these findings indicate that TRPV1-positive sensory neurons play an essential role in acute noxious heat sensing and heat-induced pain. However, to explain the residual noxious heat response in TRPV1 KO mice, TRPV1-positive neurons must express additional heat sensors.

In the last two decades, several other ion channels have been put forward as candidate molecular sensors for acute heat-induced pain. Notable candidates included the heat-activated TRP channels TRPV2, TRPV3, TRPV4, and transient receptor potential melastatin 3 (TRPM3), as well as calcium-activated chloride channels of the anoctamin (ANO)/transmembrane protein 16 (TMEM16) family (Caterina, Rosen, Tominaga, Brake, & Julius, 1999; Cho et al., 2012; H. Lee, Iida, Mizuno, Suzuki, & Caterina, 2005; Moqrich et al., 2005; Vriens et al., 2011) (Figure 1). However, several KO studies in which these channels were eliminated in mice revealed either no or relatively mild phenotypes with respect to acute noxious heat sensing, even when TRPV1 function was concurrently inhibited genetically or pharmacologically (Vriens et al., 2014). These findings suggested that acute heat sensing relies on multiple redundant heat sensors or on a heat-sensing mechanism that remained to be identified.

In a recent study, Vandewauw et al. provided compelling evidence that acute noxious heat sensing relies on three ion channels, all members of the TRP channel superfamily: TRPV1, TRPM3, and transient receptor potential ankyrin 1 (TRPA1) (Vandewauw et al., 2018). They studied sensory neurons from double-knockout (DKO) mice lacking both TRPV1 and TRPM3 and found that the residual heat responses correlated with responses to the TRPA1 agonist mustard oil (allyl isothiocyanate) and were inhibited by the TRPA1 antagonist HC030031. Encouraged by these results, a triple-knockout (TKO) mouse line with a combined deficiency for TRPV1, TRPM3, and TRPA1 was created, which showed a striking and specific deficit in acute heat sensing. Indeed, TKO mice lacked a pain response in the hot-plate and tail-immersion assays, to such an extent that they could readily burn their paws or tails without withdrawing. At the same time, responses to mechanical or cold stimuli were indistinguishable from wild-type animals, indicating that the deficit in heat sensing is not due to a general deficiency in nociceptor signaling. Importantly, DKO mice lacking two of these three TRP channels in any combination retain robust heat responsiveness at the cellular and behavioral levels. Moreover, reintroduction of TRPV1, TRPM3, or TRPA1 into TKO sensory neurons restored heat responsiveness (Vandewauw et al., 2018). Taken together, these recent findings indicate that there is triple redundancy at the level of the molecular sensors responsible for initiating the acute heat-induced pain response, which may represent a fault-tolerant mechanism to avoid burn injury.

The finding that any of these three TRP channels can support a robust heat response at the cellular and behavioral levels does not imply that the three molecular heat sensors are functionally equivalent. On heterologous expression, TRPV1 and TRPM3 both give rise to robust heat-activated inward currents, but the activation profile for TRPM3 is shifted to higher temperatures compared to TRPV1 (Caterina et al., 1997; Vriens et al., 2011). In contrast, heat-activated currents have not consistently been measured in cells heterologously expressing mammalian TRPA1 (Jabba et al., 2014). However, heat-evoked activation of TRPA1 can be more pronounced depending on the cellular context and the oxidative potential (Arenas et al., 2017; Moparthi et al., 2016; Vandewauw et al., 2018). In behavioral experiments, DKO mice deficient for TRPA1 and TRPM3 (and thus expressing TRPV1) showed wild-type-like withdrawal responses to acute heat. DKO mice deficient for TRPV1 and TRPA1 (expressing TRPM3) showed a mild but significant increase in response latency, and a more pronounced prolongation of the heat response latency was found for DKO mice deficient for TRPV1 and TRPM3 (expressing TRPA1) (Vandewauw et al., 2018). Overall, the available evidence suggests that in healthy tissue there is a hierarchy between heat sensors, where TRPV1 is the first in line to be activated by hot temperatures, followed by TRPM3. The contribution of TRPA1 only becomes evident after elimination of TRPV1 and TRPM3. However, since the activity of all three TRP channels is differentially modulated by a variety of cellular and environmental factors, including pH, mechanical stress, protein phosphorylation, membrane (phospho)lipids, G proteins, and intracellular calcium, their relative contribution to heat sensing may well be different in various pathological conditions, such as inflammation or nerve injury (see the section on thermal hypersensitivity).

Molecular Sensors for Noxious Cold

Despite important advances made during recent years, the cellular and molecular mechanism of innocuous cold sensing and cold pain are incompletely understood (Belmonte, Brock, & Viana, 2009; Foulkes & Wood, 2007; Lolignier et al., 2016). Classic neurophysiological studies on single sensory fibers in different animal species, including primates, identified two classes of fibers activated by cold, with very distinct characteristics. A first class is characterized by spontaneous activity at skin thermoneutral temperatures and shows a remarkable transient increase in activity in response to moderate temperature decreases (Hensel, 1981). Application of menthol also excites these fibers, and shifts their stimulus response curve to warmer temperatures. They originate from slow-conducting, thinly myelinated or unmyelinated axons, terminating as naked peripheral endings that innervate small spot-like areas of the skin and other exposed tissues like the cornea (Hensel, Andres, & von During, 1974; Heppelmann, Gallar, Trost, Schmidt, & Belmonte, 2001). This class of fibers is thought to signal innocuous cold sensations and is known as low-threshold cold thermoreceptors or simply cold thermoreceptors.

A second class of sensory neurons is silent at thermoneutral skin temperatures but shows sustained, low-frequency, delayed action potential firing in response to prolonged cold stimuli. In comparison to the low-threshold thermoreceptors, their threshold for action potential firing is shifted to much lower temperatures, within the noxious range. These neurons are known as cold nociceptors. Intriguingly, many of the cold nociceptors are also activated by heat and mechanical stimuli, indicating their polymodal nature as sensors of multiple damaging stimuli (Georgopoulos, 1976).

The discovery of molecular sensors for cold temperature in the somatosensory system was grounded on the earlier identification of TRPV1 as a capsaicin-sensitive, heat-activated channel described previously. In this case, menthol, a natural product from the mint plant known to evoke a cooling sensation when applied to the skin, was fundamental in the identification and functional characterization or TRPM8, a channel steeply activated by cold temperatures and cooling compounds (McKemy, Neuhausser, & Julius, 2002; Peier et al., 2002; Voets et al., 2004). Like the heat sensors described previously, TRPM8 is a member of the TRP superfamily of cation channels (reviewed by Almaraz, Manenschijn, de la Pena, & Viana, 2014; McKemy et al., 2002). It is expressed in a small subset of trigeminal and DRG neurons that are sensitive to cooling and cooling agents such as menthol or icilin. Pharmacological and genetic studies have provided compelling evidence that TRPM8 is a critical sensor for innocuous cold temperatures. Thus, animals lacking TRPM8 are unable to discriminate between 30 and 20°C (Bautista et al., 2007; Dhaka et al., 2007; Knowlton, Bifolck-Fisher, Bautista, & McKemy, 2010). However, TRPM8-deficient mice still avoid temperatures below 10–15°C, indicating the presence of additional sensors for noxious cold.

