The Mysteries of Capsaicin-Sensitive Afferents

A fundamental subdivision of nociceptive sensory neurons is named after their unique sensitivity to capsaicin, the pungent ingredient in hot chili peppers: these are the capsaicin-sensitive afferents. The initial excitation by capsaicin of these neurons manifested as burning pain sensation is followed by a lasting refractory state, traditionally referred to as “capsaicin desensitization,” during which the previously excited neurons are unresponsive not only to capsaicin but a variety of unrelated stimuli including noxious heat. The long sought-after capsaicin receptor, now known as TRPV1 (transient receptor potential cation channel, subfamily V member 1), was cloned more than two decades ago. The substantial reduction of the inflammatory phenotype of Trpv1 knockout mice has spurred extensive efforts in the pharmaceutical industry to develop small molecule TRPV1 antagonists. However, adverse effects, most importantly hyperthermia and burn injuries, have so far prevented any compounds from progressing beyond Phase 2. There is increasing evidence that these limitations can be at least partially overcome by approaches outside of the mainstream pharmaceutical development, providing novel therapeutic options through TRPV1. Although ablation of the whole TRPV1-expressing nerve population by high dose capsaicin, or more selectively by intersectional genetics, has allowed researchers to investigate the functions of capsaicin-sensitive afferents in health and disease, several “mysteries” remain unsolved to date, including the molecular underpinnings of “capsaicin desensitization,” and the exact role these nerves play in thermoregulation and heat sensation. This review tries to shed some light on these capsaicin mechanisms.

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The Contractile Phenotype of Skeletal Muscle in TRPV1 Knockout Mice Is Gender-Specific and Exercise-Dependent

Life ◽

10.3390/life10100233 ◽

2020 ◽

Vol 10 (10) ◽

pp. 233

Author(s):

Aude Lafoux ◽

Sabine Lotteau ◽

Corinne Huchet ◽

Sylvie Ducreux

Keyword(s):

Skeletal Muscle ◽

Skeletal Muscles ◽

Transient Receptor Potential ◽

Heat Stroke ◽

Receptor Potential ◽

Muscle Physiology ◽

Transient Receptor Potential Vanilloid ◽

Noxious Heat ◽

Contractile Phenotype ◽

Transient Receptor

The transient receptor potential vanilloid 1 (TRPV1) belongs to the transient receptor potential superfamily of sensory receptors. TRPV1 is a non-selective cation channel permeable to Ca2+ that is capable of detecting noxious heat temperature and acidosis. In skeletal muscles, TRPV1 operates as a reticular Ca2+-leak channel and several TRPV1 mutations have been associated with two muscle disorders: malignant hyperthermia (MH) and exertional heat stroke (EHS). Although TRPV1−/− mice have been available since the 2000s, TRPV1’s role in muscle physiology has not been thoroughly studied. Therefore, the focus of this work was to characterize the contractile phenotype of skeletal muscles of TRPV1-deficient mice at rest and after four weeks of exercise. As MS and EHS have a higher incidence in men than in women, we also investigated sex-related phenotype differences. Our results indicated that, without exercise, TRPV1−/− mice improved in vivo muscle strength with an impairment of skeletal muscle in vitro twitch features, i.e., delayed contraction and relaxation. Additionally, exercise appeared detrimental to TRPV1−/− slow-twitch muscles, especially in female animals.

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Abnormal Somatosensory Behaviors Associated With a Gain-of-Function Mutation in TRPV3 Channels

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.790435 ◽

2022 ◽

Vol 14 ◽

Author(s):

Mahar Fatima ◽

Hannah Slade ◽

Lorraine Horwitz ◽

Angela Shi ◽

Jingyi Liu ◽

...

Keyword(s):

