TRPV1 drugs alter core body temperature via central projections of primary afferent sensory neurons
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Evaluation Summary:
The manuscript by Yue et al describes studies investigating the role of sensory neuron versus arteriole expression of Trpv1 in body temperature control. This is a detail about the contribution of different cells which has significance because of the reported on-target side-effect of hyperthermia by Trpv1-antagonists. The study shows that the effects on body temperature are predominantly produced through sensory neurons. From these studies it is speculated that the actions of Trpv1 might be pharmacologically modified to permit dissociation of the effects on neurogenic inflammation and the undesirable effects on body temperature.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. All reviewers agreed to share their names with the authors.)
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Abstract
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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Evaluation Summary:
The manuscript by Yue et al describes studies investigating the role of sensory neuron versus arteriole expression of Trpv1 in body temperature control. This is a detail about the contribution of different cells which has significance because of the reported on-target side-effect of hyperthermia by Trpv1-antagonists. The study shows that the effects on body temperature are predominantly produced through sensory neurons. From these studies it is speculated that the actions of Trpv1 might be pharmacologically modified to permit dissociation of the effects on neurogenic inflammation and the undesirable effects on body temperature.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. All …
Evaluation Summary:
The manuscript by Yue et al describes studies investigating the role of sensory neuron versus arteriole expression of Trpv1 in body temperature control. This is a detail about the contribution of different cells which has significance because of the reported on-target side-effect of hyperthermia by Trpv1-antagonists. The study shows that the effects on body temperature are predominantly produced through sensory neurons. From these studies it is speculated that the actions of Trpv1 might be pharmacologically modified to permit dissociation of the effects on neurogenic inflammation and the undesirable effects on body temperature.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. All reviewers agreed to share their names with the authors.)
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Reviewer #1 (Public Review):
TRPV1-targeted therapies for pain have failed because of the effects of these drugs on thermoregulation: TRPV1 channel agonists produce acute hypothermia in animals and humans, whereas TRPV1 antagonists cause acute hyperthermia. TRPV1 activity in sensory neurons sends pain signals to the brain, but also causes the release of pro-inflammatory neuropeptides such as CGRP. TRPV1 channels are also expressed in vascular smooth muscle cells of arterioles. It is unclear which of these TRPV1-associated functions is responsible for the alterations in thermoregulation caused by TRPV1 channel agonists and antagonists. In this study it is shown that ablation of TRPV1 only in sensory neurons of transgenic mice prevents hypothermia caused by the selective channel agonist capsaicin and hyperthermia by the selective …
Reviewer #1 (Public Review):
TRPV1-targeted therapies for pain have failed because of the effects of these drugs on thermoregulation: TRPV1 channel agonists produce acute hypothermia in animals and humans, whereas TRPV1 antagonists cause acute hyperthermia. TRPV1 activity in sensory neurons sends pain signals to the brain, but also causes the release of pro-inflammatory neuropeptides such as CGRP. TRPV1 channels are also expressed in vascular smooth muscle cells of arterioles. It is unclear which of these TRPV1-associated functions is responsible for the alterations in thermoregulation caused by TRPV1 channel agonists and antagonists. In this study it is shown that ablation of TRPV1 only in sensory neurons of transgenic mice prevents hypothermia caused by the selective channel agonist capsaicin and hyperthermia by the selective antagonist AMG 517. Conversely, ablation of TRPV1 channel expression in vascular smooth muscle cells slightly accentuated the hypo- or hyper-thermic responses caused by delivery of the agonist or antagonist, respectively. These results indicate that drug-induced changes in TRPV1 channel activity in sensory neurons are responsible for the alterations in body temperature, whereas activity of TRPV1 channels in the vasculature appear to counteract these alterations to a small extent. Importantly, transgenic mice did not show any impairments in body temperature regulation in the absence of drugs. The effects of drugs on body temperature were also eliminated in mice where central sensory terminals were ablated with capsaicin. In this setting, the sensory nerve endings can still release neuropeptides when TRPV1 channels activate, but have no electrical communication with the brain, indicating that it is the electrical signaling and not the neuroinflammatory responses which cause alterations in body temperature when TRPV1 channels are challenged by an agonist. This was further supported by results in mice deficient in the neuropeptide CGRP, which still experienced hypothermic responses when treated with capsaicin.