Note, however, that limiting the role of TRPM8 to innocuous cold detection is an oversimplification of these findings. Indeed, many preclinical studies suggested that TRPM8 also participates in acute noxious cold detection (Gentry, Stoakley, Andersson, & Bevan, 2010; Knowlton et al., 2010). In addition, studies in healthy volunteers showed that application of menthol to the skin induced a cooling sensation and augmented cold-evoked pain, suggesting a possible role for TRPM8-expressing fibers in cold pain (Hatem, Attal, Willer, & Bouhassira, 2006; Namer, Kleggetveit, Handwerker, Schmelz, & Jorum, 2008). It should be noted here that menthol, in contrast to the very specific action of capsaicin on TRPV1, is not a very selective pharmacological tool, having effects on other ion channels (including TRPA1; see discussion that follows); thus, attributing all sensory effects of menthol to TRPM8 is not warranted. Finally, the molecular profiling of single sensory neurons indicated that TRPM8 defines more than one subclass of cold-sensitive neurons. Individual cold-sensitive neurons expressing TRPM8 have variable temperature thresholds (Madrid, de la Pena, Donovan-Rodriguez, Belmonte, & Viana, 2009), which can be explained by a combinatorial mechanism: Single neurons express different levels of TRPM8 along with several potassium channels that act as brakes to their excitability (Madrid et al., 2009), and the balance between these two opposing mechanisms sets the threshold for neuronal activation. A further level of complexity arises from the finding that TRPM8 activation can also have analgesic effects. Indeed, it has been shown that TRPM8 is essential for cooling-induced analgesia in mice, suggesting that a single molecular sensor can have multiple functions, determined by its localization in specific subpopulations of sensory neurons and the wiring of different afferents. Altogether, these and other findings suggest that TRPM8 not only is essential for innocuous cold detection but also plays a role in cold pain, in association with other cold sensors.

The quest for additional cold temperature sensors led to the identification of TRPA1 (Story et al., 2003). TRPA1 is found in a fraction of polymodal nociceptive neurons without overlap with TRPM8 expression (but with significant overlap with TRPV1), and the channel is activated at significantly lower temperatures than TRPM8 on heterologous expression (Zygmunt & Hogestatt, 2014). These and other observations made TRPA1 a prime candidate to act as a molecular transducer for noxious cold detection in peripheral neurons (Story et al., 2003). However, the specific role of TRPA1 in physiological cold sensing has been the topic of intense debate (Bautista et al., 2006; Karashima et al., 2009; Kwan & Corey, 2009). The phenotype of TRPA1 KO mice in regard to cold sensitivity was not uniform across studies; some even reported that TRPA1-null mice exhibited normal responses to noxious cold. However, the evidence for a role of this channel in noxious cold detection, especially after inflammation and nerve injury, is becoming well established (reviewed by Viana, 2016). In addition, TRPA1 appears to be the main mechanism for cold sensitivity of nodose ganglion neurons that innervate major viscera, including the lungs and the gut (Fajardo, Meseguer, Belmonte, & Viana, 2008).

The TRPA1 channels are also gated by various natural pungent compounds, by environmental irritants, and by endogenous products of tissue injury, evidencing the polymodal nature of this TRP channel (Bandell et al., 2004; Bautista et al., 2006; Macpherson et al., 2007). Given the sensitivity of this channel to many reactive species, it is ideally suited to monitor cellular stress and tissue damage (Viana, 2016). Because very cold or hot temperatures can also trigger tissue damage, this could be an indirect but physiological mechanism of TRPA1 activation by extreme temperatures. Regardless of the controversy surrounding TRPA1 as a cold sensor, mice that lack both TRPM8 and TRPA1 still avoid noxious cold (Knowlton et al., 2010), indicating the existence of additional cold sensors (Belmonte et al., 2009).

The sensitivity of nociceptors to cold temperatures is strongly modulated by the expression of other ion channels at the same nerve endings. In particular, the expression of the tetrodotoxin (TTX)–resistant sodium channels, NaV1.8 and NaV1.9, has a strong influence on their thermal response (reviewed by Foulkes & Wood, 2007; Lolignier et al., 2016). NaV1.8 is resistant to cooling-induced inactivation. In this way, it contributes to the depolarizing current generated in nociceptors during intense cooling (Zimmermann et al., 2007). NaV1.9 is also resistant to TTX and characterized by ultraslow inactivation. NaV1.9 KO mice also have an increased tolerance to noxious cold stimulation, and nociceptors in these animals showed reduced activation in response to low temperatures (Lolignier et al., 2015).

Additional cold temperature sensors that may contribute to cold pain include several potassium channels that are open at the resting membrane potential of the neuron, known as leak potassium channels. The closure of these channels by cold temperatures can cause depolarization and the firing of action potentials (Noel et al., 2009; Viana, de la Pena, & Belmonte, 2002).

Thermal Hypersensitivity

Thermal hypersensitivity (also known as thermal hyperesthesia) is a common but variable phenomenon in many conditions linked to inflammation or tissue injury, including damage to the nervous system. Several factors contribute to the large variability observed in the prevalence of cold and heat hypersensitivity in epidemiological studies, including poor standardization of testing protocols, cultural influences in pain perception, and the inherent subjectivity of pain (Jensen & Finnerup, 2014).

A distinction has been made between thermal allodynia (pain in response to a nonnoxious, mildly cold or warm temperatures) and thermal hyperalgesia (increased pain response to noxious cold or hot) (Loeser & Treede, 2008). However, it should be noted that allodynia and hyperalgesia are clinical terms that do not imply distinct underlying mechanism(s) (Sandkuhler, 2009); for simplicity, in the material that follows the more general term thermal hypersensitivity is used to describe enhanced pain responses to thermal stimuli.

Mechanism of Heat Hypersensitivity

Skin injury (e.g., a burn or incision), inflammation, or nerve damage can cause innocuous heat to become painful and can exaggerate the pain response to noxious heat. Hypersensitivity to heat is also a common sign in systemic inflammatory disorders such as rheumatoid arthritis and in different neuropathic conditions such as peripheral nerve injuries, chemotherapy-induced neuropathy, postherpetic neuralgia, diabetic neuropathy, and autoimmune pathologies (Colloca et al., 2017; Jensen & Finnerup, 2014). Multiple mechanisms are thought to participate in the increased sensitivity to temperature following injury or inflammation, broadly categorized as peripheral sensitization of nociceptors (Gold & Gebhart, 2010) and central sensitization in the pain pathway (Simone, 1992; Woolf, 2011). The latter represents a form of activity-dependent plasticity following prolonged nociceptor activation and involves pre- and postsynaptic changes within the dorsal horn, with features that resemble synaptic plasticity in higher brain areas. The discussion that follows focuses on the initial, peripheral mechanisms of heat hyperalgesia.

The hyperalgesia to heat and mechanical stimuli that occurs at the site of injury, known as primary hyperalgesia, is caused by a peripheral sensitization mechanism in slow-conducting (i.e., unmyelinated) mechanoheat nociceptors, which results in a reduction in their activation threshold and an augmented response to suprathreshold stimuli (reviewed by Gold & Gebhart, 2010; LaMotte, Thalhammer, Torebjork, & Robinson, 1982). Furthermore, these sensitized polymodal nociceptors develop abnormal spontaneous activity, explaining the ongoing pain that is commonly observed in patients (Bostock, Campero, Serra, & Ochoa, 2005). Importantly, a fraction of these nociceptor neurons is peptidergic. Their activation releases vasoactive substances from their peripheral terminals, including neurokinin A, substance P, and CGRP, leading to plasma extravasation and edema (i.e., neurogenic inflammation).

