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TRPV1 drugs alter core body temperature via central projections of primary afferent sensory neurons

TRPV1, a capsaicin- and heat-activated ion channel, is expressed by peripheral nociceptors and has been implicated in various inflammatory and neuropathic pain conditions. Although pharmacological modulation of TRPV1 has attracted therapeutic interest, many TRPV1 agonists and antagonists produce the...

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Autores principales: Yue, Wendy Wing Sze, Yuan, Lin, Braz, Joao M, Basbaum, Allan I, Julius, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9377796/
https://www.ncbi.nlm.nih.gov/pubmed/35968676
http://dx.doi.org/10.7554/eLife.80139
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author Yue, Wendy Wing Sze
Yuan, Lin
Braz, Joao M
Basbaum, Allan I
Julius, David
author_facet Yue, Wendy Wing Sze
Yuan, Lin
Braz, Joao M
Basbaum, Allan I
Julius, David
author_sort Yue, Wendy Wing Sze
collection PubMed
description TRPV1, a capsaicin- and heat-activated ion channel, is expressed by peripheral nociceptors and has been implicated in various inflammatory and neuropathic pain conditions. Although pharmacological modulation of TRPV1 has attracted therapeutic interest, many TRPV1 agonists and antagonists produce thermomodulatory side effects in animal models and human clinical trials, limiting their utility. These on-target effects may result from the perturbation of TRPV1 receptors on nociceptors, which transduce signals to central thermoregulatory circuits and release proinflammatory factors from their peripheral terminals, most notably the potent vasodilative neuropeptide, calcitonin gene-related peptide (CGRP). Alternatively, these body temperature effects may originate from the modulation of TRPV1 on vascular smooth muscle cells (vSMCs), where channel activation promotes arteriole constriction. Here, we ask which of these pathways is most responsible for the body temperature perturbations elicited by TRPV1 drugs in vivo. We address this question by selectively eliminating TRPV1 expression in sensory neurons or vSMCs and show that only the former abrogates agonist-induced hypothermia and antagonist-induced hyperthermia. Furthermore, lesioning the central projections of TRPV1-positive sensory nerve fibers also abrogates drug-mediated thermomodulation, whereas eliminating CGRP has no effect. Thus, TRPV1 drugs alter core body temperature by modulating sensory input to the central nervous system, rather than through peripheral actions on the vasculature. These findings suggest how mechanistically distinct TRPV1 antagonists may diminish inflammatory pain without affecting core body temperature.
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spelling pubmed-93777962022-08-16 TRPV1 drugs alter core body temperature via central projections of primary afferent sensory neurons Yue, Wendy Wing Sze Yuan, Lin Braz, Joao M Basbaum, Allan I Julius, David eLife Neuroscience TRPV1, a capsaicin- and heat-activated ion channel, is expressed by peripheral nociceptors and has been implicated in various inflammatory and neuropathic pain conditions. Although pharmacological modulation of TRPV1 has attracted therapeutic interest, many TRPV1 agonists and antagonists produce thermomodulatory side effects in animal models and human clinical trials, limiting their utility. These on-target effects may result from the perturbation of TRPV1 receptors on nociceptors, which transduce signals to central thermoregulatory circuits and release proinflammatory factors from their peripheral terminals, most notably the potent vasodilative neuropeptide, calcitonin gene-related peptide (CGRP). Alternatively, these body temperature effects may originate from the modulation of TRPV1 on vascular smooth muscle cells (vSMCs), where channel activation promotes arteriole constriction. Here, we ask which of these pathways is most responsible for the body temperature perturbations elicited by TRPV1 drugs in vivo. We address this question by selectively eliminating TRPV1 expression in sensory neurons or vSMCs and show that only the former abrogates agonist-induced hypothermia and antagonist-induced hyperthermia. Furthermore, lesioning the central projections of TRPV1-positive sensory nerve fibers also abrogates drug-mediated thermomodulation, whereas eliminating CGRP has no effect. Thus, TRPV1 drugs alter core body temperature by modulating sensory input to the central nervous system, rather than through peripheral actions on the vasculature. These findings suggest how mechanistically distinct TRPV1 antagonists may diminish inflammatory pain without affecting core body temperature. eLife Sciences Publications, Ltd 2022-08-15 /pmc/articles/PMC9377796/ /pubmed/35968676 http://dx.doi.org/10.7554/eLife.80139 Text en © 2022, Yue et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Neuroscience
Yue, Wendy Wing Sze
Yuan, Lin
Braz, Joao M
Basbaum, Allan I
Julius, David
TRPV1 drugs alter core body temperature via central projections of primary afferent sensory neurons
title TRPV1 drugs alter core body temperature via central projections of primary afferent sensory neurons
title_full TRPV1 drugs alter core body temperature via central projections of primary afferent sensory neurons
title_fullStr TRPV1 drugs alter core body temperature via central projections of primary afferent sensory neurons
title_full_unstemmed TRPV1 drugs alter core body temperature via central projections of primary afferent sensory neurons
title_short TRPV1 drugs alter core body temperature via central projections of primary afferent sensory neurons
title_sort trpv1 drugs alter core body temperature via central projections of primary afferent sensory neurons
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9377796/
https://www.ncbi.nlm.nih.gov/pubmed/35968676
http://dx.doi.org/10.7554/eLife.80139
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