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Review

Thermoreceptors and thermosensitive afferents

Raf J. Schepers, Matthias Ringkamp *

Dept of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21218, USA

Contents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

2. Innocuous temperatures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

2.1. Cold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

2.1.1. Afferent nerve fibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

2.1.2. Transducer molecules for non-noxious cold. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1792.2. Warmth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179


2.2.2. Transducer molecules for non-noxious warmth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179

3. Noxious temperatures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180

3.1. Cold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180


3.1.2. Transducer molecules of noxious cold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180

3.2. Heat. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180


3.2.2. Transducer molecules of noxious heat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

1. Introduction

The skin forms a protective layer around the body against

physical, chemical and thermal environmental challenges. In

addition to providing a physical barrier, theskin serves as a sensory

organ that enables the body to detect stimuli of the outside world

so that an appropriate behavior can be initiated. Thermosensation

is one of the sensory modalities of the skin. It provides (1) a

thermoregulatory afferent signal for homeostatic mechanisms

which keep the body at an optimal working temperature, (2) the

capability to detect potentially noxious thermal stimuli that pose

an immediate threatto the integrityof the integument (i.e. noxious

Neuroscience and Biobehavioral Reviews 34 (2010) 177184

A R T I C L E I N F O

Keywords:

Noxious

Innocuous

TRP

NociceptorSkin

Transduction

Monkey

A B S T R A C T

Cutaneous thermosensation plays an important role in thermal regulation and detection of potentially

harmful thermal stimuli. Multiple classes of primary afferentsare responsive to thermal stimuli. Afferent

nerve fibers mediating the sensation of non-painful warmth or cold seem adapted to convey thermal

information over a particular temperature range. In contrast, nociceptive afferents are oftenactivated by

both, painful cold and heat stimuli. The transduction mechanisms engaged by thermal stimuli have only

recently been discovered. Transient receptor potential (TRP) ion channels that can be activated by

temperatures over specific ranges potentially provide the molecular basis for thermosensation.

However, non-TRP mechanisms are also likely to contribute to the transduction of thermal stimuli. This

review summarizes findings regarding the transduction proteins and the primary afferents activated by

innocuous and noxious cold and heat.

2009 Elsevier Ltd. All rights reserved.

DOI of original article: 10.1016/j.neubiorev.2008.07.009 This paper was originally published in a previous issue of Neuroscience and

Biobehavioral Reviews. For citation purposes please use the original publication

details: Schepers, R.J., Ringkamp, M., 2008. Thermoreceptors and thermosensitive

afferents. Neurosci. Biobehav. Rev., doi:10.1016/j.neubiorev.2008.07.009.

* Corresponding author at: Dept of Neurosurgery, School of Medicine, Johns

Hopkins University, 600 N Wolfe St, Meyer 5-109, Baltimore, MD 21287, USA.

Tel.: +1 410 614 1998; fax: +1 410 955 1032.

E-mail address: [email protected](M. Ringkamp).

Contents lists available atScienceDirect

Neuroscience and Biobehavioral Reviews

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / n e u b i o r e v

0149-7634/$ see front matter 2009 Elsevier Ltd. All rights reserved.

doi:10.1016/j.neubiorev.2009.10.003
http://dx.doi.org/10.1016/j.neubiorev.2008.07.009mailto:[email protected]://www.sciencedirect.com/science/journal/01497634http://dx.doi.org/10.1016/j.neubiorev.2009.10.003http://dx.doi.org/10.1016/j.neubiorev.2009.10.003http://www.sciencedirect.com/science/journal/01497634mailto:[email protected]://dx.doi.org/10.1016/j.neubiorev.2008.07.009

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cold and heat stimuli) (3) afferent signals which contribute to the

identification of objects and materials through touch, e.g. metals

are easily discriminated from wood because metals feel colder

than wood.

Thermal stimuli applied to the skin induce distinct sensations.

Small changes in skin temperature are perceived as warm or cool,

but these sensations adapt quickly. Adaptation of thermal

sensation can be observed over a relatively wide temperature

range. Thermal stimuli that lead to skin temperatures outside this

range lead to non-adapting thermal sensations. With decreasing

stimulus temperatures the quality of sensation may change from

cool, cold, icy to painful. Similarly, stimuli of increasing tempera-

ture cause sensations of warmth, heat and pain. The reported

temperatures that cause these different sensations vary consider-

ably. This variability can be explained by differences in the

characteristics of the stimulus used (temperature ramp rate,

duration and area of thermal stimulus, stimulus history), experi-

mental conditions employed (site of testing, skin condition and

properties, day time of measurement), and individual differences

(previous pain experiences, ethnicity, sex) (Chery-Croze, 1983a).

Cutaneous thermosensation is mediated by a variety of primary

afferent nerve fibers that transduce, encode and transmit thermal

information. Over the last decade, a number of transient receptor

potential (TRP) ion channels have been identified whose activitydepends on the temperature of their environment (Voets et al.,

2004). Each of these receptors operates over a specific temperature

range, thereby providing a potential molecular basis for thermo-

sensation. These specialized thermal receptors are embedded in

the terminals of afferent fibers which end as free nerve endings in

the skin. In humans, 28 differentTRP channels have been identified

and these can be grouped into 6 families (Pedersen et al., 2005). Of

these,members of 3 families,i.e. thevanilloidTRP channels (TRPV),

the melastatin or long TRP channels (TRPM), and the ankyrin

transmembrane protein channels (TRPA) are of particular interest

as thermoreceptors. This review summarizes findings regarding

the different classes of primary afferents involved in innocuous

and noxious thermal sensation and their thermosensors.