Transient Receptor Potential ◽

Receptor Potential ◽

Skin Microbiome ◽

Gain Of Function ◽

Noxious Heat ◽

Genetic Mouse Model ◽

Function Point ◽

Specific Pathogen ◽

Cold Acetone ◽

Transient Receptor

Thermosensitive transient receptor potential V3 (TRPV3) is a polymodal receptor implicated in nociceptive, thermoceptive, pruritoceptive, and inflammatory pathways. Reports focused on understanding the role of TRPV3 in thermoception or nociception are not conclusive. Previous studies also show that aberrant hyperactivity of TRPV3 channels results in spontaneous itch and dermatitis-like symptoms, but the resultant behavior is highly dependent on the background of the animal and the skin microbiome. To determine the function of hyperactive TRPV3 channels in somatosensory sensations, we tested different somatosensory behaviors using a genetic mouse model that carries a gain-of-function point mutation G573S in the Trpv3 gene (Trpv3G573S). Here we report that Trpv3G573S mutants show reduced perception of cold, acetone-induced cooling, punctate, and sharp mechanical pain. By contrast, locomotion, noxious heat, touch, and mechanical itch are unaffected in Trpv3G573S mice. We fail to observe any spontaneous itch responses and/or dermatitis in Trpv3G573S mutants under specific pathogen (Staphylococcus aureus)-free conditions. However, we find that the scratching events in response to various pruritogens are dramatically decreased in Trpv3G573S mice in comparison to wild-type littermates. Interestingly, we observe sensory hypoinnervation of the epidermis in Trpv3G573S mutants, which might contribute to the deficits in acute mechanical pain, cool, cold, and itch sensations.

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VR1 in inflammatory thermal hyperalgesia

10.1093/med/9780198834359.003.0028 ◽

2018 ◽

Author(s):

Istvan Nagy

Keyword(s):

Transient Receptor Potential ◽

Thermal Hyperalgesia ◽

Receptor Potential ◽

Pain Sensation ◽

Burning Pain ◽

Relieve Pain ◽

Starting Point ◽

Hot Peppers ◽

Transient Receptor

The landmark paper discussed in this chapter, published by Davis et al. in 2000, describes the role of the capsaicin receptor, which is called transient receptor potential cation channel subfamily vanilloid member 1 (TRPV1), in inflammatory thermal hyperalgesia. Capsaicin, the pungent agent found in hot peppers, has been linked to pain for centuries because it induces a burning pain sensation which, after prolonged application of the agent, turns into analgesia. Because of this, capsaicin has been used to relieve pain, most likely since prehistoric times. The elucidation of the role of TRPV1 in nociceptive processing was heralded as the starting point for the development of agents which would revolutionize pain management. Unfortunately, that promise is yet to be realized and apparently we need a more detailed understanding of the role of TRPV1 in physiological and pathological processes in order to fulfil the analgesic potential of drugs acting on this receptor.

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Abstract 326: TRPV2 Regulates Cardiomyocyte Function via Altering Ca 2+ Cycling

Circulation Research ◽

10.1161/res.111.suppl_1.a326 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Xiaoqian Gao ◽

Sheryl Koch ◽

Min Jiang ◽

Nathan Robbins ◽

Wenfeng Cai ◽

...

Keyword(s):

Transient Receptor Potential ◽

Ventricular Myocytes ◽

Receptor Potential ◽

Ruthenium Red ◽

Transient Receptor Potential Vanilloid ◽

Dependent Manner ◽

Noxious Heat ◽

Cardiac Tissues ◽

Membrane Stretching ◽

Transient Receptor

TRPV2 is a member of transient receptor potential vanilloid (TRPV) family. As a Ca 2+ channel, it can detect various stimuli such as noxious heat (>52°C), membrane stretching, as well as a number of exogenous chemicals, including probenecid, 2-aminoethoxydiphenyl borate, and lysophospholipids. TRPV2 has been found in many tissue types, including neuron and kidney, but the function of TRPV2 in the heart is poorly understood. Here we show TRPV2 is involved in the Ca 2+ cycling process and then regulates the function of the cardiomyocyte. We identified the mRNA expression of TRPV2 in the cardiac tissues of mice using real-time PCR. By performing echocardiography we found that administration of probenecid, a selective TRPV2 agonist, increased cardiac ejection fraction in mice. This positive inotropic effect of probenecid was also shown in Langendorff perfused mice hearts as increased peak +dP/dt. In isolated ventricular myocytes, we found that probenecid significantly increased myocyte fractional shortening in a dose-dependent manner, which was fully blocked by ruthenium red, a non-selective TRPV2 blocker. We also performed fluorescent studies to examine myocyte Ca 2+ cycling. We found that probenecid significantly increased Ca 2+ transient and resting-state Ca 2+ sparks and this effect was eliminated by ruthenium red. When Ca 2+ storage in sarcoplasmic reticulum (SR) was depleted with caffeine, and SR Ca 2+ reuptake was blocked by thapsigargin at the same time, probenecid did not show any effects in either Ca 2+ transient or Ca 2+ sparks. Our patch clamp experiments indicate that probenecid treatment does not trigger any significant transmembrane Ca 2+ influx. These results point to the important role of TRPV2 in regulating SR Ca 2+ release. In conclusion, TRPV2 activation may contribute to increased SR Ca 2+ release, leading to the enhancement of myocyte contractility. Thus, TRPV2 plays a potentially important role in controlling the cellular function of heart.

