Capsaicin and central control of thermoregulation

Hori, Tetsuro

doi:10.1016/0163-7258(84)90041-x

Cited by 131 publications

(106 citation statements)

References 122 publications

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“…In particular, such targets include two temperaturesensitive ion channels from the TRP superfamily, namely TRPM8 and TRPV1, which are expressed within the afferent pathways for temperature sensation (23,30). Pharmacologic inhibition of TRPM8 and activation of TRPV1 alter the afferent signals from thermoreceptors to the neural centers of thermoregulation, thereby modifying thermoregulatory responses and decreasing core temperature in conscious organisms of a number of species (1,10,14,17). Accordingly, it has been proposed to use TRPV1 agonists and TRPM8 antagonists to induce or modulate TH in human patients (1,10,26).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, inhibitors of the transient receptor potential (TRP) melastatin 8 (TRPM8) ion channel and activators of the TRP vanilloid 1 (TRPV1) ion channel were shown to decrease core temperature in conscious organisms of a number of species (1,10,11,14,17). TRPM8 is a molecular cold sensor of the primary coldsensitive neurons, while TRPV1 is a heat and pain receptor expressed within peripheral and central sensory nervous system (23,30).…”

mentioning

confidence: 99%

“…TRPM8 is a molecular cold sensor of the primary coldsensitive neurons, while TRPV1 is a heat and pain receptor expressed within peripheral and central sensory nervous system (23,30). Modulators of the TRPM8 and TRPV1 channels decrease heat generation and increase heat dissipation, even at typical room ambient temperatures in the absence of physical cooling (1,14,30). Because the rate of heat loss is directly proportional to the gradient between the core and ambient temperatures, the drop in core temperature may be achieved faster if subjects are also exposed to external cooling by physical methods.…”

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confidence: 99%

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Shivering and tachycardic responses to external cooling in mice are substantially suppressed by TRPV1 activation but not by TRPM8 inhibition

Feketa

Balasubramanian

Flores

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Feketa VV, Balasubramanian A, Flores CM, Player MR, Marrelli SP. Shivering and tachycardic responses to external cooling in mice are substantially suppressed by TRPV1 activation but not by TRPM8 inhibition. Am J Physiol Regul Integr Comp Physiol 305: R1040-R1050, 2013. First published September 4, 2013 doi:10.1152/ajpregu.00296.2013.-Mild decrease of core temperature (32-34°C), also known as therapeutic hypothermia, is a highly effective strategy of neuroprotection from ischemia and holds significant promise in the treatment of stroke. However, induction of hypothermia in conscious stroke patients is complicated by cold-defensive responses, such as shivering and tachycardia. Although multiple thermoregulatory responses may be altered by modulators of thermosensitive ion channels, TRPM8 (transient receptor potential melastatin 8) and TRPV1 (TRP vanilloid 1), it is unknown whether these agents affect cold-induced shivering and tachycardia. The current study aimed to determine the effects of TRPM8 inhibition and TRPV1 activation on the shivering and tachycardic responses to external cooling. Conscious mice were treated with TRPM8 inhibitor compound 5 or TRPV1 agonist dihydrocapsaicin (DHC) and exposed to cooling at 10°C. Shivering was measured by electromyography using implanted electrodes in back muscles, tachycardic response by electrocardiography, and core temperature by wireless transmitters in the abdominal cavity. The role of TRPM8 was further determined using TRPM8 KO mice. TRPM8 ablation had no effect on total electromyographic muscle activity (vehicle: 24.0 Ϯ 1.8; compound 5: 23.8 Ϯ 2.0; TRPM8 KO: 19.7 Ϯ 1.9 V·s/min), tachycardia (⌬HR ϭ 124 Ϯ 31; 121 Ϯ 13; 121 Ϯ 31 beats/min) and drop in core temperature (Ϫ3.6 Ϯ 0.1; Ϫ3.4 Ϯ 0.4; Ϫ3.6 Ϯ 0.5°C) during cold exposure. TRPV1 activation substantially suppressed muscle activity (vehicle: 25.6 Ϯ 3.0 vs. DHC: 5.1 Ϯ 2.0 V·s/min), tachycardia (⌬HR ϭ 204 Ϯ 25 vs. 3 Ϯ 35 beats/min) and produced a profound drop in core temperature (Ϫ2.2 Ϯ 0.6 vs. Ϫ8.9 Ϯ 0.6°C). In conclusion, external cooling-induced shivering and tachycardia are suppressed by TRPV1 activation, but not by TRPM8 inhibition. This suggests that TRPV1 agonists may be combined with external physical cooling to achieve more rapid and effective hypothermia. therapeutic hypothermia; pharmacological hypothermia; shivering; transient receptor potential; physical cooling; electromyography; dihydrocapsaicin MILD DECREASE OF CORE TEMPERATURE to 32-34°C has been shown to effectively protect the brain from ischemia and has become a basis for the clinical method of therapeutic hypo-

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Shivering and tachycardic responses to external cooling in mice are substantially suppressed by TRPV1 activation but not by TRPM8 inhibition