2. Innocuous temperatures

2.1. Cold

2.1.1. Afferent nerve fibers

In vivo electrophysiology studies have long demonstrated the

existence of a class of afferent fibers in the skin of various

mammals and frogs which are exclusively activated by cool

stimuli. These so-called cold fibers often exhibit ongoing action

potential activity at normal skin temperatures. The cutaneous

receptive fields of cold fibers consist of a single or multiple cold

sensitive spots and they are unresponsive to mechanical stimula-

tion (Darian-Smith et al., 1973; Dubner et al., 1975; Kenshalo and

Gallegos, 1967). Previous studies in cat located cold receptors at adepth of 100150mm (Hensel et al., 1951) or at the dermalepidermal border (Hensel et al., 1974). Results from more recent

studies in rat suggest that cold fibers project into the epidermis

(Dhaka et al., 2008). At steadystate temperatures cold fibers have a

characteristic stimulus response function which is bell-shaped,

with a maximal steady state activity between 20 and 30 8C and

lower activity at lower and higher temperatures (Darian-Smith

et al., 1973; Dubner et al., 1975; Kenshalo and Duclaux, 1977). The

reported temperature range over which cold fibersare activevaries

(Hensel, 1973b). At maintained temperatures above 40 8C orbelow

17 8C, cold fibers maintain a very low frequency discharge or

become silent. However, some cold fibers can also be activated by

high temperatures in the noxious range (Campero et al., 2001;

Dubner et al., 1975; Kenshalo and Duclaux, 1977; Long, 1977), and

this activation may be the basis for the paradoxical cold sensation

that can be elicited by stimulation of cold spots with noxious heat

stimuli. Cold afferents respond vigorously when the skin is actively

cooled; conversely, when the skin is warmed, activity is inhibited.

These dynamic responses are transient (Darian-Smith et al., 1973;

Dubner et al., 1975; Kenshalo and Duclaux, 1977), i.e. the activity

of the neuron decreases to a steady level shortly after reaching a

discharge rate appropriate for the steady state temperature

(Hensel and Zotterman, 1951c).

Cold fibers are activated by menthol (Hensel and Zotterman,

1951a). At temperatures when cold fibers are already active,

menthol increases the stationary discharge rate drastically, i.e. it

sensitizes cold fibers. Upon repetitive stimulus presentation at

short intervals (2 8C/s); static tempera-

tures do not induce activity. Since their response to cold stimuli is

small compared to that induced by mechanical stimuli, their role in

the percept of cold is questionable. The above studies demonstrate

that C fibers respond to innocuous cold stimuli. Yet, a role of C fiber

afferents in the sensation of innocuous cold is unlikely, since

psychophysical experiments in humans employing differential

nerve fiber blocks indicate that cold sensation is mediated by smallmyelinated (Ad) afferents (Mackenzie et al., 1975).

Cold sensitivity can also be found in large myelinated afferents

which respond vigorously to mechanical stimuli. Thus, about half

of the slowly adapting mechanoreceptors (SA fibers), i.e. the

Merkel discs in superficial skin layers and the Rufini endings in

deeper skin layers, respond to cooling thermal gradients from

normal skin temperature to 14.5 8C (Cahusac and Noyce, 2007;

Duclaux and Kenshalo, 1972; Hensel and Zotterman, 1951b; Iggo

and Muir, 1969; Tapper, 1965). The sensitivity of these mechan-

oreceptors to cold stimulation provides an explanation for Webers

deception or the silverThaler (a coin used in Europe in the 1819th

century) illusion, i.e. the perception that cold objects appear

heavier than warm objects. Nevertheless, it is rather unlikely that

activity in large myelinated afferents actively contributes to the

R.J. Schepers, M. Ringkamp / Neuroscience and Biobehavioral Reviews 34 (2010) 177184178

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sensation of cool, since the response to cool is negligible compared

to one following mechanical stimulation or in comparison to the

response of cold fibers (Johnson et al., 1973).

2.1.2. Transducer molecules for non-noxious cold

The transient receptor potential melastatin 8 (TRPM8) ion

channel is activated by temperatures below 26 8C, and it is

expressed in about 15% of small dorsal root ganglion (DRG)

neurons (McKemy et al., 2002; Peier et al., 2002). TRPM8 is

activated by agents known to produce the sensation of cold in

humans, e.g. menthol, eucalyptol and the synthetic super-cooling

agent icilin. Icilin is structurally not related to menthol or

eucalyptol, and the amino-acid residues of the channel underlying

icilin sensitivity are different as compared to menthol (Chuang

et al., 2004). Channel activation by cold and menthol involve a

PI(4,5)P2 dependent mechanism and channel inactivation is likely

due to PI(4,5)P2 depletion by hydrolysis through phospolipase C

(Rohacs et al., 2005), whereas channel activation by icilin is

dependent on the availability of calcium (Chuang et al., 2004). In

slowly adapting mechanoreceptors, capsazepine, a TRPV1 blocker

with antagonistic activity at TRPM8, blocked cold-evoked

responses, whereas its agonist, ()-menthol, enhanced cold

responses (Cahusac and Noyce, 2007). Animals in which TRPM8

expression has been abolished by gene knock out (KO) showreduced sensitivity to cold stimuli; importantly, however, their

behavioral responses to noxious cold temperatures (

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3. Noxious temperatures

3.1. Cold


The cold temperatures that produce the sensation of pain in

human vary considerably (Chery-Croze, 1983a), with tempera-

tures between 10 and 15 8C and about 18 8C inducing the sensation

of pain in glabrous and hairy skin, respectively (Davis, 1998;

Harrison and Davis, 1999; Yarnitsky and Ochoa, 1990). With slow

temperature ramps the pain threshold temperature is higher than

with fast ramps, and cold stimuli become more painful ( Harrison

and Davis, 1999). The intensity of cold pain increases linearly with

stimulus intensity between 20 and 0 8C (Chery-Croze, 1983b).

Noxious cold stimuli cause distinct sensations such as pricking,

burning and aching and heat (Davis and Pope, 2002; Harrison and

Davis, 1999), suggesting that differentfiber populations,i.e. Ad andC fibers, are activated by these stimuli. Mechanosensitive Adafferent fibers (A-MSA), including those sensitive to heat stimuli

can be activated by noxious cold (Simone and Kajander, 1996;

Simone and Kajander, 1997). Even though the response thresholds

vary considerably between fibers (Georgopoulos, 1976; Simone

and Kajander, 1997), the average response, the discharge rate and

the peak discharge rate of Adnociceptors increases monotonicallywith the decrease in temperature (Cain et al., 2001; Simone and

Kajander, 1997). Instead of signaling the intensity of a cold

stimulus, A-MSA fibers might encode the pricking sensation

associatedwith noxious cold stimuli. Indeed, cold induced pricking

sensation is largely reduced when Ad fibers are blocked (Davis,1998).