The peripheral sensitization of nociceptors is triggered by the rapid accumulation of a variety of inflammatory mediators at the site of injury (Basbaum et al., 2009). These substances leak from damaged cells or can be released by resident or migrating immune cells. A plethora of molecules found in damaged tissues have been shown to produce nociceptor sensitization. Often, they operate synergistically, activating multiple intracellular pathways and effectors, including ion channels on nerve endings. The list includes protons, adenosine, adenosine triphosphate (ATP), RNA, serotonin, histamine, platelet-activating factor, bradykinin, prostanoids, cytokines, and growth factors (Chiu, von Hehn, & Woolf, 2012; Tilley, Coffman, & Koller, 2001). Through their membrane receptors, these mediators activate intracellular signaling cascades (e.g., protein kinase A and C [PKA and PKC, respectively]), which result in facilitation of the gating of different channels to increase nociceptor excitability. In addition, they can also produce changes in the expression of channel proteins, leading to more persistent changes in nociceptor activity.

Interestingly, the TRP channels that were implicated in acute heat sensing, TRPV1, TRPM3, and TRPA1 (Vandewauw et al., 2018), have all been linked to nociceptor sensitization and heat hyperalgesia. For instance, both TRPV1-deficient and TRPM3-deficient mice failed to develop heat hyperalgesia following experimental inflammation induced by local injection of Complete Freund’s Adjuvant (CFA) (Caterina et al., 2000; Vriens et al., 2011). Whereas TRPA1-deficient mice do develop CFA-induced heat hyperalgesia, they fail to develop heat hypersensitivity following injection of the inflammatory mediator bradykinin or application of the TRPA1 agonist allylisothiocyanate (Bautista et al., 2006). There are also numerous preclinical studies showing that pharmacological inhibition of TRPV1 using a variety of antagonists reduced heat hypersensitivity in various models of inflammatory, skin burn, postoperative, and neuropathic pain (Bevan, Quallo, & Andersson, 2014; Y. Lee et al., 2015; Moran & Szallasi, 2018). Likewise, a growing number of more recent studies showed that TRPM3 antagonists reduced inflammatory and neuropathic heat hypersensitivity (Jia, Zhang, & Yu, 2017; Krugel, Straub, Beckmann, & Schaefer, 2017). Oppositely, TRPA1 antagonists do not show consistent efficacy against heat hypersensitivity (Lennertz, Kossyreva, Smith, & Stucky, 2012).

Although some central effects of TRP channel inhibition have been proposed, the most common mechanism whereby heat-sensitive TRP channels promote pathological heat hypersensitivity is by contributing to peripheral sensitization. This has been extensively studied for TRPV1, where it has been shown that a large variety of inflammatory mediators can sensitize the channel, potentiating responses to heat (Bevan et al., 2014; Zhang, Li, & McNaughton, 2008). In particular, TRPV1 channels can become sensitized to such a degree that they show significant activity at body temperature, which can explain the ongoing burning pain occurring in many inflammatory conditions (Moriyama et al., 2005).

It is beyond the scope of this work to describe in detail the multiple cellular/molecular mechanisms that have been proposed to contribute to enhanced TRPV1 activity in sensory neurons of injured tissue and thereby to heat hypersensitivity. Broadly, these mechanism include (a) increased TRPV1 expression levels; (b) enhanced transport of TRPV1 to the plasma membrane; (c) increased TRPV1 channel activity due to post-translational modification (e.g., phosphorylation); (d) increased TRPV1 channel activity due to alterations in the membrane phospholipid composition (e.g., phosphatidylinositol 4,5-bisphosphate); and (e) local increases in endogenous channel ligands (e.g., protons, lysophosphatidic acid) (Bevan et al., 2014; Zhang et al., 2008). TRPA1 channels are regulated by many of the same pathways modulating TRPV1 (Bautista et al., 2013). Moreover, TRPA1 and TRPV1 can functionally and physically interact at sensory nerve endings, thereby contributing to altered thermal sensitivity and ongoing pain in injured tissue (reviewed by Viana, 2016). Recent studies also provided evidence that TRPM3 activity can be modulated following activation of various metabotropic receptors, both via phospholipase C–mediated changes in plasma membrane phosphoinositides (Badheka, Borbiro, & Rohacs, 2015; Toth et al., 2015) and via the Gβγ subunit of trimeric G proteins (Badheka et al., 2017; Dembla et al., 2017; Quallo, Alkhatib, Gentry, Andersson, & Bevan, 2017). However, the relevance of these mechanisms to TRPM3 activity in the context of tissue injury and heat hyperalgesia remain to be established.

In addition to TRP channels, several other ion channels expressed in sensory neurons can contribute to the development of heat hypersensitivity. For instance, various lines of evidence point toward the voltage-gated sodium channels NaV1.7 as a key determinant of hypersensitivity to heat, in particular in the context of burn injury (Nassar et al., 2004; Shields et al., 2012). This ion channel is preferentially expressed within peripheral sensory and sympathetic neurons, where it is thought to play a major role in controlling the threshold and the gain of nociceptors. In humans, dominant mutations in the SCN9A gene, coding for NaV1.7, cause inherited erythromelalgia (IEM), a disorder characterized by reddening, swelling, and warming of the skin in the distal extremities, associated with bouts of severe burning pain (McDonnell et al., 2016). Two-pore potassium (K2P) channels such as TWIK-1-related K+ channel (TREK-1), TREK-2, and TWIK-related arachidonic acid-stimulated K+ channel (TRAAK) show steep heat sensitivity and act as brakes of neuronal excitability in sensory neurons. In line therewith, TREK-1-deficient mice exhibited a lower heat pain threshold and increased heat hypersensitivity following inflammation (Noel et al., 2009). A deficit in the development of heat hypersensitivity following inflammation or nerve injury was also observed following elimination of the heat-sensitive, calcium-activated chloride channel ANO1/TMEM16A (Cho et al., 2012).

Mechanisms of Cold Hypersensitivity

Augmented cold sensitivity is a frequent symptom in many neuropathies, including peripheral neuropathies caused by chemotherapeutic agents (e.g., oxaliplatin and paclitaxel), diabetic neuropathy, and following traumatic nerve damage (e.g., bone fractures and sport injuries) (Jensen & Finnerup, 2014). Cold hypersensitivity is also a hallmark of ciguatera poisoning, caused by consumption of ciguatoxins produced by marine dinoflagellates; these ciguatoxins accumulate in certain tropical and subtropical species of fish (Isbister & Kiernan, 2005). The clinical manifestations of cold hypersensitivity vary in individual patients and for particular diseases, which may suggest differences in the underlying mechanisms.

The mechanisms that lead to cold hypersensitivity in different clinical conditions remain poorly understood (reviewed by Belmonte et al., 2009; Jensen & Finnerup, 2014). Classical studies attributed these perturbations in thermal sensitivity to altered processing at the level of the spinal cord of the peripheral information carried by low-threshold cold receptors and nociceptors (Scholz & Woolf, 2007). However, more recent data suggest that hypersensitivity to cold following injury also involves changes in ion channel function at peripheral cold-sensitive nerve terminals. The specific changes are still unclear and the evidence in favor of different receptors and pathways is still fragmentary (Lolignier et al., 2016). It is important to realize that information carried by nociceptive afferents is strongly modulated by the activity of other afferents, converging on the same neurons at the level of the spinal cord. For example, the peripheral block of A-fiber conduction by mechanical compression in experimental subjects eliminated their cold sensibility and gave rise to cold allodynia, characterized by burning pain to a mild cold stimulus. These observations suggest that, under normal circumstances, cold-specific Aδ afferent activity produces central inhibition of C-nociceptive inputs (Wahren, Torebjork, & Jorum, 1989; Yarnitsky & Ochoa, 1990). In mice, the ablation of TRPV1 lineage nociceptors prevents the development of cold allodynia after nerve injury, while tactile allodynia develops normally, suggesting the involvement of different populations of afferents (Cobos et al., 2018).