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FXYD6 promotes thermal nociception by regulating TRPV1

Molecular Pain ◽

10.1177/1744806921992249 ◽

2021 ◽

Vol 17 ◽

pp. ???

Author(s):

Hao Luo ◽

Bing Cai ◽

Jing Pan ◽

Hai-Xiang Shi ◽

Kai-Kai Wang ◽

...

Keyword(s):

Transient Receptor Potential ◽

Small Diameter ◽

Receptor Potential ◽

Transient Receptor Potential Channel ◽

Hek293 Cells ◽

Drg Neurons ◽

Intraplantar Injection ◽

Noxious Heat ◽

Thermal Nociception ◽

Transient Receptor

FXYD6, an unnecessary auxiliary subunit of Na+,K+-ATPase, is expressed in the nervous system. However, its functions remain largely unclear. In the present study, we find that FXYD6 is involved in the thermal nociception. FXYD6 was mainly expressed in small-diameter DRG neurons expressing transient receptor potential channel V1 (TRPV1). In the SNS-Cre/ Fxyd6F/F mice, loss of FXYD6 in these sensory neurons impaired the behavioral responses to noxious heat stimulus and intraplantar injection of capsaicin. The capsaicin-induced and TRPV1-mediated currents were decreased in the FXYD6–deficient DRG neurons. Heterologous expression of FXYD6 could increase the TRPV1 capsaicin-sensitive currents in HEK293 cells. Furthermore, we found that the negatively charged PGDEE motif in C-terminal of FXYD6 is required for the FXYD6/TRPV1 interaction and FXYD6-mediated enhancement of TRPV1. Disrupting the FXYD6/TRPV1 interaction with the TAT-PGDEE peptide could elevate the threshold of thermal nociception. Therefore, FXYD6 maintains the thermal nociception via interacting with TRPV1 channel in nociceptors.

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Activation of TRPM3 by a potent synthetic ligand reveals a role in peptide release

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1419845112 ◽

2015 ◽

Vol 112 (11) ◽

pp. E1363-E1372 ◽

Cited By ~ 54

Author(s):

Katharina Held ◽

Tatjana Kichko ◽

Katrien De Clercq ◽

Hugo Klaassen ◽

Rieta Van Bree ◽

...

Keyword(s):

Transient Receptor Potential ◽

Calcium Influx ◽

Sensory Nerve ◽

Somatosensory System ◽

Receptor Potential ◽

Intradermal Injection ◽

Dependent Manner ◽

Noxious Heat ◽

Isolated Pancreatic Islets ◽

Transient Receptor

Transient receptor potential (TRP) cation channel subfamily M member 3 (TRPM3), a member of the TRP channel superfamily, was recently identified as a nociceptor channel in the somatosensory system, where it is involved in the detection of noxious heat; however, owing to the lack of potent and selective agonists, little is known about other potential physiological consequences of the opening of TRPM3. Here we identify and characterize a synthetic TRPM3 activator, CIM0216, whose potency and apparent affinity greatly exceeds that of the canonical TRPM3 agonist, pregnenolone sulfate (PS). In particular, a single application of CIM0216 causes opening of both the central calcium-conducting pore and the alternative cation permeation pathway in a membrane-delimited manner. CIM0216 evoked robust calcium influx in TRPM3-expressing somatosensory neurons, and intradermal injection of the compound induced a TRPM3-dependent nocifensive behavior. Moreover, CIM0216 elicited the release of the peptides calcitonin gene-related peptide (CGRP) from sensory nerve terminals and insulin from isolated pancreatic islets in a TRPM3-dependent manner. These experiments identify CIM0216 as a powerful tool for use in investigating the physiological roles of TRPM3, and indicate that TRPM3 activation in sensory nerve endings can contribute to neurogenic inflammation.

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Epithelial TRPV1 Signaling Accelerates Gingival Epithelial Cell Proliferation

Journal of Dental Research ◽

10.1177/0022034514552826 ◽

2014 ◽

Vol 93 (11) ◽

pp. 1141-1147 ◽

Cited By ~ 8

Author(s):

N. Takahashi ◽

Y. Matsuda ◽

H. Yamada ◽

K. Tabeta ◽

T. Nakajima ◽

...