In addition to Ad fibers, C fiber nociceptors can be excited bynoxious cold (Bessou and Perl, 1969; Campero et al., 1996;

Georgopoulos, 1976, 1977; Kumazawa and Perl, 1977; LaMotte

and Thalhammer, 1982; Simone and Kajander, 1996; Torebjork,

1974) and they may therefore contribute to the sensation of cold

pain. Similar to Ad fibers, most of cold sensitive C fibers arepolymodal, i.e. they are also responsive to mechanical and heat

stimuli, and their thresholdtemperatures foractivation vary over awide range with values above 20 8C to values below 10 8C(Cain

et al., 2001; Campero et al., 1996; Simone and Kajander, 1996).

Analogous to A-MSAs, the discharge frequency of mechanosensi-

tive C fiber afferents exhibits a positive correlation with the

absolute value of the low temperature stimulus (Campero et al.,

1996; LaMotte and Thalhammer, 1982; Saumet et al., 1985;

Simone and Kajander, 1996), matching the psychophysical

function described for cold pain in humans between 20 and 0 8C

(Chery-Croze, 1983b).

Arndt and colleagues hypothesized that deeper (peri)vascular

nociceptors encode cold pain (Arndt and Klement, 1991; Klement

and Arndt, 1991, 1992) since the cold stimulus itself is able to

impair the conduction of the superficial nerve endings. Indeed,

these unmyelinated nerve segments fail to propagate actionpotentials when they are exposed to temperatures of 32 8C (Franz

and Iggo, 1968; Hensel, 1973a; Paintal, 1965a,b). Since cold pain

persists and can even increase in intensity when the superficial

skin is already numbed by surface cooling, and since cold pain is

relieved by perivenous or intravenous administration of a local

anesthetics, the (peri)vascular nociceptors likely play a role in

signaling noxious cold sensation (Arndt and Klement, 1991;

Klement and Arndt, 1992).

Previously, Hensel and co-workers described a subset of cold

fibers in the nose of the cat for which the maximum discharge rate

occurred for a static skin surface temperature of 15, 10 and 5 and

even 5 8C, instead of 2025 8C for the regular cold fibers in the

cat (Duclaux et al., 1980). Similar cold fibers were not identified in

monkey skin (Darian-Smith et al., 1973; Dubner et al., 1975; Iggo,

1969), and therefore a role of these fibers seems limited to detect

cold exposure to the nose.

In summary, a noxious cold stimulus activates Ad and Cnociceptors. During an Ad fiber block, when C afferents are stillactive, the percept of a noxious cold stimulus is experienced as

burning orheat(Davis, 1998; Mackenzieet al., 1975; Wahrenet al.,

1989; Yarnitsky and Ochoa, 1990). These data suggest that input

from the Ad fibers that signal cool sensation either blocks ormodifies the C fiber input into the central nervous system and that

the sensory experience induced by noxious cold stimuli depends

on the integration of neuronal activity in small myelinated and

unmyelinated afferents.

3.1.2. Transducer molecules of noxious cold

Electrophysiology data demonstrate that TRPA1 is activated by

temperatures of ca. 17 8C (i.e. at temperatures about 5 8C lower

than for TRPM8) making it a prime candidate for transducing

noxious cold (Story et al., 2003; Story and Gereau, 2006). TRPA1 is

activated by icilin (Story et al., 2003). In expression systems TRPA1

can be directly activated by intracellular calcium (Zurborg et al.,

2007), andactivation by icilin requires calcium (Doerner). TRPA1 is

insensitive to menthol and capsaicin (Bautista et al., 2006; Jordt

et al., 2004). The role of TRPA1 in sensing noxious cold, however,

needs further clarification. Studies in TRPA1 KO mice show either areduced (Kwan et al., 2006) or a normal sensitivity to cold

temperatures (Bautista et al., 2006). Furthermore, DRG neurons

from TRPA1 KO animals are still sensitive to noxious cold (Bautista

et al., 2006, 2007), and the remaining cold sensitivity in TRPM8 KO

animals is independent of TRPA1 (Bautista et al., 2007). Conflicting

results can also be found inin vitroelectrophysiology experiments

where cold activation of TRPA1 appears present in (over)expres-

sion systems but not in native DRG neurons (Reid, 2005). However,

treatment with antisense oligonucleotides directed against TRPA1

reduced cold hyperalgesia induced by inflammation or nerve

injury(Obata et al., 2005), suggesting that TRPA1may sense cold in

these disease states.

Alternatively, peripheral TRPA1 channels may operate as

peripheral mechanosensors, e.g. during inflammation or neuro-pathy. Yet, behavioral observations to endorse such function are

contradictory (Kwan et al., 2006; Obata et al., 2005). Nevertheless,

in support of mechanosensation, osmosensitivity of TRPA1 has

been demonstrated (Zhang et al., 2008).

Recent experimental evidence suggests that the tetrodotoxin

(TTX) resistant sodium channel NaV1.8 is critical for the detection

of noxious cold stimuli (Zimmermann et al., 2007). Cooling

enhances slow inactivation of TTX sensitive sodium channels,

and NaV1.8 does not undergo such cold induced inactivation.

Therefore, action potential generation and conduction in primary

afferents in a cold environment becomes dependent on NaV1.8.

Indeed, NaV1.8 KO animals do not show the typical behavior

(jumping, foot lifting) when placed on a cold plate, suggesting that

they lost the ability to detect noxious cold (Zimmermann et al.,2007).

3.2. Heat


Following heat stimulation of hairy skin of the lower arm or

dorsum of the hand or foot two distinct pain sensations are usually

felt: a first, sharp or pricking pain, which appears almost

instantaneously (0.4 s following onset of the heat stimulus)

followed by a second, dull or burning pain that appears later (1

2 s) (Campbell and LaMotte, 1983; Chery-Croze, 1983a). The two

components of heat pain are felt distinctly when the stimulus is

applied at the distal extremities. When the stimulus is applied

more proximately, e.g. the shoulder or back, the sensations merge


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into each other. Notably, heat stimulation of the glabrous skin (e.g.

palm) does not induce a dual pain sensation (Campbell and

LaMotte, 1983). The fast onset of the first pain sensation indicates

that it is mediated by fast conducting Adfibers, whereas the longlatency of the second pain sensation is consistent with the

activation of the slower conducting C fibers (Campbell and

LaMotte, 1983; Gronroos et al., 1996; Price et al., 1977). Consistent

with this model, an A fiber block (e.g. pressure or ischemic block)

abolishes first pain (Price et al., 1977). Taken together these

findings demonstrate that heat pain is mediated by activity in Adand C fibers.