Normal activity in a cold-activated sensory afferent is kept under check by the presence of multiple potassium channels, which act as molecular excitability brakes (Madrid et al., 2009; Noel et al., 2009). An unbalance between excitatory and inhibitory mechanisms can result in abnormal activity, similar to what happens in the cortex of patients with epilepsy. Several preclinical studies, including transcriptomic profiling of sensory neurons, indicated that alteration in the expression of different potassium channels following nerve injury plays a major role in preventing abnormal responses to cold stimuli in primary sensory neurons (Cobos et al., 2018; Gonzalez et al., 2017). The variety of potassium channels involved in these processes opens a window to selective treatment (Tsantoulas & McMahon, 2014), although their widespread expression in the brain and other tissues poses a challenge as useful drug targets.

Several observations also point toward a key role for TRPM8 in pathological cold hypersensitivity. For example, some preclinical studies of neuropathic pain found an upregulation of TRPM8 expression. In addition, TRPM8 KO mice and administration of TRPM8 antagonists reduced cold nociceptive responses in several inflammatory and nerve injury pain models (Colburn et al., 2007; Knowlton, Daniels, Palkar, McCoy, & McKemy, 2011; Patel et al., 2014). Silencing of TRPM8-expressing sensory neurons through TRPM8-dependent intracellular loading with QX-314, a cell-impermeable lidocaine derivative that blocks voltage-gated sodium channels, reverses cold hypersensitivity in mice (Ongun, Sarkisian, & McKemy, 2018). In the future, these findings may translate into novel therapies based on the selective silencing of subpopulations of nociceptors.

While the role of TRPA1 in physiological cold pain is still debated (reviewed by Viana, 2016; Vriens et al., 2014), different preclinical studies suggested a major role of TRPA1 in the hypersensitivity to cold in various pathological conditions. During inflammation, and following peripheral nerve injury, the levels of TRPA1 in rat DRG neurons were elevated (Obata et al., 2005), and downregulation of TRPA1 alleviated their cold hypersensitivity symptoms (Katsura et al., 2006). Interestingly, a rare gain-of-function mutation in TRPA1 (N855S) causes familial episodic pain syndrome (FEPS), characterized by attacks of debilitating upper body pain triggered by physical stress, particularly cold (Kremeyer et al., 2010). It should be noted that this study did not reveal differences in heat or cold sensitivity in the patients with FEPS compared to their unaffected family members (Kremeyer et al., 2010). However, the number of subjects that could be tested was probably too low to detect smaller differences in acute cold/heat sensing.

The most characteristic clinical symptom during treatment with oxaliplatin, a chemotherapeutic agent used in the treatment of colorectal cancer, are cold-triggered painful paresthesias in distal extremities and the perioral region at early stages (i.e., acute phase), followed by chronic, cumulative neuropathy. Considering the rapid onset, cold-induced paresthesias probably involve different molecular mechanism than slow-onset cumulative neurotoxicity. Studies in rodents suggested that the acute symptoms are mediated by alterations in TTX-sensitive, voltage-gated sodium channels expressed in nociceptors (Deuis et al., 2013; Lolignier et al., 2015; Park et al., 2009). However, other preclinical studies attributed the hyperexcitability of nociceptors to cold temperature after oxaliplatin treatment to TRPA1 channels (Nassini et al., 2011) or to a more extensive functional remodeling involving alterations in the expression of multiple ion channels in TRPM8-positive fibers, including K2P channels, hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1), and NaV1.8 (Descoeur et al., 2011).

The symptoms of ciguatera poisoning provide an intriguing illustration of the complexity of the cellular mechanisms involved in cold pain (Voets, 2012). The typical neurological symptoms include paraesthesias, numbness of the lips and extremities, and intense stabbing and burning pain sensations in response to mild cooling (Isbister & Kiernan, 2005). The cold hypersensitivity appear to arise peripherally, as it can be reproduced in human subjects by intracutaneous injection of the ciguatoxin. Studies in mice have shown that TRPA1 channels are essential for the hyperexcitability of C fibers and the pain manifestations after peripheral ciguatoxin injection. Yet, TRPA1 does not seem to be the direct target of the toxin. Instead, ciguatoxin affects the activity of voltage-gated sodium channels, which drives TRPA1-dependent calcium influx and abnormal firing (Vetter et al., 2012; Zimmermann et al., 2013).

Finally, T-type voltage-gated calcium channels have been implicated in cold hypersensitivity. These channels are present in small- and medium-size cold- and menthol-sensitive primary sensory neurons and in certain classes of nociceptors. Experiments in different animal species, including pharmacological studies in humans, suggested that inhibition of these channels can alleviate cold hypersensitivity (Obradovic et al., 2014; Samour, Nagi, & Mahns, 2015).

Conclusions and Perspectives

In the last two decades, important advances have been made in delineating the principal molecular sensors for detecting acute noxiously hot and cold stimuli. Recent evidence suggests that the initiation of acute noxious heat pain relies on a triad of heat-activated TRP channels (TRPV1, TRPM3, and TRPA1), which, on combined elimination, result in a selective lack of heat-induced pain. A full delineation of the sensors for acute cold pain is still lacking: Whereas the role of TRPM8 in the process is well accepted, the contribution of TRPA1 to cold pain remains debated, and it is clear that one or more additional cold sensors needs to be identified.

In addition to identifying the ion channels involved in translating the thermal stimulus into an electrical signal at the nerve endings, a multitude of mechanisms have been revealed that can shift the temperature response profile of sensory neurons and thereby contribute to pathological cold or heat hypersensitivity. These include processes that increase not only the expression or activity of the key temperature-sensitive ion channels but also modulation of other ion channels that influence the excitability of the sensory neurons, as well as synaptic alterations that affect central processing of thermal pain stimuli. We are only starting to understand how these different mechanisms relate to the pain symptoms in specific human conditions and diseases. A deeper understanding of the molecular processes and circuitry underlying pathological thermal sensations can form the basis for the development of novel analgesic drugs that are safer and more effective than the current therapeutic arsenal. The ultimate goal is to develop selective drug therapies that are tailored to only influence deregulated sensory mechanisms without affecting processes responsible for normal thermosensation or thermoregulation. The development of selective drugs targeting key sensory ion channels and the selective targeting of subpopulations of sensory afferents responsible for aberrant noxious heat and cold sensations using restricted uptake of blockers represent promising avenues to reach this goal.

Acknowledgments

We thank Stuart Ingham for help with the illustration. During preparation of this manuscript F. V. was supported by projects MINECO SAF2016-77233-R and the Severo Ochoa Programme for Centres of Excellence in R&D (SEV-2017-0723). T. V. acknowledges support from KU Leuven Research Council (C1-TRPLe), the Queen Elisabeth Medical Foundation for Neurosciences, the Belgian Foundation Against Cancer, and the Research Foundation—Flanders (FWO G.084515N).