Keyword(s):

Cell Proliferation ◽

Epithelial Cell ◽

Epithelial Cells ◽

Molecular Mechanisms ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Epithelial Cell Line ◽

Noxious Heat ◽

Gingival Epithelial Cell ◽

Transient Receptor

Transient receptor potential cation channel subfamily V member 1 (TRPV1), a member of the calcium-permeable thermosensitive transient receptor potential superfamily, is a sensor of thermal and chemical stimuli. TRPV1 is activated by noxious heat (> 43°C), acidic conditions (pH < 6.6), capsaicin, and endovanilloids. This pain receptor was discovered on nociceptive fibers in the peripheral nervous system. TRPV1 was recently found to be expressed by non-neuronal cells, such as epithelial cells. The oral gingival epithelium is exposed to multiple noxious stimuli, including heat and acids derived from endogenous and exogenous substances; however, whether gingival epithelial cells (GECs) express TRPV1 is unknown. We show that both TRPV1 mRNA and protein are expressed by GECs. Capsaicin, a TRPV1 agonist, elevated intracellular Ca2+ levels in the gingival epithelial cell line, epi 4. Moreover, TRPV1 activation in epi 4 cells accelerated proliferation. These responses to capsaicin were inhibited by a specific TRPV1 antagonist, SB-366791. We also observed GEC proliferation in capsaicin-treated mice in vivo. No effects were observed on GEC apoptosis by epithelial TRPV1 signaling. To examine the molecular mechanisms underlying this proliferative effect, we performed complementary (c)DNA microarray analysis of capsaicin-stimulated epi 4 cells. Compared with control conditions, 227 genes were up-regulated and 232 genes were down-regulated following capsaicin stimulation. Several proliferation-related genes were validated by independent experiments. Among them, fibroblast growth factor-17 and neuregulin 2 were significantly up-regulated in capsaicin-treated epi 4 cells. Our results suggest that functional TRPV1 is expressed by GECs and contributes to the regulation of cell proliferation.

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Evolution of thermoTRP ion channel homologs in vertebrates

Physiological Genomics ◽

10.1152/physiolgenomics.00322.2005 ◽

2006 ◽

Vol 27 (3) ◽

pp. 219-230 ◽

Cited By ~ 67

Author(s):

Shigeru Saito ◽

Ryuzo Shingai

Keyword(s):

Ion Channels ◽

Transient Receptor Potential ◽

Phylogenetic Analyses ◽

Draft Genome ◽

Receptor Potential ◽

Synonymous Substitution ◽

Temperature Sensitive ◽

Noxious Heat ◽

Transient Receptor ◽

Clawed Frog

In mammalian thermosensation, nine temperature-sensitive ion channels that are activated by distinct temperature thresholds have been identified as thermosensors. These ion channels belong to the transient receptor potential (TRP) superfamily and are referred to as “thermoTRPs” (TRPV1, TRPV2, TRPV3, TRPV4, TRPM2, TRPM4, TRPM5, TRPM8, and TRPA1). To elucidate the evolutionary processes of thermoTRPs, we conducted comprehensive searches for mammalian thermoTRP gene homologs in the draft genome sequences of chicken ( Gallus gallus), western clawed frog ( Xenopus tropicalis), zebrafish ( Danio rerio), and pufferfish ( Fugu rubripes). Newly identified homologs were compared with known thermoTRPs, and phylogenetic analyses were conducted. Our comparative analyses revealed that most of the mammalian thermo-TRP members already existed in the common ancestor of fishes and tetrapods. Tetrapods shared almost the same repertoire, except that the western clawed frog expanded TRPV4s (six copies) and TRPM8s (two copies), which were diversified considerably. Comparisons of nonsynonymous and synonymous substitution rates among TRPV4s suggested that one copy of the TRPV4 channel in the western clawed frog retained its original function, while the other copies diversified and obtained slightly different properties. In fish lineages, several members of thermo-TRPs have duplicated in the whole genome duplication occurred in the ancestral ray-finned fish; however, some of the copies have subsequently been lost. Furthermore, fishes do not possess the three members of thermoTRPs existed in mammals, e.g., thermoTRPs activated by noxious heat, warm, and cool temperatures. Our results suggest that thermosensation mechanisms have changed through vertebrate evolution with respect to thermosensor repertoires.