Based on teased fiber recordings from peripheral nerves in

monkey, A fiber nociceptors have been classified into two types

according to their responsiveness to heat stimuli (Treede et al.,

1995; Treede et al., 1998). Type I afferents have high heat

thresholds to short lasting heat stimuli (median threshold>53 8C).

Upon stimulation with intense heat stimuli (53 8C, 30 s), their

activation is delayed (average response latency about 5 s) with a

late peak discharge, and their response increases during the

stimulation. Type I afferents are present in glabrous and hairy skin.

Following a burn injury, type I afferents become sensitized to heat

stimuli (Treede et al., 1995), and they mediate thermal hyper-

algesia from glabrous skin (Meyer and Campbell, 1981b).

Type II afferents, in contrast, have lower heat thresholds(47 8C), respond vigorously and immediately (43 8C (Caterina et al., 1997; Jordt and Julius, 2002).

In addition to heat, TRPV1 is also activated by capsaicin, the

pungent ingredient of chili peppers (Caterina et al., 1997). In mice,

TRPV1 is expressed primarily on small/medium diameter pepti-

dergic sensory neurons, characteristic of nociceptive Ad and Cnociceptors (Caterina et al., 1997; Tominaga et al., 1998).

Consistent with the expression of TRPV1 in medium size DRG

cells is the observation that capsaicin can activate Adnociceptiveafferents with a type II heat response (Ringkamp et al., 2001).

TRPV1 KO animals showed normal behavioral responses to

noxious heat stimuli (Caterina et al., 2000; Davis et al., 2000). In

cultured sensory neurons and skin-nerve preparations from TRPV1

R.J. Schepers, M. Ringkamp / Neuroscience and Biobehavioral Reviews 34 (2010) 177184 181

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KO mice, thermal sensitivity wasdefective butnot absent(Caterina

et al., 2000; Davis et al., 2000; Zimmermann et al., 2005 ) (see,

however,Woodbury et al., 2004). Therefore, other heat transduc-

tion mechanisms besides TRPV1 must exist that can detect

temperatures between 45 and 50 8C. TRPV1 channels are sensitized

by inflammatory mediators such as low pH, bradykinin, nerve

growth factor, and prostaglandins (Tominaga and Caterina, 2004).

Indeed, signs of thermal hyperalgesia following inflammation are

drastically reduced in TRPV1 KO animals (Caterina et al., 2000;

Davis et al., 2000), demonstrating that TRPV1 plays a crucial role in

sensitization of nociceptors to heat stimuli and inflammatory pain.

TRPV2 is activated by high temperatures (heat thresholds

>52 8C), but it is unresponsive to typical activators of TRPV1 (e.g.

low pH, capsaicin). Because of its high heat threshold, its

expression in medium and large DRG cells, and its sensitization

by repetitive heat stimuli, TRPV2 may be the thermosensor

mediating the type I heat response in Ad nociceptors (Caterinaet al., 1999). Indeed the majority of such afferents in monkey are

unresponsive to intradermal capsaicin injection (Ringkamp et al.,

2001). The finding that many of the heat sensitive primary

afferents in TRPV1 KO mice do not express TRPV2 indicates that

noxious heat stimuli are not exclusively mediated through TRPV1

and TPRV2 (Woodbury et al., 2004). Indeed, TRPV3 channels can

also be activated by temperatures >50 8C, i.e. stimuli that areclearly noxious; capsaicin, capsazepine and low pH do not activate

TRPV3 (Peier et al., 2002; Smith et al., 2002). Since withdrawal

from acute thermal stimuli >50 8C is impaired in TRPV3 KO mice

(Moqrich et al., 2005), these data also indicate that TRPV3 and

TRPV1 and V2 all might contribute to noxious heat sensation.

Interestingly, TRPV1 function is increased when co-expressed with

TRPV3, suggesting that these channels can form heterodimers

(Smith et al., 2002).

4. Conclusions

Multiple classes of afferent cutaneous fibers have the ability

to encode thermal stimuli. Most of these afferents have

characteristic response functions enabling them to encode theintensity of the stimulus. The sensations of warmth and cold are

mediated through the activity in dedicated primary afferents, i.e.

warm and cold fibers. The labeled lines for warmth and cold are

preserved in spinal, thalamic and cortical neurons (Craig, 2003;

Craig and Andrew, 2002; Craig and Dostrovsky, 2001). Noxious

cold and noxious heat stimuli are detected by Ad and C fibernociceptors. The activity in these afferents correlates well with

psychophysical pain ratings during the application of noxious

thermal stimuli.

The TRPchannel family provides a group of molecules equipped

to detect thermal changes. The full range of temperatures, from

noxious cold to noxious heat, appears to be transduced by the

activity in these ionchannels.TRPM8 andTRPV3/4 encode cool and

warm, respectively, TRPA1 transduces noxious cold and TRPV1/2sense noxious heat. Some of the thermosensitive TRP channels

respond to chemical and mechanical stimuli as well. For example,

TRPV4 has been reported to play a role in mechano-transduction

(Liedtke, 2007; Liedtke and Friedman, 2003; Suzuki et al., 2003),

TRPV2 can be activated by membrane stretch and hypotonic

stimulation (Muraki et al., 2003), and TRPV1 can be activated by

protons and anandamide (Tominaga et al., 1998; Zygmunt et al.,

1999). In addition, some of these channels are expressed in organs

where temperatures that typically activate these channels are

unlikely to occur, e.g. TRPV1 receptors are expressed in cells of the

inner ear (Balaban et al., 2003; Mezey et al., 2000; Sasamura et al.,

1998; Zheng et al., 2003). Therefore, the role of these TRP channels

is unlikely to be restricted to thermosensation, and it is likely that

they act as polymodal receptors.

While the discovery of thermosensitive TRP channels has

greatly enhanced our understanding of transduction mechanisms

of thermal stimuli, findings in animals with selective gene

deletions clearly indicate that multiple and yet unknown

transduction mechanisms are engaged by thermal stimuli. Further

research is needed to uncover these transduction mechanisms.

References

Alessandri-Haber, N., Yeh, J.J., Boyd, A.E., Parada, C.A., Chen, X., Reichling, D.B.,Levine, J.D., 2003. Hypotonicity induces TRPV4-mediated nociception in rat.Neuron 39, 497511.

Arndt, J.O., Klement, W., 1991. Pain evoked by polymodal stimulation of hand veinsin humans. J. Physiol. (Lond.) 440, 467478.

