The Transient Receptor Potential Vanilloid-1 Channel in Thermoregulation: A Thermosensor It Is Not

Romanovsky, Andrej A.; Almeida, Maria Camila; Garami, András; Steiner, Alexandre A.; Norman, Mark H.; Morrison, Shaun F.; Nakamura, Kazuhiro; Burmeister, J; Nucci, Tatiane B.

doi:10.1124/pr.109.001263

Cited by 224 publications

(280 citation statements)

References 301 publications

(417 reference statements)

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“…Moreover, focal microinfusion of an NK 3 R agonist activates MnPO neurons (as measured by Fos), elicits a robust drop in T CORE and inhibits sympathetic vasoconstriction (25). MnPO neurons project to other thermoregulatory regions of the hypothalamus (24,44,45) as well as neurons in the ventromedial medulla controlling tail vasomotion (42,(46)(47)(48). Thus, removal of excitatory KNDy neuron projections to the MnPO or medial preoptic area (or both) could provide a mechanism for the lower levels of tail skin vasodilatation in KNDy-ablated rats.…”

Section: Discussionmentioning

confidence: 99%

Role for kisspeptin/neurokinin B/dynorphin (KNDy) neurons in cutaneous vasodilatation and the estrogen modulation of body temperature

Mittelman-Smith

Williams

Krajewski-Hall

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

165

110

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Estrogen withdrawal in menopausal women leads to hot flushes, a syndrome characterized by the episodic activation of heat dissipation effectors. Despite the extraordinary number of individuals affected, the etiology of flushes remains an enigma. Because menopause is accompanied by marked alterations in hypothalamic kisspeptin/neurokinin B/dynorphin (KNDy) neurons, we hypothesized that these neurons could contribute to the generation of flushes. To determine if KNDy neurons participate in the regulation of body temperature, we evaluated the thermoregulatory effects of ablating KNDy neurons by injecting a selective toxin for neurokinin-3 expressing neurons [NK 3 -saporin (SAP)] into the rat arcuate nucleus. Remarkably, KNDy neuron ablation consistently reduced tail-skin temperature (T SKIN ), indicating that KNDy neurons facilitate cutaneous vasodilatation, an important heat dissipation effector. Moreover, KNDy ablation blocked the reduction of T SKIN by 17β-estradiol (E 2 ), which occurred in the environmental chamber during the light phase, but did not affect the E 2 suppression of T SKIN during the dark phase. At the high ambient temperature of 33°C, the average core temperature (T CORE ) of ovariectomized (OVX) control rats was significantly elevated, and this value was reduced by E 2 replacement. In contrast, the average T CORE of OVX, KNDy-ablated rats was lower than OVX control rats at 33°C, and not altered by E 2 replacement. These data provide unique evidence that KNDy neurons promote cutaneous vasodilatation and participate in the E 2 modulation of body temperature. Because cutaneous vasodilatation is a cardinal sign of a hot flush, these results support the hypothesis that KNDy neurons could play a role in the generation of flushes.reproduction | gonadotropin-releasing hormone | thermoregulation E strogen withdrawal leads to hot flushes in the majority of menopausal women (1). Hot flushes are also experienced by men and women treated with tamoxifen for breast cancer, men undergoing androgen-ablation therapy for prostate cancer, young oophorectomized women, and hypogonadal men (2, 3). A hot flush is characterized by episodic activation of heat dissipation effectors, including cutaneous vasodilatation, sweating, and behavioral thermoregulation. After a flush is initiated, the activation of heat dissipation mechanisms is so effective that core temperature frequently drops (4). Despite the vast numbers of individuals affected, the etiology of flushes remains an enigma.Hot flushes are closely timed with luteinizing hormone (LH) pulses, providing a clue that the generation of flushes is linked to the hypothalamic neural circuitry controlling pulsatile gonadotropin-releasing hormone (GnRH) secretion (5, 6). Current evidence suggests that pulsatile GnRH secretion is modulated by a subpopulation of neurons in the arcuate (infundibular) nucleus that express estrogen receptor α (ERα), neurokinin 3 receptor (NK 3 R), kisspeptin, neurokinin B (NKB), and dynorphin (7-11). In the hypothalamus of postmenopausal women, ...

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Section: Discussionmentioning

confidence: 99%

Role for kisspeptin/neurokinin B/dynorphin (KNDy) neurons in cutaneous vasodilatation and the estrogen modulation of body temperature

Mittelman-Smith

Williams

Krajewski-Hall

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

165

110

View full text Add to dashboard Cite

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“…It is now recognized that the thermoregulatory system controls body temperature as a results of the activity in a number of relatively independent effector loops (218,219,255), without the need of a specific "set point" (25). According to the type of external stimuli (i.e.…”

Section: Autonomic Temperature Regulationmentioning

confidence: 99%

“…Furthermore, studies endorsing pharmacological manipulation of such channels in humans have recently started to be performed (116), and have shown significant analogies with findings from animal models. Nevertheless, numerous questions on the specificity of these channels and on their role in modulating conscious thermal sensations remain outstanding (255).…”

Section: Neurophysiology Of Temperature Sensationmentioning

confidence: 99%

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Neurophysiology of Skin Thermal Sensations

Filingeri

2016

Comprehensive Physiology

111

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Undoubtedly, adjusting our thermoregulatory behavior represents the most effective mechanism to maintain thermal homeostasis and ensure survival in the diverse thermal environments that we face on this planet. Remarkably, our thermal behavior is entirely dependent on the ability to detect variations in our internal (i.e. body) and external environment, via sensing changes in skin temperature and wetness. In the past 30 years, we have seen a significant expansion of our understanding of the molecular, neuroanatomical and neurophysiological mechanisms that allow humans to sense temperature and humidity. The discovery of temperature-activated ion channels which gate the generation of action potentials in thermosensitive neurons, along with the characterization of the spino-thalamo-cortical thermosensory pathway, and the development of neural models for the perception of skin wetness, are only some of the recent advances which have provided incredible insights on how biophysical changes in skin temperature and wetness are transduced into those neural signals which constitute the physiological substrate of skin thermal and wetness sensations. Understanding how afferent thermal inputs are integrated and how these contribute to behavioral and autonomic thermoregulatory responses under normal brain function is critical to determine how these mechanisms are disrupted in those neurological conditions which see the concurrent presence of afferent thermosensory abnormalities and efferent thermoregulatory dysfunctions. Furthermore, advancing the knowledge on skin thermal and wetness sensations is crucial to support the development of neuro-prosthetics. In light of the above, this review will focus on the peripheral and central neurophysiological mechanisms underpinning skin thermal and wetness sensations in humans.

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“…This finding provided the experimental foundation for the concept (most recently refuted by Romanovsky and colleagues, [122]) that the predominant function of TRPV1 is body temperature regulation [123]. It was postulated that TRPV1 has an endogenous tone which is important for the maintenance of normal body temperature [121,124].…”

Section: Hyperthermia Caused By Trpv1 Blockadementioning

confidence: 87%

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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The Transient Receptor Potential Vanilloid-1 Channel in Thermoregulation: A Thermosensor It Is Not

Cited by 224 publications

References 301 publications

Role for kisspeptin/neurokinin B/dynorphin (KNDy) neurons in cutaneous vasodilatation and the estrogen modulation of body temperature

Role for kisspeptin/neurokinin B/dynorphin (KNDy) neurons in cutaneous vasodilatation and the estrogen modulation of body temperature

Neurophysiology of Skin Thermal Sensations

TRPV1 Antagonists as Analgesic Agents

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