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Role of TRPM8 in Switching Between Fever and Hypothermia in Adult Mice During Endotoxin-Induced Inflammation

10.21203/rs.3.rs-120058/v1 ◽

2020 ◽

Author(s):

Chinatsu Shiraki ◽

Ririka Horikawa ◽

Momoka Fujimoto ◽

Kaho Okamoto ◽

Erkin Kurganov ◽

...

Keyword(s):

Low Dose ◽

Transient Receptor Potential ◽

Receptor Potential ◽

High Dose ◽

Wild Type ◽

Adult Mice ◽

Severe Hypothermia ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor

Abstract Transient receptor potential melastatin 8 (TRPM8) functions in the sensing of noxious and innocuous colds; however, its significance in pathogen-induced thermoregulation and inflammation remains unclear. In the present study, we investigated the role of TRPM8 in the regulation of endotoxin-induced body temperature control and inflammation. The peripheral administration of low-dose LPS or zymosan generated fever in wild-type (WT) mice and hypothermia in TRPM8 knockout (KO) animals. TRPM8 KO mice exhibited severe hypothermia and sickness responses following the peripheral administration of high-dose LPS. An intracerebroventricular injection of LPS and interleukin-1ß (Il-1ß) elicited hypothermia in TRPM8 KO mice, in contrast to fever in WT animals, whereas that of prostaglandin E2 induced normal fever. Fos immunohistochemistry showed the stronger activation of hypothalamic thermoregulation-associated nuclei following the peripheral administration of low-dose LPS. Therefore, TRPM8 is necessary for switching between fever and hypothermia during endotoxin-induced inflammation.

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Pharmacological or genetic targeting of Transient Receptor Potential (TRP) channels can disrupt the planarian escape response

10.1101/753244 ◽

2019 ◽

Author(s):

Ziad Sabry ◽

Alicia Ho ◽

Danielle Ireland ◽

Christina Rabeler ◽

Olivier Cochet-Escartin ◽

...

Keyword(s):

Transient Receptor Potential ◽

Trp Channels ◽

Escape Behavior ◽

Receptor Potential ◽

Allyl Isothiocyanate ◽

Noxious Heat ◽

Dugesia Japonica ◽

Noxious Stimuli ◽

Transient Receptor ◽

Genetic Targeting

AbstractIn response to noxious stimuli, planarians cease their typical ciliary gliding and exhibit an oscillatory type of locomotion called scrunching. We have previously characterized the biomechanics of scrunching and shown that it is induced by specific stimuli, such as amputation, noxious heat, and extreme pH. Because these specific inducers are known to activate Transient Receptor Potential (TRP) channels in other systems, we hypothesized that TRP channels control scrunching. We found that chemicals known to activate TRPA1 (allyl isothiocyanate (AITC) and hydrogen peroxide) and TRPV (capsaicin and anandamide) in other systems induce scrunching in the planarian species Dugesia japonica and, except for anandamide, in Schmidtea mediterranea. To confirm that these responses were specific to either TRPA1 or TRPV, respectively, we tried to block scrunching using selective TRPA1 or TRPV antagonists and RNA interference (RNAi) mediated knockdown. Unexpectedly, co-treatment with a mammalian TRPA1 antagonist, HC-030031, enhanced AITC-induced scrunching by decreasing the latency time, suggesting an agonistic relationship in planarians. We further confirmed that TRPA1 in both species is necessary for AITC-induced scrunching using RNAi. Conversely, while co-treatment of a mammalian TRPV antagonist, SB-366791, also enhanced capsaicin-induced reactions in D. japonica, combined knockdown of two previously identified D. japonica TRPV genes (DjTRPVa and DjTRPVb) did not inhibit capsaicin-induced scrunching. Surprisingly, RNAi of either DjTRPAa or DjTRPVa/DjTRPVb disrupted scrunching induced by the endocannabinoid and TRPV agonist, anandamide. Overall, our results show that although scrunching induction can involve different initial pathways for sensing stimuli, this behavior’s signature dynamical features are independent of the inducer, implying that scrunching is a stereotypical planarian escape behavior in response to various noxious stimuli that converge on a single downstream pathway. Understanding which aspects of nociception are conserved or not across different organisms can provide insight into the underlying regulatory mechanisms to better understand pain sensation.

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