Balaban, C.D., Zhou, J., Li, H.S., 2003. Type 1 vanilloid receptor expression bymammalian inner ear ganglion cells. Hear. Res. 175, 165170.

Bautista,D.M., Jordt, S.-E., Nikai, T., Tsuruda,P.R., Read, A.J.,Poblete, J., Yamoah,E.N.,Basbaum, A.I., Julius, D., 2006. TRPA1 mediates the inflammatory actions ofenvironmental irritants and proalgesic agents. Cell 124, 12691282.

Bautista, D.M., Siemens, J., Glazer, J.M., Tsuruda, P.R., Basbaum, A.I., Stucky, C.L.,Jordt, S.-E., Julius, D., 2007. The menthol receptor TRPM8 is the principaldetector of environmental cold. Nature 448, 204208.

Beitel, R.E., Dubner, R., 1976. Response of unmyelinated (C) polymodal nociceptorsto thermal stimuli applied to monkeys face. J. Neurophysiol. 39, 11601175.

Bessou, P., Perl, E.R., 1969. Response of cutaneous sensory units with unmyelinatedfibers to noxious stimuli. J. Neurophysiol. 32, 10251043.

Cahusac,P.M.,Noyce,R., 2007. A pharmacologicalstudy of slowly adaptingmechan-oreceptors responsive to coldthermalstimulation. Neuroscience 148,489500.

Cain, D.M., Khasabov, S.G., Simone, D.A., 2001. Response properties of mechanor-eceptors and nociceptors in mouse glabrous skin: an in vivo study. J. Neuro-physiol. 85, 15611574.

Campbell, J.N.,LaMotte, R.H.,1983. Latency to detection of firstpain. Brain Res. 266,203208.

Campbell, J.N., Meyer, R.A., 1983. Sensitization of unmyelinated nociceptive affer-ents in the monkey varies with skin type. J. Neurophysiol. 49, 98110.

Campero, M., Serra, J., Bostock, H., Ochoa, J.L., 2001. Slowly conducting afferentsactivated by innocuous low temperature in human skin. J. Physiol. 535, 855865.

Campero, M., Serra, J., Ochoa, J.L., 1996. C-polymodal nociceptors activated bynoxious low temperature in human skin. J. Physiol. 497 (Pt 2), 565572.

Caterina, M.J.,Leffler, A.,Malmberg, A.B., Martin,W.J., Trafton,J., Petersen-Zeitz,K.R.,Koltzenburg, M., Basbaum, A.I., Julius, D., 2000. Impaired nociception and painsensation in mice lacking the capsaicin receptor. Science 288, 306313.

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, 436441.

Caterina, M.J., Schumacher, M.A., Tominaga, M., Rosen, T.A., Levine, J.D., Julius, D.,1997. The capsaicin receptor: a heat-activated ion channelin the painpathway.Nature 389, 816824.

Chery-Croze, S., 1983a. Painful sensation induced by a thermal cutaneous stimulus.Pain 17, 109137.

Chery-Croze, S., 1983b. Relationship between noxious cold stimuli and the magni-tude of pain sensation in man. Pain 15, 265269.

Chuang, H.H., Neuhausser, W.M., Julius, D., 2004. The super-cooling agent icilinreveals a mechanism of coincidence detection by a temperature-sensitive TRPchannel. Neuron 43, 859869.

Craig, A.D., 2003. A newview of painas a homeostatic emotion.TrendsNeurosci. 26,303307.

Craig, A.D., Andrew, D., 2002. Responses of spinothalamic lamina I neurons torepeated brief contact heat stimulation in the cat. J. Neurophysiol. 87, 19021914.

Craig, A.D., Dostrovsky, J.O., 2001. Differential projections of thermoreceptive andnociceptive lamina I trigeminothalamic and spinothalamicneurons in the cat.J.Neurophysiol. 86, 856870.

Croze, S., Duclaux,R., Kenshalo, D.R.,1976. Thethermalsensitivity of the polymodal

nociceptors in the monkey. J. Physiol. 263, 539562.Darian-Smith, I., Johnson, K.O., Dykes, R., 1973. Cold fiber population innervating

palmar and digital skin of the monkey: responses to cooling pulses. J. Neuro-physiol. 36, 325346.

Darian-Smith, I., Johnson, K.O., LaMotte, C., Shigenaga, Y., Kenins, P., Champness, P.,1979. Warm fibers innervating palmar and digital skin of the monkey:responses to thermal stimuli. J. Neurophysiol. 42, 12971315.

Davis, J.B., Gray, J., Gunthorpe, M.J., Hatcher, J.P., Davey, P.T., Overend, P., Harries,M.H., Latcham, J., Clapham, C., Atkinson, K., Hughes, S.A., Rance, K., Grau, E.,Harper, A.J., Pugh, P.L., Rogers, D.C., Bingham, S., Randall, A., Sheardown, S.A.,2000. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia.Nature 405, 183187.

Davis, K.D.,1998. Cold-induced painand prickle in the glabrousand hairy skin. Pain75, 4757.

Davis, K.D., Pope, G.E., 2002. Noxious cold evokes multiple sensations with distincttime courses. Pain 98, 179185.

Dhaka, A., Earley, T.J., Watson, J., Patapoutian, A., 2008. Visualizing cold spots:TRPM8-expressing sensory neurons and their projections. J. Neurosci. 28, 566575.


8/12/2019 Sche Pers 10

7/8

Dubner, R., Sumino, R., Wood, W.I., 1975. A peripheral cold fiber populationresponsive to innocuous and noxious thermal stimuli applied to monkeys face.

J. Neurophysiol. 38, 13731389.Duclaux, R., Kenshalo, D.R., 1972. The temperature sensitivity of the type I slowly

adapting mechanoreceptors in cats and monkeys. J. Physiol. 224, 647664.Duclaux, R., Kenshalo Sr., D.R., 1980. Response characteristics of cutaneous warm

receptors in the monkey. J. Neurophysiol. 43, 115.Duclaux, R., Schafer, K., Hensel, H., 1980. Response of cold receptors to low skin

temperatures in nose of the cat. J. Neurophysiol. 43, 15711577.Franz, D.N., Iggo, A., 1968. Conduction failure in myelinated and non-myelinated

axons at low temperatures. J. Physiol. 199, 319345.

Georgopoulos, A.P., 1976. Functional properties of primary afferent units probablyrelated to pain mechanisms in primate glabrous skin. J. Neurophysiol. 39,7183.