References

Almaraz, L., Manenschijn, J. A., de la Pena, E., & Viana, F. (2014). Trpm8. Handbook of Experimental Pharmacology, 222, 547–579. doi:10.1007/978-3-642-54215-2_22Find this resource:

Apkarian, A. V., Bushnell, M. C., Treede, R. D., & Zubieta, J. K. (2005). Human brain mechanisms of pain perception and regulation in health and disease. European Journal of Pain, 9(4), 463–484. doi:10.1016/j.ejpain.2004.11.001Find this resource:

Arenas, O. M., Zaharieva, E. E., Para, A., Vasquez-Doorman, C., Petersen, C. P., & Gallio, M. (2017). Activation of planarian TRPA1 by reactive oxygen species reveals a conserved mechanism for animal nociception. Nature Neuroscience, 20(12), 1686–1693. doi:10.1038/s41593-017-0005-0Find this resource:

Badheka, D., Borbiro, I., & Rohacs, T. (2015). Transient receptor potential melastatin 3 is a phosphoinositide-dependent ion channel. Journal of General Physiology, 146(1), 65–77. doi:10.1085/jgp.201411336Find this resource:

Badheka, D., Yudin, Y., Borbiro, I., Hartle, C. M., Yazici, A., Mirshahi, T., & Rohacs, T. (2017). Inhibition of transient receptor potential melastatin 3 ion channels by G-protein betagamma subunits. Elife, 6, 26147. doi:10.7554/eLife.26147Find this resource:

Bandell, M., Story, G. M., Hwang, S. W., Viswanath, V., Eid, S. R., Petrus, M. J., … Patapoutian, A. (2004). Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron, 41(6), 849–857.Find this resource:

Basbaum, A. I., Bautista, D. M., Scherrer, G., & Julius, D. (2009). Cellular and molecular mechanisms of pain. Cell, 139(2), 267–284. doi:10.1016/j.cell.2009.09.028Find this resource:

Bautista, D. M., Jordt, S. E., Nikai, T., Tsuruda, P. R., Read, A. J., Poblete, J., … Julius, D. (2006). TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell, 124(6), 1269–1282. doi:10.1016/j.cell.2006.02.023Find this resource:

Bautista, D. M., Pellegrino, M., & Tsunozaki, M. (2013). TRPA1: A gatekeeper for inflammation. Annu Rev Physiol, 75, 181–200. doi:10.1146/annurev-physiol-030212-183811Find this resource:

Bautista, D. M., Siemens, J., Glazer, J. M., Tsuruda, P. R., Basbaum, A. I., Stucky, C. L., … Julius, D. (2007). The menthol receptor TRPM8 is the principal detector of environmental cold. Nature, 448(7150), 204–208. doi:10.1038/nature05910Find this resource:

Belmonte, C., Brock, J. A., & Viana, F. (2009). Converting cold into pain. Experimental Brain Research, 196(1), 13–30. doi:10.1007/s00221-009-1797-2Find this resource:

Bevan, S., Quallo, T., & Andersson, D. A. (2014). Trpv1. Handbook of Experimental Pharmacology, 222, 207–245. doi:10.1007/978-3-642-54215-2_9Find this resource:

Binshtok, A. M., Bean, B. P., & Woolf, C. J. (2007). Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature, 449(7162), 607–610. doi:10.1038/nature06191Find this resource:

Bostock, H., Campero, M., Serra, J., & Ochoa, J. L. (2005). Temperature-dependent double spikes in C-nociceptors of neuropathic pain patients. Brain, 128(Pt. 9), 2154–2163. doi:10.1093/brain/awh552Find this resource:

Buchheim, R. (1873). Über die “scharfen” Stoffe. Archiv der Heilkunde, 14, 4.Find this resource:

Caterina, M. J., Leffler, A., Malmberg, A. B., Martin, W. J., Trafton, J., Petersen-Zeitz, K. R., … Julius, D. (2000). Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science, 288(5464), 306–313.Find this resource:

Caterina, M. J., Rosen, T. A., Tominaga, M., Brake, A. J., & Julius, D. (1999). A capsaicin-receptor homologue with a high threshold for noxious heat. Nature, 398(6726), 436–441. doi:10.1038/18906Find this resource:

Caterina, M. J., Schumacher, M. A., Tominaga, M., Rosen, T. A., Levine, J. D., & Julius, D. (1997). The capsaicin receptor: A heat-activated ion channel in the pain pathway. Nature, 389(6653), 816–824. doi:10.1038/39807Find this resource:

Cavanaugh, D. J., Lee, H., Lo, L., Shields, S. D., Zylka, M. J., Basbaum, A. I., & Anderson, D. J. (2009). Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli. Proceedings of the National Academy of Sciences of the United States of America, 106(22), 9075–9080. doi:10.1073/pnas.0901507106Find this resource:

Chiu, I. M., von Hehn, C. A., & Woolf, C. J. (2012). Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nature Neuroscience, 15(8), 1063–1067. doi:10.1038/nn.3144Find this resource:

Cho, H., Yang, Y. D., Lee, J., Lee, B., Kim, T., Jang, Y., … Oh, U. (2012). The calcium-activated chloride channel anoctamin 1 acts as a heat sensor in nociceptive neurons. Nature Neuroscience, 15(7), 1015–1021. doi:10.1038/nn.3111Find this resource:

Cobos, E. J., Nickerson, C. A., Gao, F., Chandran, V., Bravo-Caparros, I., Gonzalez-Cano, R., … Costigan, M. (2018). Mechanistic differences in neuropathic pain modalities revealed by correlating behavior with global expression profiling. Cell Reports, 22(5), 1301–1312. doi:10.1016/j.celrep.2018.01.006Find this resource:

Colburn, R. W., Lubin, M. L., Stone, D. J., Jr., Wang, Y., Lawrence, D., D’Andrea, M. R., … Qin, N. (2007). Attenuated cold sensitivity in TRPM8 null mice. Neuron, 54(3), 379–386. doi:10.1016/j.neuron.2007.04.017Find this resource:

Colloca, L., Ludman, T., Bouhassira, D., Baron, R., Dickenson, A. H., Yarnitsky, D., … Raja, S. N. (2017). Neuropathic pain. Nature Reviews Disease Primers, 3, 17002. doi:10.1038/nrdp.2017.2Find this resource:

Davis, J. B., Gray, J., Gunthorpe, M. J., Hatcher, J. P., Davey, P. T., Overend, P., … Sheardown, S. A. (2000). Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature, 405(6783), 183–187. doi:10.1038/35012076Find this resource:

Dembla, S., Behrendt, M., Mohr, F., Goecke, C., Sondermann, J., Schneider, F. M., … Oberwinkler, J. (2017). Anti-nociceptive action of peripheral mu-opioid receptors by G-beta-gamma protein-mediated inhibition of TRPM3 channels. Elife, 6, 26280. doi:10.7554/eLife.26280Find this resource:

Descoeur, J., Pereira, V., Pizzoccaro, A., Francois, A., Ling, B., Maffre, V., … Bourinet, E. (2011). Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors. EMBO Molecular Medicine, 3(5), 266–278. doi:10.1002/emmm.201100134Find this resource:

Deuis, J. R., Zimmermann, K., Romanovsky, A. A., Possani, L. D., Cabot, P. J., Lewis, R. J., & Vetter, I. (2013). An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for NaV1.6 in peripheral pain pathways. Pain, 154(9), 1749–1757. doi:10.1016/j.pain.2013.05.032Find this resource:

Dhaka, A., Murray, A. N., Mathur, J., Earley, T. J., Petrus, M. J., & Patapoutian, A. (2007). TRPM8 is required for cold sensation in mice. Neuron, 54(3), 371–378. doi:10.1016/j.neuron.2007.02.024Find this resource:

Eglin, C. M., Montgomery, H., & Tipton, M. J. (2018). Non-freezing cold injury: A multi-faceted syndrome. Brain, 141(2), e9. doi:10.1093/brain/awx321Find this resource:

Fajardo, O., Meseguer, V., Belmonte, C., & Viana, F. (2008). TRPA1 channels mediate cold temperature sensing in mammalian vagal sensory neurons: pharmacological and genetic evidence. Journal of Neuroscience, 28(31), 7863–7875. doi:10.1523/JNEUROSCI.1696–08.2008Find this resource:

Fitzgerald, M. (1983). Capsaicin and sensory neurones—A review. Pain, 15(2), 109–130.Find this resource:

Foulkes, T., & Wood, J. N. (2007). Mechanisms of cold pain. Channels (Austin), 1(3), 154–160.Find this resource:

Gentry, C., Stoakley, N., Andersson, D. A., & Bevan, S. (2010). The roles of iPLA2, TRPM8 and TRPA1 in chemically induced cold hypersensitivity. Molecular Pain, 6, 4. doi:10.1186/1744-8069-6-4Find this resource:

Georgopoulos, A. P. (1976). Functional properties of primary afferent units probably related to pain mechanisms in primate glabrous skin. Journal of Neurophysiology, 39(1), 71–83. doi:10.1152/jn.1976.39.1.71Find this resource:

Gold, M. S., & Gebhart, G. F. (2010). Nociceptor sensitization in pain pathogenesis. Nature Medicine, 16(11), 1248–1257. doi:10.1038/nm.2235Find this resource:

Gonzalez, A., Ugarte, G., Restrepo, C., Herrera, G., Pina, R., Gomez-Sanchez, J. A., … Madrid, R. (2017). Role of the excitability brake potassium current IKD in cold allodynia induced by chronic peripheral nerve injury. Journal of Neuroscience, 37(12), 3109–3126. doi:10.1523/JNEUROSCI.3553-16.2017Find this resource:

Hatem, S., Attal, N., Willer, J. C., & Bouhassira, D. (2006). Psychophysical study of the effects of topical application of menthol in healthy volunteers. Pain, 122(1–2), 190–196. doi:10.1016/j.pain.2006.01.026Find this resource:

Heil, K., Thomas, R., Robertson, G., Porter, A., Milner, R., & Wood, A. (2016). Freezing and non-freezing cold weather injuries: a systematic review. British Medical Bulletin, 117(1), 79–93. doi:10.1093/bmb/ldw001Find this resource:

Henriques, F. C., & Moritz, A. R. (1947). Studies of thermal injury: I. The conduction of heat to and through skin and the temperatures attained therein. A theoretical and an experimental investigation. American Journal of Pathology, 23(4), 530–549.Find this resource:

Hensel, H. (1981). Thermoreception and temperature regulation. Monographs of the Physiological Society, 38, 1–321.Find this resource:

Hensel, H., Andres, K. H., & von During, M. (1974). Structure and function of cold receptors. Pflügers Archiv, 352(1), 1–10.Find this resource:

Heppelmann, B., Gallar, J., Trost, B., Schmidt, R. F., & Belmonte, C. (2001). Three-dimensional reconstruction of scleral cold thermoreceptors of the cat eye. Journal of Comparative Neurology, 441(2), 148–154.Find this resource:

Isbister, G. K., & Kiernan, M. C. (2005). Neurotoxic marine poisoning. Lancet Neurology, 4(4), 219–228. doi:10.1016/S1474-4422(05)70041-7Find this resource:

Jabba, S., Goyal, R., Sosa-Pagan, J. O., Moldenhauer, H., Wu, J., Kalmeta, B., … Grandl, J. (2014). Directionality of temperature activation in mouse TRPA1 ion channel can be inverted by single-point mutations in ankyrin repeat six. Neuron, 82(5), 1017–1031. doi:10.1016/j.neuron.2014.04.016Find this resource:

Jensen, T. S., & Finnerup, N. B. (2014). Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. Lancet Neurology, 13(9), 924–935. doi:10.1016/S1474-4422(14)70102-4Find this resource:

Jia, S., Zhang, Y., & Yu, J. (2017). Antinociceptive effects of isosakuranetin in a rat model of peripheral neuropathy. Pharmacology, 100(3–4), 201–207. doi:10.1159/000478986Find this resource:

Karashima, Y., Talavera, K., Everaerts, W., Janssens, A., Kwan, K. Y., Vennekens, R., … Voets, T. (2009). TRPA1 acts as a cold sensor in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America, 106(4), 1273–1278. doi:10.1073/pnas.0808487106Find this resource:

Katsura, H., Obata, K., Mizushima, T., Yamanaka, H., Kobayashi, K., Dai, Y., … Noguchi, K. (2006). Antisense knock down of TRPA1, but not TRPM8, alleviates cold hyperalgesia after spinal nerve ligation in rats. Experimental Neurology, 200(1), 112–123. doi:10.1016/j.expneurol.2006.01.031Find this resource:

Knowlton, W. M., Bifolck-Fisher, A., Bautista, D. M., & McKemy, D. D. (2010). TRPM8, but not TRPA1, is required for neural and behavioral responses to acute noxious cold temperatures and cold-mimetics in vivo. Pain, 150(2), 340–350. doi:10.1016/j.pain.2010.05.021Find this resource:

Knowlton, W. M., Daniels, R. L., Palkar, R., McCoy, D. D., & McKemy, D. D. (2011). Pharmacological blockade of TRPM8 ion channels alters cold and cold pain responses in mice. PLoS One, 6(9), e25894. doi:10.1371/journal.pone.0025894Find this resource:

Kremeyer, B., Lopera, F., Cox, J. J., Momin, A., Rugiero, F., Marsh, S., … Ruiz-Linares, A. (2010). A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome. Neuron, 66(5), 671–680. doi:10.1016/j.neuron.2010.04.030Find this resource:

Krugel, U., Straub, I., Beckmann, H., & Schaefer, M. (2017). Primidone inhibits TRPM3 and attenuates thermal nociception in vivo. Pain, 158(5), 856–867. doi:10.1097/j.pain.0000000000000846Find this resource:

Kwan, K. Y., & Corey, D. P. (2009). Burning cold: Involvement of TRPA1 in noxious cold sensation. Journal of General Physiology, 133(3), 251–256. doi:10.1085/jgp.200810146Find this resource:

LaMotte, R. H., Thalhammer, J. G., Torebjork, H. E., & Robinson, C. J. (1982). Peripheral neural mechanisms of cutaneous hyperalgesia following mild injury by heat. Journal of Neuroscience, 2(6), 765–781.Find this resource:

Larrey, D. J. (1812). Mémoirs de chirurgie militaire, et campagnes. Paris, France: J. Smith.Find this resource:

Lee, H., Iida, T., Mizuno, A., Suzuki, M., & Caterina, M. J. (2005). Altered thermal selection behavior in mice lacking transient receptor potential vanilloid 4. Journal of Neuroscience, 25(5), 1304–1310. doi:10.1523/JNEUROSCI.4745.04.2005Find this resource:

Lee, Y., Hong, S., Cui, M., Sharma, P. K., Lee, J., & Choi, S. (2015). Transient receptor potential vanilloid type 1 antagonists: A patent review (2011–2014). Expert Opinion on Therapeutic Patents, 25(3), 291–318. doi:10.1517/13543776.2015.1008449Find this resource:

Lennertz, R. C., Kossyreva, E. A., Smith, A. K., & Stucky, C. L. (2012). TRPA1 mediates mechanical sensitization in nociceptors during inflammation. PLoS One, 7(8), e43597. doi:10.1371/journal.pone.0043597Find this resource:

Loeser, J. D., & Treede, R. D. (2008). The Kyoto protocol of IASP Basic Pain Terminology. Pain, 137(3), 473–477. doi:10.1016/j.pain.2008.04.025Find this resource:

Lolignier, S., Bonnet, C., Gaudioso, C., Noel, J., Ruel, J., Amsalem, M., … Busserolles, J. (2015). The NaV1.9 channel is a key determinant of cold pain sensation and cold allodynia. Cell Reports, 11(7), 1067–1078. doi:10.1016/j.celrep.2015.04.027Find this resource:

Lolignier, S., Gkika, D., Andersson, D., Leipold, E., Vetter, I., Viana, F., … Busserolles, J. (2016). New insight in cold pain: Role of ion channels, modulation, and clinical perspectives. Journal of Neuroscience, 36(45), 11435–11439. doi:10.1523/JNEUROSCI.2327–16.2016Find this resource:

Macpherson, L. J., Dubin, A. E., Evans, M. J., Marr, F., Schultz, P. G., Cravatt, B. F., & Patapoutian, A. (2007). Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines. Nature, 445(7127), 541–545. doi:10.1038/nature05544Find this resource:

Madrid, R., de la Pena, E., Donovan-Rodriguez, T., Belmonte, C., & Viana, F. (2009). Variable threshold of trigeminal cold-thermosensitive neurons is determined by a balance between TRPM8 and Kv1 potassium channels. Journal of Neuroscience, 29(10), 3120–3131. doi:10.1523/JNEUROSCI.4778-08.2009Find this resource:

McDonnell, A., Schulman, B., Ali, Z., Dib-Hajj, S. D., Brock, F., Cobain, S., … Waxman, S. G. (2016). Inherited erythromelalgia due to mutations in SCN9A: Natural history, clinical phenotype and somatosensory profile. Brain, 139(Pt. 4), 1052–1065. doi:10.1093/brain/aww007Find this resource:

McKemy, D. D., Neuhausser, W. M., & Julius, D. (2002). Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature, 416(6876), 52–58. doi:10.1038/nature719Find this resource:

Mertens, P., Blond, S., David, R., & Rigoard, P. (2015). Anatomy, physiology and neurobiology of the nociception: a focus on low back pain (part A). Neurochirurgie, 61(Suppl. 1), S22–S34. doi:10.1016/j.neuchi.2014.09.001Find this resource:

Mishra, S. K., Tisel, S. M., Orestes, P., Bhangoo, S. K., & Hoon, M. A. (2011). TRPV1-lineage neurons are required for thermal sensation. EMBO Journal, 30(3), 582–593. doi:10.1038/emboj.2010.325Find this resource:

Mohr, W. J., Jenabzadeh, K., & Ahrenholz, D. H. (2009). Cold injury. Hand Clinics, 25(4), 481–496. doi:10.1016/j.hcl.2009.06.004Find this resource:

Moparthi, L., Kichko, T. I., Eberhardt, M., Hogestatt, E. D., Kjellbom, P., Johanson, U., … Zygmunt, P. M. (2016). Human TRPA1 is a heat sensor displaying intrinsic U-shaped thermosensitivity. Science Reports, 6, 28763. doi:10.1038/srep28763Find this resource:

Moqrich, A., Hwang, S. W., Earley, T. J., Petrus, M. J., Murray, A. N., Spencer, K. S., … Patapoutian, A. (2005). Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science, 307(5714), 1468–1472. doi:10.1126/science.1108609Find this resource:

Moran, M. M., & Szallasi, A. (2018). Targeting nociceptive transient receptor potential channels to treat chronic pain: current state of the field. British Journal of Pharmacology, 175(12), 2185–2203. doi:10.1111/bph.14044Find this resource:

Moritz, A. R. (1947). Studies of thermal injury: III. The pathology and pathogenesis of cutaneous burns. An experimental study. American Journal of Pathology, 23(6), 915–941.Find this resource:

Moritz, A. R., & Henriques, F. C. (1947). Studies of thermal injury: II. The relative importance of time and surface temperature in the causation of cutaneous burns. American Journal of Pathology, 23(5), 695–720.Find this resource:

Moriyama, T., Higashi, T., Togashi, K., Iida, T., Segi, E., Sugimoto, Y., … Tominaga, M. (2005). Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins. Molecular Pain, 1, 3. doi:10.1186/1744-8069-1-3Find this resource:

Murphy, J. V., Banwell, P. E., Roberts, A. H., & McGrouther, D. A. (2000). Frostbite: Pathogenesis and treatment. Journal of Trauma, 48(1), 171–178.Find this resource:

Namer, B., Kleggetveit, I. P., Handwerker, H., Schmelz, M., & Jorum, E. (2008). Role of TRPM8 and TRPA1 for cold allodynia in patients with cold injury. Pain, 139(1), 63–72. doi:10.1016/j.pain.2008.03.007Find this resource:

Nassar, M. A., Stirling, L. C., Forlani, G., Baker, M. D., Matthews, E. A., Dickenson, A. H., & Wood, J. N. (2004). Nociceptor-specific gene deletion reveals a major role for NaV1.7 (PN1) in acute and inflammatory pain. Proceedings of the National Academy of Sciences of the United States of America, 101(34), 12706–12711. doi:10.1073/pnas.0404915101Find this resource:

Nassini, R., Gees, M., Harrison, S., De Siena, G., Materazzi, S., Moretto, N., … Geppetti, P. (2011). Oxaliplatin elicits mechanical and cold allodynia in rodents via TRPA1 receptor stimulation. Pain, 152(7), 1621–1631. doi:10.1016/j.pain.2011.02.051Find this resource:

Noel, J., Zimmermann, K., Busserolles, J., Deval, E., Alloui, A., Diochot, S., … Lazdunski, M. (2009). The mechano-activated K+ channels TRAAK and TREK-1 control both warm and cold perception. EMBO Journal, 28(9), 1308–1318. doi:10.1038/emboj.2009.57Find this resource:

Obata, K., Katsura, H., Mizushima, T., Yamanaka, H., Kobayashi, K., Dai, Y., … Noguchi, K. (2005). TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury. Journal of Clinical Investigation, 115(9), 2393–2401. doi:10.1172/JCI25437Find this resource:

Obradovic, A., Hwang, S. M., Scarpa, J., Hong, S. J., Todorovic, S. M., & Jevtovic-Todorovic, V. (2014). CaV3.2 T-type calcium channels in peripheral sensory neurons are important for mibefradil-induced reversal of hyperalgesia and allodynia in rats with painful diabetic neuropathy. PLoS One, 9(4), e91467. doi:10.1371/journal.pone.0091467Find this resource:

Ongun, S., Sarkisian, A., & McKemy, D. D. (2018). Selective cold pain inhibition by targeted block of TRPM8-expressing neurons with quaternary lidocaine derivative QX-314. Communications Biology, 1, 53.Find this resource:

Park, S. B., Lin, C. S., Krishnan, A. V., Goldstein, D., Friedlander, M. L., & Kiernan, M. C. (2009). Oxaliplatin-induced neurotoxicity: Changes in axonal excitability precede development of neuropathy. Brain, 132(Pt. 10), 2712–2723. doi:10.1093/brain/awp219Find this resource:

Patel, R., Goncalves, L., Newman, R., Jiang, F. L., Goldby, A., Reeve, J., … Dickenson, A. H. (2014). Novel TRPM8 antagonist attenuates cold hypersensitivity after peripheral nerve injury in rats. Journal of Pharmacology and Experimental Therapeutics, 349(1), 47–55. doi:10.1124/jpet.113.211243Find this resource:

Peier, A. M., Moqrich, A., Hergarden, A. C., Reeve, A. J., Andersson, D. A., Story, G. M., … Patapoutian, A. (2002). A TRP channel that senses cold stimuli and menthol. Cell, 108(5), 705–715.Find this resource:

Quallo, T., Alkhatib, O., Gentry, C., Andersson, D. A., & Bevan, S. (2017). G protein betagamma subunits inhibit TRPM3 ion channels in sensory neurons. Elife, 6, 26138. doi:10.7554/eLife.26138Find this resource:

Samour, M. S., Nagi, S. S., & Mahns, D. A. (2015). Cav3.2-expressing low-threshold C fibres in human hairy skin contribute to cold allodynia—A non-TRPV1- and non-TRPM8-dependent phenomenon. Pain, 156(8), 1566–1575. doi:10.1097/j.pain.0000000000000202Find this resource:

Sandkuhler, J. (2009). Models and mechanisms of hyperalgesia and allodynia. Physiological Review, 89(2), 707–758. doi:10.1152/physrev.00025.2008Find this resource:

Scholz, J., & Woolf, C. J. (2007). The neuropathic pain triad: neurons, immune cells and glia. Nature Neuroscience, 10(11), 1361–1368. doi:10.1038/nn1992Find this resource:

Shields, S. D., Cheng, X., Uceyler, N., Sommer, C., Dib-Hajj, S. D., & Waxman, S. G. (2012). Sodium channel Na(v)1.7 is essential for lowering heat pain threshold after burn injury. Journal of Neuroscience, 32(32), 10819–10832. doi:10.1523/JNEUROSCI.0304–12.2012Find this resource:

Simone, D. A. (1992). Neural mechanisms of hyperalgesia. Current Opinion in Neurobiology, 2(4), 479–483.Find this resource:

Smith, H., & Brooks, J. R. (2014). Capsaicin-based therapies for pain control. Progress in Drug Research, 68, 129–146.Find this resource:

Smith, J. L., Ritchie, J., & Dawson, J. (1915). On the pathology of trench frost-bite. Lancet, 186, 595–598.Find this resource:

Story, G. M., Peier, A. M., Reeve, A. J., Eid, S. R., Mosbacher, J., Hricik, T. R., … Patapoutian, A. (2003). ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell, 112(6), 819–829.Find this resource:

Thresh, J. C. (1876). Isolation of capsaicin. The Pharmaceutical Journal and Transactions, 6, 941–947.Find this resource:

Tilley, S. L., Coffman, T. M., & Koller, B. H. (2001). Mixed messages: Modulation of inflammation and immune responses by prostaglandins and thromboxanes. Journal of Clinical Investigation, 108(1), 15–23. doi:10.1172/JCI13416Find this resource:

Toth, B. I., Konrad, M., Ghosh, D., Mohr, F., Halaszovich, C. R., Leitner, M. G., … Voets, T. (2015). Regulation of the transient receptor potential channel TRPM3 by phosphoinositides. Journal of General Physiology, 146(1), 51–63. doi:10.1085/jgp.201411339Find this resource:

Tsantoulas, C., & McMahon, S. B. (2014). Opening paths to novel analgesics: The role of potassium channels in chronic pain. Trends in Neuroscience, 37(3), 146–158. doi:10.1016/j.tins.2013.12.002Find this resource:

Vandewauw, I., De Clercq, K., Mulier, M., Held, K., Pinto, S., Van Ranst, N., … Voets, T. (2018). A TRP channel trio mediates acute noxious heat sensing. Nature, 555(7698), 662–666. doi:10.1038/nature26137Find this resource:

Vetter, I., Touska, F., Hess, A., Hinsbey, R., Sattler, S., Lampert, A., … Zimmermann, K. (2012). Ciguatoxins activate specific cold pain pathways to elicit burning pain from cooling. EMBO Journal, 31(19), 3795–3808. doi:10.1038/emboj.2012.207Find this resource:

Viana, F. (2016). TRPA1 channels: Molecular sentinels of cellular stress and tissue damage. Journal of Physiology, 594(15), 4151–4169. doi:10.1113/JP270935Find this resource:

Viana, F., de la Pena, E., & Belmonte, C. (2002). Specificity of cold thermotransduction is determined by differential ionic channel expression. Nature Neuroscience, 5(3), 254–260. doi:10.1038/nn809Find this resource:

Voets, T. (2012). TRP channel blamed for burning cold after a tropical fish meal. EMBO Journal, 31(19), 3785–3787. doi:10.1038/emboj.2012.255Find this resource:

Voets, T., Droogmans, G., Wissenbach, U., Janssens, A., Flockerzi, V., & Nilius, B. (2004). The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Nature, 430(7001), 748–754. doi:10.1038/nature02732Find this resource:

von Hehn, C. A., Baron, R., & Woolf, C. J. (2012). Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron, 73(4), 638–652. doi:10.1016/j.neuron.2012.02.008Find this resource:

Vriens, J., Nilius, B., & Voets, T. (2014). Peripheral thermosensation in mammals. Nature Reviews Neuroscience, 15(9), 573–589. doi:10.1038/nrn3784Find this resource:

Vriens, J., Owsianik, G., Hofmann, T., Philipp, S. E., Stab, J., Chen, X., … Voets, T. (2011). TRPM3 is a nociceptor channel involved in the detection of noxious heat. Neuron, 70(3), 482–494. doi:10.1016/j.neuron.2011.02.051Find this resource:

Wahren, L. K., Torebjork, E., & Jorum, E. (1989). Central suppression of cold-induced C fibre pain by myelinated fibre input. Pain, 38(3), 313–319.Find this resource:

Whitaker, J. (2016). Non-freezing cold injury, lessons from history for future prevention. Trauma, 18(3), 178–185.Find this resource:

Wolf, S., & Hardy, J. D. (1941). Studies on pain. Observations on pain due to local cooling and on factors involved in the “cold pressor” effect. Journal of Clinical Investigation, 20(5), 521–533. doi:10.1172/JCI101245Find this resource:

Woolf, C. J. (2011). Central sensitization: Implications for the diagnosis and treatment of pain. Pain, 152(3, Suppl.), S2–S15. doi:10.1016/j.pain.2010.09.030Find this resource:

Yarnitsky, D., & Ochoa, J. L. (1990). Release of cold-induced burning pain by block of cold-specific afferent input. Brain, 113(Pt. 4), 893–902.Find this resource:

Zhang, X., Li, L., & McNaughton, P. A. (2008). Proinflammatory mediators modulate the heat-activated ion channel TRPV1 via the scaffolding protein AKAP79/150. Neuron, 59(3), 450–461. doi:10.1016/j.neuron.2008.05.015Find this resource:

Zimmermann, K., Deuis, J. R., Inserra, M. C., Collins, L. S., Namer, B., Cabot, P. J., … Vetter, I. (2013). Analgesic treatment of ciguatoxin-induced cold allodynia. Pain, 154(10), 1999–2006. doi:10.1016/j.pain.2013.06.015Find this resource:

Zimmermann, K., Leffler, A., Babes, A., Cendan, C. M., Carr, R. W., Kobayashi, J., … Reeh, P. W. (2007). Sensory neuron sodium channel NaV1.8 is essential for pain at low temperatures. Nature, 447(7146), 855–858. doi:10.1038/nature05880Find this resource:

Zygmunt, P. M., & Hogestatt, E. D. (2014). Trpa1. Handbook of Experimental Pharmacology, 222, 583–630. doi:10.1007/978-3-642-54215-2_23Find this resource: