Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1

Trevisani, Marcello; Smart, Darren; Gunthorpe, Martin J.; Tognetto, Michele; Barbieri, Mario; Campi, Barbara; Amadesi, Silvia; Gray, Julie; Jerman, Jeffrey C.; Brough, Stephen; Owen, Davina E.; Smith, G.; Randall, Andrew; Harrison, Selena; Bianchi, A.; Davis, John B.; Geppetti, Pierangelo

doi:10.1038/nn0602-852

Cited by 391 publications

(275 citation statements)

References 23 publications

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“…This concept may be adapted to TRPV1 regulation, which could be constitutively suppressed by [Na ϩ ] o . It is well known that the [Ca 2ϩ ] i increase through the activation of TRPV1 channels located on sensory nerve endings leads to secretion of algesic substances such as glutamate and neuropeptides (34,35). In addition, [Ca 2ϩ ] i accumulation after the activation of TRPV1 promotes neural cell death due to the excessive mitochondrial Ca 2ϩ load (36).…”

Section: Discussionmentioning

confidence: 99%

Novel Gating and Sensitizing Mechanism of Capsaicin Receptor (TRPV1)

Ohta

Imagawa

2008

Journal of Biological Chemistry

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Transient receptor potential V1 (TRPV1) is a nonselective cation channel expressed in nociceptors andsurrounding several proton-sensitive sites on the extracellular side of the pore-forming loop of the TRPV1 channel may play an important role as a brake to suppress the excessive activity of this channel under physiological conditions. Transient receptor potential V1 (TRPV1) 2 is a nonselective cation channel with high Ca 2ϩ permeability found in sensory neurons that functions as a molecular integrator of pain perception (1). TRPV1 is activated by polymodal stimuli such as capsaicin, protons, and noxious heat (2). Some endogenous ligands termed endovanilloids (3), including 15-hydroperoxyeicosa-5Z,8Z,11Z,13E-tetraenoic acid (15(S)-HPETE), a lipoxygenase product, also activate TRPV1 (4). Because mice genetically lacking the TRPV1 channel exhibit impaired nociception (5, 6) and several TRPV1 antagonists have antinociceptive activity in vivo (7-9), TRPV1 is considered to be a key component of signal transduction pathways in the nociceptive system. Several regulatory mechanisms of TRPV1 function have been elucidated. Sensitization can arise from phosphorylation of TRPV1 at multiple sites via protein kinase C and protein kinase A downstream of activation of GTP-binding protein-coupling receptor by bradykinin, ATP, nerve growth factor, calcitonin gene-related peptide, and prostaglandins (10). Our recent report also showed that the metabotropic 5-HT receptor facilitates TRPV1 functions through protein kinase C/protein kinase A pathways (11). TRPV1 is subject to tonic inhibition by phosphatidylinositol 4,5-bisphosphate (PIP 2 ) (12), providing an additional biochemical pathway through which the activity of the channel can be regulated after GTPbinding protein-coupling receptor activation. Recently, increases of cationic strength have been shown to contribute to inflammatory pain signaling through modulation of TRPV1 channels, since extracellular cations such as Na ϩ , Mg 2ϩ , and Ca 2ϩ gate and sensitize them (13). Hyponatremia, a disease due to reduction of the plasma Na ϩ concentration, is one of the most common electrolyte disorders (14). It occurs via excess loss of plasma Na ϩ as a result of various causes such as chronic renal failure and congestive heart failure. When the serum Na ϩ level falls gradually over a period of several days or weeks, sodium levels as low as 110 meq/liter may be reached with minimal symptomatology. Its symptoms are often concomitant with pain (15). However, the molecular detector of pain perception in hyponatremia has not yet been identified.We recently cloned a porcine orthologue of TRPV1 (pTRPV1) and analyzed its functional properties using a heterologous expression system (16). We showed that pTRPV1 was a nonselective cation channel sensitive to a number of vanilloid agonists, including capsaicin and endovanilloids, heat, and protons. In pharmacological characteristics of TRPV1, there are remarkable species differences; chicken TRPV1 is not sensitive * This work was supported by grants...

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Section: Discussionmentioning

confidence: 99%

Novel Gating and Sensitizing Mechanism of Capsaicin Receptor (TRPV1)

Ohta

Imagawa

2008

Journal of Biological Chemistry

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“…The specificity of each of these receptors is difficult to assess since at least the first two of them also respond to temperature in the warm/hot and cool/cold range, respectively. Capsaicin receptors can be modulated by H+ and activated by chemicals structurally distinct from vanilloids and even by an unrelated VOC such as ethanol (Trevisani et al 2002). In fact, a diverse family of GPCRs has been found to be expressed in nociceptive sensory neurons (Dong et al 2001).…”

Section: Discussionmentioning

confidence: 99%

Chemosensory additivity in trigeminal chemoreception as reflected by detection of mixtures

2004

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A series of experiments probed into the degree of chemosensory detection additivity exhibited by mixtures of ethyl propanoate and heptanoate in terms of their trigeminal detectability via nasal pungency (i.e., irritation) and eye irritation. Nasal pungency was tested in subjects lacking a functional sense of smell (i.e., anosmics) to avoid olfactory biases. First, we built concentrationdetection functions for each chemical and sensory endpoint. Second, we used the data from the functions to prepare mixtures of the two compounds in complementary proportions, and suitable single-chemical standards, all of which should be equally detectable under a rule of complete additivity, i.e., independence of detection. Third, we compared the experimentally obtained detectability with that expected under such rule. The outcome revealed that, at a low detectability level (but still above chance), the mixtures showed complete additivity for both trigeminal endpoints. At a high detectability level (but below perfect detection), the mixtures showed complete additivity for nasal pungency but less than complete additivity for eye irritation. In the context of previous studies, the results consolidate a picture of higher degree of detection additivity at perithreshold levels in trigeminal than in olfactory chemoreception. The outcome presents another line of evidence suggesting broader chemical tuning in chemesthesis compared to olfaction.

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“…Other pathophysiologically relevant agents may also regulate TRPV1. The recent observation that ethanol stimulates TRPV1 channels and releases CGRP, by lowering the threshold temperature for channel activation [44], suggests that the ability of alcoholic beverages to trigger the migraine attack may be due to this neurogenic inflammatory mechanism. The presence of excitatory CGRP receptors on sensory neurons, within the dorsal root ganglia, which may act as stimulatory autoreceptors, has been reported recently [45].…”

Section: Prejunctional Modulation Of Cgrp Releasementioning

confidence: 99%

CGRP and migraine: neurogenic inflammation revisited

Geppetti

Capone²,

Trevisani

et al. 2005

J Headache Pain

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The term 'neurogenic inflammation' refers to a series of proinflammatory responses produced by the stimulation of peripheral terminals of a subset of primary sensory neurons and the subsequent release of the neuropeptides, calcitonin gene-related peptide (CGRP) and the tachykinins, substance P (SP) and neurokinin A (NKA) [1]. The neurons that produce inflammation comprise a heterogeneous cell population with A-delta and C fibres, defined as polymodal nociceptors because they sense thermal, chemical and high-threshold mechanical stimuli. These neurons express on their plasma membrane a large panel of excitatory and inhibitory receptors and channels, and some of these signalling proteins have been successfully used as targets for analgesic or anti-inflammatory drugs. Among the channels expressed on peptidergic primary sensory neurons, transient receptor potential vanilloid-1 (TRPV1) [2], activated by the xenobiotic capsaicin, the pungent ingredient of plants of the genus Capsicum, is of paramount importance. Capsaicin produces burning pain by stimulating TRPV1 and by releasing sensory neuropeptides causes neurogenic inflammation. However, high concentrations/doses of capsaicin have the ability, after an initial excitatory phase, to desensitise the sensory nerve terminals, thus reducing the transmission of sensory/pain signals and abolishing neurogenic inflammation [3, 4]. This specific feature of capsaicin has greatly contributed to define the role of this subset of sensory nerves in pathophysiological models of human diseases and has been Pierangelo Geppetti Jay Guido Capone Marcello Trevisani Paola Nicoletti Giovanni Zagli Maria Rosalia Tola Abstract For more than a century neurogenic inflammation has been proposed to have a role in various human diseases. The present review will cover the conceptual steps of the itinerary that has led to the conclusion that neurogenic inflammation is important in migraine. Of particular relevance for the object of this article is the observation that tachykinindependent neurogenic inflammatory responses are evident in rodents, but much less pronounced or absent in other mammal species, including man, whereas neurogenic vasodilatation, most likely mediated by CGRP, occurs in most mammalian species and also in man. Recent evidence that a CGRP receptor antagonist was effective in the treatment of migraine attack supports the hypothesis that neurogenic vasodilatation is a major underlying mechanism of migraine.

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Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1

Cited by 391 publications

References 23 publications

Novel Gating and Sensitizing Mechanism of Capsaicin Receptor (TRPV1)

Novel Gating and Sensitizing Mechanism of Capsaicin Receptor (TRPV1)

Chemosensory additivity in trigeminal chemoreception as reflected by detection of mixtures

CGRP and migraine: neurogenic inflammation revisited

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