Feketa

Balasubramanian

Flores

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Minute, systemically ineffective amounts of intrabrain capsaicin cause tail-skin vasodilation (Hori, 1984). To test whether TRPV1 channels in the brain are desensitized, a rat was placed in the thermocouple-respirometry setup at a slightly subneutral T a (22°C) and infused intracerebroventricularly with capsaicin (25 g) in 50% ethanol, while the T sk , T b , and T a were monitored.…”

Section: Desensitization Testsmentioning

confidence: 99%

Nonthermal Activation of Transient Receptor Potential Vanilloid-1 Channels in Abdominal Viscera Tonically Inhibits Autonomic Cold-Defense Effectors

Steiner¹,

Turek²,

Almeida³

et al. 2007

J. Neurosci.

202

242

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An involvement of the transient receptor potential vanilloid (TRPV) 1 channel in the regulation of body temperature (T b ) has not been established decisively. To provide decisive evidence for such an involvement and determine its mechanisms were the aims of the present study. We synthesized a new TRPV1 antagonist, AMG0347 [(E)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-3-(2-(piperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)acrylamide], and characterized it in vitro. We then found that this drug is the most potent TRPV1 antagonist known to increase T b of rats and mice and showed (by using knock-out mice) that the entire hyperthermic effect of AMG0347 is TRPV1 dependent. AMG0347-induced hyperthermia was brought about by one or both of the two major autonomic cold-defense effector mechanisms (tail-skin vasoconstriction and/or thermogenesis), but it did not involve warmth-seeking behavior. The magnitude of the hyperthermic response depended on neither T b nor tail-skin temperature at the time of AMG0347 administration, thus indicating that AMG0347-induced hyperthermia results from blockade of tonic TRPV1 activation by nonthermal factors. AMG0347 was no more effective in causing hyperthermia when administered into the brain (intracerebroventricularly) or spinal cord (intrathecally) than when given systemically (intravenously), which indicates a peripheral site of action. We then established that localized intra-abdominal desensitization of TRPV1 channels with intraperitoneal resiniferatoxin blocks the T b response to systemic AMG0347; the extent of desensitization was determined by using a comprehensive battery of functional tests. We conclude that tonic activation of TRPV1 channels in the abdominal viscera by yet unidentified nonthermal factors inhibits skin vasoconstriction and thermogenesis, thus having a suppressive effect on T b .

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“…It is well known that the agonist capsaicin transiently decreases body temperature in various species, including man, by operating the TRPV1 channel [26,119]. In the course of evaluating the ability of TRPV1 antagonists to block capsaicin-induced hypothermia, it was found that some of them caused hyperthermia per se [101,120,121].…”

Section: Hyperthermia Caused By Trpv1 Blockadementioning

confidence: 99%

TRPV1 Antagonists as Analgesic Agents

Trevisani

Gatti²

2013

TOPAINJ

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Abstract:The last decade (2001 -2010), declared as the Decade of Pain Control and Research by the United States Congress, brought significantly advances in our understanding of pain biology. Unfortunately, this has not translated into additional effective treatments of chronic pain conditions. Chronic pain is a debilitating and complex clinical state usually associated with diabetic neuropathy, postherpetic neuralgia, low back pathology, fibromyalgia, and neurological disorders. Standard pain drugs, even narcotic opioid analgesic agents, often provide unsatisfactory pain relief while causing important side-effect such as sedation, tolerance, dependence, respiratory depression and constipation. Furthermore, the effective management of chronic pain needs a multidisciplinary management approach and still represents one of the most urgent unmet medical need. Recently, preclinical research has uncovered new molecular mechanisms underlying the generation and transduction of pain, many of which represent new targets for innovative pharmacological interventions. This review focuses on Transient Receptor Potential (TRP) Vanilloid Type 1 (TRPV1) channel as a target for treating chronic pain. TRPV1 is a multifunctional ion channel involved in thermosensation (heat) and taste perception. Importantly, TRPV1 also functions as a molecular integrator for a broad variety of seemingly unrelated noxious stimuli. Indeed, TRPV1 is thought to be a major transducer of the thermal hyperalgesia that follows inflammation and/or tissue injury. Desensitization to topical TRPV1 agonists (e.g. capsaicin creams and patches) has been in clinical use for decades to treat chronic painful conditions like diabetic neuropathy. Most recently, a number of potent, small molecule TRPV1 antagonists have been advanced into clinical trials for pain relief. Perhaps not unexpectedly given the prominent role of TRPV1 in thermosensation, some of these antagonists showed worrisome adverse effects (hyperthermia and impaired noxious heat sensation) in humans, leading to their withdrawal from clinical trials. However, recent reports of TRPV1 antagonists that do not affect core body temperature in preclinical species suggest a potential opportunity to reduce at least this important side effect.

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Capsaicin and central control of thermoregulation

Cited by 131 publications

References 122 publications

Shivering and tachycardic responses to external cooling in mice are substantially suppressed by TRPV1 activation but not by TRPM8 inhibition

Shivering and tachycardic responses to external cooling in mice are substantially suppressed by TRPV1 activation but not by TRPM8 inhibition

Nonthermal Activation of Transient Receptor Potential Vanilloid-1 Channels in Abdominal Viscera Tonically Inhibits Autonomic Cold-Defense Effectors

TRPV1 Antagonists as Analgesic Agents

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