Georgopoulos, A.P., 1977. Stimulusresponse relations in high-threshold mechan-othermal fibers innervating primate glabrous skin. Brain Res. 128, 547552.

Gronroos, M., Reunala, T., Pertovaara, A., 1996. Influence of selective nerve fiberblocks on argon laser-induced thermal pain in the human skin. Neurosci. Lett.211, 143145.

Guler, A.D., Lee, H., Iida, T., Shimizu, I., Tominaga, M., Caterina, M., 2002.Heat-evoked activation of the ion channel, TRPV4. J. Neurosci. 22, 64086414.

Gybels, J., Handwerker, H.O., Van Hees, J., 1979. A comparison between the dis-charges of human nociceptive nerve fibers and the subjects ratings of hissensations. J. Physiol. (Lond.) 292, 193206.

Harrison, J.L., Davis, K.D., 1999. Cold-evoked pain varies with skin type and coolingrate: a psychophysical study in humans. Pain 83, 123135.

Hensel, H., 1973a. Thermal Sensations and Thermoreceptors in Man. Springfield,Charles C. Thomas.

Hensel, H., 1973b. Cutaneous thermoreceptors. In: Iggo, A. (Ed.), SomatosensorySystem, Handbook of Physiology, vol 2., SpringerVerlag, Berlin Heidelberg, New

York, pp 79100.Hensel, H., Andres, K.H., von, D.M., 1974. Structure and function of cold receptors.

Pflugers Arch. 352, 110.Hensel, H., Iggo, A., 1971. Analysis of cutaneous warm and cold fibres in primates.

Pflugers Arch. 329, 18.Hensel, H., Kenshalo, D.R., 1969. Warm receptors in the nasal region of cats. J.

Physiol. 204, 99112.Hensel, H., STROM, L., Zotterman, Y., 1951. Electrophysiological measurements of

depth of thermoreceptors. J. Neurophysiol. 14, 423429.Hensel, H., Zotterman, Y., 1951a. Theeffectof menthol on thethermoreceptors. Acta

Physiol. Scand. 24, 2734.Hensel, H., Zotterman, Y., 1951b. The response of mechanoreceptors to thermal

stimulation. J. Physiol. 115, 1624.Hensel, H., Zotterman, Y., 1951c. The responses of the cold receptors to constant

cooling. Acta Physiol. Scand. 22, 96105.Iggo, A., 1969. Cutaneous thermoreceptors in primates and sub-primates. J. Physiol.

(Lond.) 200, 403430.Iggo, A., Muir, A.R., 1969. The structure and function of a slowly adapting touch

corpuscle in hairy skin. J. Physiol. 200, 763796.

Johnson, K.O., Darian, S.I., LaMotte, C., 1973. Peripheral neural determinants oftemperature discrimination in man: a correlative study of responses to coolingskin. J. Neurophysiol. 36, 347370.

Jordt, S.-E., Bautista, D.M., Chuang, H.H., McKemy, D.D., Zygmunt, P.M., Hogestatt,E.D., Meng, I.D., Julius, D., 2004. Mustard oils and cannabinoids excite sensorynerve fibres through the TRP channel ANKTM1. Nature 427, 260265.

Jordt, S.-E., Julius, D., 2002. Molecular basis for species-specific sensitivity to hotchili peppers. Cell 108, 421430.

Kenshalo, D.R., Duclaux, R., 1977. Response characteristics of cutaneous coldreceptors in the monkey. J. Neurophysiol. 40, 319332.

Kenshalo, D.R., Gallegos, E.S., 1967. Multiple temperature-sensitive spots inner-vated by single nerve fibers. Science 158, 10641065.

Klement, W., Arndt, J.O., 1991. Pain but no temperature sensations are evoked bythermal stimulation of cutaneous veins in man. Neurosci. Lett. 123, 119122.

Klement, W., Arndt, J.O., 1992. The role of nociceptors of cutaneous veins in themediation of cold pain in man. J. Physiol. (Lond.) 449, 7383.

Konietzny, F., 1984. Peripheral neural correlates of temperature sensations in man.Hum. Neurobiol. 3, 2132.

Kumazawa, T., Perl, E.R., 1977. Primate cutaneous sensory units with unmyelinated(C) afferent fibers. J. Neurophysiol. 40, 13251338.Kwan, K.Y., Allchorne, A.J., Vollrath, M.A., Christensen, A.P., Zhang, D.S., Woolf, C.J.,

Corey, D.P., 2006. TRPA1 contributes to cold, mechanical, and chemical noci-ception but is not essential for hair-cell transduction. Neuron 50, 277289.

LaMotte, R.H., Campbell, J.N., 1978. Comparison of responses of warm and noci-ceptive C-fiber afferents in monkey with human judgements of thermal pain. J.Neurophysiol. 41, 509528.

LaMotte, R.H., Thalhammer, J.G., 1982. Response properties of high-thresholdcutaneous cold receptors in the primate. Brain Res. 244, 279287.

Lee, H., Iida,T., Mizuno,A., Suzuki, M., Caterina, M.J., 2005. Altered thermal selectionbehaviorin micelackingtransient receptorpotential vanilloid4. J. Neurosci. 25,13041310.

Liedtke, W., 2007. TRPV channels role in osmotransduction and mechanotransduc-tion. Handb. Exp. Pharmacol. 473487.

Liedtke, W., Friedman, J.M., 2003. Abnormal osmotic regulation in trpv4/ mice.Proc. Natl. Acad. Sci. U.S.A. 100, 1369813703.

Long, R.R., 1977. Sensitivity of cutaneous cold fibers to noxious heat: paradoxicalcold discharge. J. Neurophysiol. 40, 489502.

Mackenzie, R.A., Burke, D., Skuse, N.F., Lethlean, A.K., 1975. Fibre function andperception during cutaneous nerve block. J. Neurol. Neurosurg. Psychiatry 38,865873.

Madrid, R., Donovan-Rodriguez, T., Meseguer, V., Acosta, M.C., Belmonte, C.,Viana, F., 2006. Contribution of TRPM8 channels to cold transduction inprimary sensory neurons and peripheral nerve terminals. J. Neurosci. 26,1251212525.

McKemy, D.D., Neuhausser, W.M., Julius, D., 2002. Identification of a cold receptorreveals a general role for TRP channels in thermosensation. Nature 416, 5258.