The data in the manuscript provide important constraints towards understanding the role of TRPV1 channels in thermoregulatory processes, and suggest that analgesic drugs that impair calcium permeability through TRPV1 channels without affecting sodium permeability could prevent pain caused by neurogenic inflammation without altering body temperature. The experimental design in this report is straightforward, adequate controls were included, and the results appear robust. However, there are also some concerns and limitations.
First, the major goal of the study is to determine whether TRPV1 channels expressed in the vasculature or in sensory neurons are responsible for the effects of drugs on body temperature. However, no clear justification is provided for how vascular TRPV1 channels could potentially give rise to the observed alterations in body temperature caused by drugs, as it would be generally expected that systemic treatment with an agonist would result in vasoconstriction and hyperthermia, and treatment with an antagonist give rise to vasodilation and hypothermia. These responses are opposite to the described effects of agonists and antagonists on body temperature, and therefore potentially rule out a contribution of vascular TRPV1 channels without necessarily requiring additional experimental testing.
Second, the effects of drugs on body temperature are shown as smoothened differences between the body temperature of control and test mice, rather than absolute body temperature in all groups of animals. This visualization obscures variability between organisms, which could contain additional relevant information, and is essential for an accurate assessment of the robustness of the results, particularly given the small numbers of animals that were tested and the high variability in the data. Statistical tests compare differences between WT and TRPV1-deficient mice after treatment with TRPV1 channel agonists and antagonists. However, these comparisons provide no information on whether there are statistically significant changes in the body temperature of TRPV1-deficient animals after treatment with drugs relative to animals treated with vehicle. This latter comparison is of higher clinical and physiological significance than what was performed in the study.
A minor third point is that experiments where TRPV1 expression was ablated in animals 8 weeks after birth appear to show opposite effects of agonists and antagonists relative to wild type mice: agonists seem to produce hyperthermia and antagonists cause hypothermia. These observations that do not align with the major conclusions of the manuscript are not discussed.
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Reviewer #2 (Public Review):
The study is short and to the point with a relatively straightforward set of hypotheses, experiments and results. The results strongly support the conclusion that, through Trpv1-sensory neurons, agonists and antagonists of Trpv1 control of body temperature. The only minor weakness is the experimental design aimed at determining the contribution of neurogenic release of peptide in regulating body temperature.
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Reviewer #3 (Public Review):
The TRPV1 receptor channel is primarily localised to sensory nerves as well as other non-neuronal tissues. It has been known for some time that TRPV1 has a role in the regulation of body temperature, as TRPV1 antagonists, being developed as analgesics, cause hyperthermia. There is a need for further mechanistic information, as the present drug discovery programme has been delayed by the inability of scientists to develop TRPV1 analgesics that act without temperature-related side effects. This manuscript is designed to investigate whether sensory nerves or smooth muscle cells are included in the mechanisms, through the study of tissue specific genetically modified mice.
This is a highly readable and concise manuscript with a relatively simple and clear take home message that advances current knowledge. …
Reviewer #3 (Public Review):
The TRPV1 receptor channel is primarily localised to sensory nerves as well as other non-neuronal tissues. It has been known for some time that TRPV1 has a role in the regulation of body temperature, as TRPV1 antagonists, being developed as analgesics, cause hyperthermia. There is a need for further mechanistic information, as the present drug discovery programme has been delayed by the inability of scientists to develop TRPV1 analgesics that act without temperature-related side effects. This manuscript is designed to investigate whether sensory nerves or smooth muscle cells are included in the mechanisms, through the study of tissue specific genetically modified mice.
This is a highly readable and concise manuscript with a relatively simple and clear take home message that advances current knowledge. However, at times the information could be more fully given.
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