Meyer, R.A.,Campbell, J.N.,1981a.Evidence fortwo distinctclassesof unmyelinatednociceptive afferents in monkey. Brain Res. 224, 149152.

Meyer, R.A., Campbell, J.N., 1981b. Myelinated nociceptiveafferents account for thehyperalgesia that follows a burn to the hand. Science 213, 15271529.Meyer, R.A., Campbell, J.N., 1981c. Peripheral neural coding of pain sensation. Johns

Hopkins APL Tech. Digest 2, 164171.Mezey, E., Toth, Z.E., Cortright, D.N., Arzubi, M.K., Krause, J.E., Elde, R., Guo, A.,

Blumberg, P.M., Szallasi, A., 2000. Distribution of mRNA for vanilloid receptorsubtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous systemof the rat and human. Proc. Natl. Acad. Sci. U.S.A. 97, 36553660.

Moqrich, A., Hwang, S.W., Earley, T.J., Petrus, M.J., Murray, A.N., Spencer, K.S.,Andahazy, M., Story, G.M., Patapoutian, A., 2005. Impaired thermosensationin mice lacking TRPV3, a heat and camphor sensor in the skin. Science 307,14681472.

Munns, C., Alqatari,M., Koltzenburg, M., 2007.Many coldsensitiveperipheralneuronsof the mouse do not express TRPM8 or TRPA1. Cell Calcium 41, 331342.

Muraki, K., Iwata, Y., Katanosaka, Y., Ito, T., Ohya, S., Shigekawa, M., Imaizumi, Y.,2003. TRPV2 is a component of osmotically sensitive cation channels in murineaortic myocytes. Circ. Res. 93, 829838.

Obata, K., Katsura, H., Mizushima, T., Yamanaka, H., Kobayashi, K., Dai, Y., Fukuoka,T., Tokunaga, A., Tominaga, M., Noguchi, K., 2005. TRPA1 induced in sensory

neuronscontributesto coldhyperalgesia after inflammation and nerve injury. J.Clin. Invest. 115, 23932401.

Paintal, A.S., 1965a. Block of conduction in mammalian myelinated nerve fibres bylow temperatures. J. Physiol. 180, 119.

Paintal, A.S., 1965b. Effects of temperature on conduction in single vagal andsaphenous myelinated nerve fibres of the cat. J. Physiol. 180, 2049.

Pedersen, S.F.,Owsianik,G., Nilius, B., 2005. TRPchannels: anoverview. CellCalcium38, 233252.

Peier, A.M., Moqrich, A., Hergarden, A.C., Reeve, A.J., Andersson, D.A., Story, G.M.,Earley, T.J., Dragoni, I., McIntyre, P., Bevan, S., Patapoutian, A., 2002. A TRPchannel that senses cold stimuli and menthol. Cell 108, 705715.

Peng, Y.B., Ringkamp, M., Meyer, R.A., Campbell, J., 2003. Fatigue and paradoxicalenhancement of heat response in C-fiber nociceptors from cross-modal excita-tion. J. Neurosci. 23, 47664774.

Price, D.D., Hu, J.W., Dubner, R., Gracely, R.H., 1977. Peripheral suppression of firstpainand central summationof second painevokedby noxious heatpulses.Pain3, 5768.

Reid, G., 2005. ThermoTRP channels and cold sensing: what are they really up to?Pflugers Arch. 451, 250263.

Ringkamp, M., Peng, Y.B., Wu, G., Hartke, T.V., Campbell, J.N., Meyer, R.A., 2001.Capsaicin responses in heat-sensitive and heat-insensitive A-fiber nociceptors.

J. Neurosci. 21, 44604468.Rohacs, T., Lopes, C.M., Michailidis, I., Logothetis, D.E., 2005. PI(4,5)P2 regulates the

activation and desensitization of TRPM8 channelsthrough theTRP domain. Nat.Neurosci. 8, 626634.

Sasamura,T., Sasaki,M., Tohda,C., Kuraishi, Y., 1998. Existence of capsaicin-sensitiveglutamatergic terminals in rat hypothalamus. Neuroreport 9, 20452048.

Saumet, J.-L., Chery-Croze, S., Duclaux, R., 1985. Response of cat skin mechan-othermal nociceptors to cold stimulation. Brain Res. Bull. 15, 529532.

Schmidt, R., Schmelz, M., Forster, C., Ringkamp, M., Torebjork, E., Handwerker, H.,1995. Novel classes of responsive and unresponsive C nociceptors in humanskin. J. Neurosci. 15, 333341.

Schmidt, R., Schmelz, M., Ringkamp, M., Handwerker, H.O., Torebjork, H.E., 1997.Innervation territories of mechanically activated C nociceptor units in humanskin. J. Neurophysiol. 78, 26412648.

Simone, D.A., Kajander, K.C., 1996. Excitation of rat cutaneous nociceptors bynoxious cold. Neurosci. Lett. 213, 5356.

Simone, D.A., Kajander, K.C., 1997. Responses of cutaneous A-fiber nociceptors tonoxious cold. J. Neurophysiol. 77, 20492060.Smith, G.D.,Gunthorpe, M.J., Kelsell, R.E.,Hayes, P.D., Reilly, P., Facer, P., Wright, J.E.,

Jerman, J.C., Walhin, J.P., Ooi, L., Egerton, J., Charles, K.J., Smart, D., Randall, A.D.,Anand, P., Davis, J.B.,2002. TRPV3 is a temperature-sensitivevanilloid receptor-like protein. Nature 418, 186190.

Story, G.M., Gereau, R.W., 2006. Numbing the senses: role of TRPA1 in mechanicaland cold sensation. Neuron 50, 177180.

Story, G.M., Peier, A.M., Reeve, A.J., Eid, S.R., Mosbacher, J., Hricik, T.R., Earley, T.J.,Hergarden, A.C., Andersson, D.A., Hwang, S.W., McIntyre, P., Jegla, T., Bevan, S.,Patapoutian, A., 2003. ANKTM1, a TRP-like channel expressed in nociceptiveneurons, is activated by cold temperatures. Cell 112, 819829.

Sumino, R., Dubner, R., Starkman, S., 1973. Responses of small myelinatedwarm fibers to noxious heat stimuli applied to the monkeys face. BrainRes. 62, 260263.

Suzuki, M., Mizuno, A., Kodaira, K., Imai, M., 2003. Impaired pressure sensation inmice lacking TRPV4. J. Biol. Chem. 278, 2266422668.

Tapper, D.N., 1965. Stimulusresponse relationships in the cutaneous slowly-adapting mechanoreceptor in hairy skin of the cat. Exp. Neurol. 13, 364385.

R.J. Schepers, M. Ringkamp / Neuroscience and Biobehavioral Reviews 34 (2010) 177184 183

8/12/2019 Sche Pers 10

8/8

Tillman, D.B., Treede, R.-D., Meyer, R.A., Campbell, J.N., 1995a. Response of C fibrenociceptors in the anaesthetized monkey to heat stimuli: correlation with painthreshold in humans. J. Physiol. 485, 767774.

Tillman, D.B., Treede, R.-D., Meyer, R.A., Campbell, J.N., 1995b. Response of C fibrenociceptors in the anaesthetized monkey to heat stimuli: estimates of receptordepth and threshold. J. Physiol. 485.3, 753765.

Todaka, H., Taniguchi, J., Satoh, J., Mizuno, A., Suzuki, M., 2004. Warm temperature-sensitivetransient receptor potential vanilloid4 (TRPV4) plays an essential rolein thermal hyperalgesia. J. Biol. Chem. 279, 3513335138.

Tominaga, M., Caterina, M.J., 2004. Thermosensation and pain. J. Neurobiol. 61,312.

Tominaga, M., Caterina, M.J., Malmberg, A.B., Rosen, T.A., Gilbert, H., Skinner, K.,Raumann, B.E., Basbaum, A.I., Julius, D., 1998. The cloned capsaicin receptorintegrates multiple pain-producing stimuli. Neuron 21, 531543.

Torebjork, H.E., 1974. Afferent C units responding to mechanical, thermal andchemical stimuli in human non-glabrous skin.Acta Physiol.Scand. 92,374390.

Treede, R.-D., Meyer, R.A., Campbell, J.N., 1990. Comparison of heat and mechanicalreceptive fieldsof cutaneous C-fiber nociceptorsin monkey. J. Neurophysiol. 64,15021513.

Treede,R.-D.,Meyer,R.A., Campbell, J.N.,1998.Myelinated mechanicallyinsensitiveafferents from monkey hairy skin: heat-response properties. J. Neurophysiol.80, 10821093.

Treede,R.-D., Meyer, R.A., Raja, S.N., Campbell, J.N., 1995. Evidence for two differentheat transduction mechanisms in nociceptive primary afferents innervatingmonkey skin. J. Physiol. 483.3, 747758.

Viana, F., De La, P.E., Belmonte, C., 2002. Specificity of cold thermotransduction isdetermined by differential ionic channel expression. Nat. Neurosci. 5, 254260.

Voets, T., Droogmans, G., Wissenbach, U., Janssens, A., Flockerzi, V., Nilius, B., 2004.The principle of temperature-dependent gating in cold- and heat-sensitive TRPchannels. Nature 430, 748754.

Wahren, L.K., Torebjork, E., Jorum, E., 1989. Central suppression of cold-induced Cfibre pain by myelinated fibre input. Pain 38, 313319.

Watanabe, H., Vriens, J., Prenen, J., Droogmans, G., Voets, T., Nilius, B., 2003.Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activateTRPV4 channels. Nature 424, 434438.

Watanabe, H., Vriens, J., Suh, S.H., Benham, C.D., Droogmans, G., Nilius, B., 2002.Heat-evoked activation of TRPV4 channels in a HEK293 cell expression systemand in native mouse aorta endothelial cells. J. Biol. Chem. 277, 4704447051.

Woodbury, C.J., Zwick, M., Wang, S., Lawson, J.J., Caterina, M.J., Koltzenburg, M.,Albers, K.M., Koerber, H.R., Davis, B.M., 2004. Nociceptors lacking TRPV1 andTRPV2 have normal heat responses. J. Neurosci. 24, 64106415.

Xu, H., Delling, M., Jun, J.C., Clapham, D.E., 2006. Oregano, thyme and clove-derivedflavors and skin sensitizers activate specific TRP channels. Nat. Neurosci. 9,628635.

Xu, H., Ramsey, I.S., Kotecha, S.A., Moran, M.M., Chong, J.A., Lawson, D., Ge, P., Lilly, J.,Silos-Santiago, I., Xie,Y., DiStefano,P.S., Curtis,R., Clapham, D.E., 2002. TRPV3 is a

calcium-permeable temperature-sensitive cationchannel. Nature 418, 181186.Yarnitsky, D., Ochoa, J.L., 1990. Release of cold-induced burning pain by block ofcold-specific afferent input. Brain 113, 893902.

Zhang, X.F., Chen, J., Faltynek, C.R., Moreland, R.B., Neelands, T.R., 2008. Transientreceptor potential A1 mediates an osmotically activated ion channel. Eur. J.Neurosci. 27, 605611.

Zheng, J., Dai, C., Steyger, P.S., Kim, Y., Vass, Z., Ren, T., Nuttall, A.L., 2003. Vanilloidreceptors in hearing:alteredcochlear sensitivity by vanilloids and expression ofTRPV1 in the organ of corti. J. Neurophysiol. 90, 444455.

Zimmermann, K.,Leffler,A., Babes, A.,Cendan,C.M., Carr, R.W.,Kobayashi,J., Nau,C.,Wood, J.N., Reeh, P.W., 2007. Sensory neuron sodium channel Nav1.8 is essen-tial for pain at low temperatures. Nature 447, 855858.

Zimmermann, K., Leffler, A., Fischer, M.M., Messlinger, K., Nau, C., Reeh, P.W., 2005.The TRPV1/2/3 activator 2-aminoethoxydiphenyl borate sensitizes native noci-ceptive neurons to heatin wildtype but notTRPV1 deficientmice. Neuroscience135, 12771284.

Zurborg, S., Yurgionas, B., Jira, J.A., Caspani, O., Heppenstall, P.A., 2007. Directactivation of the ion channel TRPA1 by Ca2+. Nat. Neurosci. 10, 277279.

Zygmunt, P.M., Petersson, J., Andersson, D.A., Chuang, H., Sorgard, M., Di, M.V.,

Julius, D., Hogestatt, E.D., 1999. Vanilloid receptors on sensory nerves mediatethe vasodilator action of anandamide. Nature 400, 452457.

Zylka, M.J., Rice, F.L., Anderson, D.J., 2005. Topographically distinct epidermalnociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron45, 1725.


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