A Pharmacological Study of the TRPV 1 Capsaicin Receptor (original) (raw)
Related papers
Neuropharmacology, 2003
Capsiate is a capsaicin-like ingredient of a non-pungent cultivar of red pepper, CH-19 sweet. To elucidate the mechanisms underlying the non-pungency of capsiate, we investigated whether capsiate activates the cloned capsaicin receptor, TRPV1 (VR1). In patch-clamp experiments, capsiate was found to activate TRPV1 expressed transiently in HEK293 cells with a similar potency as capsaicin. Capsiate induced nociceptive responses in mice when injected subcutaneously into their hindpaws with a similar dose dependency as capsaicin. These data indicate that the non-pungent capsiate is an agonist for TRPV1 and could excite peripheral nociceptors. In contrast to this, capsiate did not induce any significant responses when applied to the skin surface, eye or oral cavity of mice, suggesting that capsiate requires direct access to nerve endings to exhibit its effects. Capsiate was proved to have high lipophilicity and to be easily broken down in normal aqueous conditions, leading to less accessibility to nociceptors. Another highly lipophilic capsaicin analogue, olvanil, was similar to capsiate in that it did not produce irritant responses when applied to the skin surface, although it could activate TRPV1. Taken together, high lipophilicity and instability might be critical determinants for pungency and so help in understanding the effects of capsaicin-related compounds.
Capsaicin, Nociception and Pain
Molecules, 2016
Capsaicin, the pungent ingredient of the hot chili pepper, is known to act on the transient receptor potential cation channel vanilloid subfamily member 1 (TRPV1). TRPV1 is involved in somatic and visceral peripheral inflammation, in the modulation of nociceptive inputs to spinal cord and brain stem centers, as well as the integration of diverse painful stimuli. In this review, we first describe the chemical and pharmacological properties of capsaicin and its derivatives in relation to their analgesic properties. We then consider the biochemical and functional characteristics of TRPV1, focusing on its distribution and biological effects within the somatosensory and viscerosensory nociceptive systems. Finally, we discuss the use of capsaicin as an agonist of TRPV1 to model acute inflammation in slices and other ex vivo preparations.
2000
Capsaicin, the active ingredient in hot chilli peppers, has selective actions on unmyelinated C-fibres and thinly myelinated A primary sensory neurones . Most capsaicin-sensitive fibres are polymodal nociceptors which respond to a range of sensory stimuli including noxious pressure, heat and chemical irritants , and are the most abundant class of nociceptive fibre. Nociceptive neurones are likely to release glutamate as a rapid central neurotransmitter, and also express neuropeptides such as calcitonin gene-related peptide (CGRP), substance P, neurokinin A and somatostatin which can be released into the spinal cord during intense stimulation . The tachykinins (e.g. substance P and neurokinin A) and excitatory amino acids (EAAs) (e.g. glutamate) cooperate and are thought to increase synaptic activation of dorsal horn neurones via EAA receptors . Noxious stimulation in the peripheral nervous system results in long-term increases in spinal excitability which may contribute to central mechanisms of allodynia and hyperalgesia . Much of the neuropeptide synthesized in the dorsal root ganglion (DRG) cell body is actually exported peripherally rather than centrally. In peripheral nerve peptide release can contribute to neurogenic inflammation.
The Capsaicin Paradox: Pain Relief by an Algesic Agent
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2011
Chemosensitive primary sensory neurones expressing the TRPV1 receptor, a molecular integrator of diverse noxious stimuli, play a fundamental role in the sensation of pain. Capsaicin, the archetypical ligand of the TRPV1 receptor, is one of the most painful chemical irritants, and its acute administration onto the skin and mucous membranes elicits severe pain. However, repeated or high-dose applications of capsaicin, and/or its administration through specific routes dramatically decreases the sensitivity of the innervated tissues to noxious chemical and heat stimuli. This review surveys the mechanisms of the antinociceptive, anti-inflammatory and anti-hyperalgesic effects of vanilloid agonists applied topically, or perineurally, or injected into the subarachnoid space in animal experiments and to put these data into a clinical perspective. The great body of available experimental evidence indicates that vanilloid agonists exert their antinociceptive actions through TRPV1 receptor-mediated selective neurotoxic/neurodegenerative effects directed against somatic and visceral C-fibre nociceptive primary afferent fibres. It is expected that vanilloid agonists will broaden the palette of analgesic drugs which do not cause addiction and tachyphylaxis.
Topical Capsaicin Response as a Phenotypic Measure in Patients with Pain
Pain Medicine, 2015
Capsaicin, the active component of chili peppers, selectively activates TRPV1 transient receptor potential cation channels, expressed primarily by a subpopulation of afferent C-fibers [1]. Local topical or intradermal application of capsaicin causes burning pain, neurogenic inflammation, hyperalgesia, and a vascular flare response [2]. It yields rather reproducible pain responses in healthy volunteers [3] and is used as an experimental human pain model. More recently, Campbell et al. reported that an increased pain response to capsaicin application is associated with a better treatment response to topical clonidine in painful diabetic neuropathy, presumably linking the capsaicin response to small fiber function [4].
Experimental and Therapeutic Medicine
Capsaicin is a natural protoalkaloid recognized as the main pungent component in hot peppers (Capsicum annuum L.). The capsaicin receptor is highly expressed in the unmyelinated type C nerve fibers originating from small diameter sensory neurons in dorsal root ganglia and cranial nerve ganglia correspondents. Capsaicin and related vanilloids have a variety of effects on primary sensory neurons function, from sensory neuron excitation characterized by local burning sensation and neurogenic inflammation, followed by conduction blockage accompanied by reversible ultrastructural changes of peripheral nociceptive endings (desensitization), going as far as irreversible degenerative changes (neurotoxicity). The main role in capsaicin-induced neurogenic inflammation relies on the capsaicin sensitive, small diameter primary sensory neurons, therefore its evaluation could be used as a diagnostic instrument in functional alterations of cutaneous sensory nerve fibers. Moreover, capsaicin-induced desensitization and neurotoxicity explain the analgesic/antinociceptive and anti-inflammatory effects of topical capsaicin and its potential use in the management of painful and inflammatory conditions. In this study, we describe the effects of capsaicin on neurogenic inflammation and nociception, as well as its potential diagnostic value and therapeutic impact in various conditions involving impairment of sensory nerve fibers. Contents 1. Introduction 2. Physicochemical properties of capsaicin 3. The capsaicin receptor-structure and functioning 4. Expression and roles of the capsaicin receptor 5. Capsaicin-induced neurogenic inflammation 6. Capsaicin-induced hyperalgesia 7. Capsaicin-induced desensitization 8. Capsaicin neurotoxicity 9. Conclusion
Neuroscience Letters, 2004
Effects of the endogenous lipid N-oleoyldopamine (OLDA) were analyzed on the rTRPV1-expressing HT1080 human fibrosarcoma cell line (HT5-1), on cultured rat trigeminal neurons, on the noxious heat threshold of rats and on nocifensive behavior of TRPV1 knockout mice. The EC 50 of capsaicin and OLDA on 45 Ca accumulation of rTRPV1-expressing HT5-1 cells was 36 nM and 1.8 mM, respectively. The efficacy of OLDA was 60% as compared to the maximum response of capsaicin. OLDA (330 nM to 3.3 mM) caused a transient increase in fluorescence of fura-2 loaded cultured small trigeminal neurons of the rat and rTRPV1-transfected HT5-1 cells measured with a ratiometric technique. Repeated application of OLDA and capsaicin caused similar desensitization in the Ca 2þ transients both in cultured neurons and rTRPV1-transfected HT5-1 cells. In the rat intraplantar injection of OLDA (5 nmol) decreased the noxious heat threshold by 6-9 8C and this response was strongly inhibited by the TRPV1 antagonist iodoresiniferatoxin (0.05 nmol intraplantarly (i.pl.)). In wild-type mice OLDA (50 nmol i.pl.) evoked paw lifting/licking which was significantly less sustained in TRPV1 knockout mice. It is concluded that on TRPV1 capsaicin receptors OLDA is 50 times less potent than capsaicin and it might serve as an endogenous ligand for TRPV1 in the rat, but more likely in humans. q
Gustatory Effects of Capsaicin that are Independent of TRPV1 Receptors
Chemical Senses, 2005
In order to choose which foods are palatable and safe to ingest, it is important to integrate information from different modalities, not only chemosensory (taste and olfaction), but also somatosensory (texture, irritation, nociception) . Capsaicin, the pungent component from chili peppers, has been shown to alter taste perception and has traditionally been added to foods to change their palatability. The effects of capsaicin on taste could emerge from the integration throughout the gustatory axis of information originating from capsaicin's direct effects on taste receptor cells (TRCs) and/or from information resulting from the effects of capsaicin on TRPV1 receptors in trigeminal nerve endings in the mouth Simon, 1996, 2000). Recent studies have shown that capsaicin can alter neural responses to tastants at the level of the nucleus tractus solitarius (NTS) and that these effects seem to be independent of trigeminal transmission . Previously, Okuni (1977)showed that chorda tympani fibers can be activated by capsaicin, indicating capsaicin can affect the gustatory pathway and more recently, presented evidence for a TRPV1 splice variant in TRCs that is responsible for the amilorideinsensitive responses to salts. Here, we found that in dissociated rat TRCs capsaicin inhibits voltage-gated inward and outward currents. Furthermore, we found that in TRPV1 -/mice capsaicin can alter taste preference to sucrose. These results demonstrate that the effects of capsaicin in taste perception do not result exclusively from the activation of capsaicin-sensitive receptors, but also through nonspecific TRPV1-independent mechanisms.
Pharmacological Research, 2011
a b s t r a c t N-acyl-vanillamide (NAVAM) analogues of the natural pungent principle of capsicum, capsaicin, were developed several years ago as potential non-pungent analgesic compounds. N-oleoyl-vanillamide (olvanil) and N-arachidonoy-vanillamide (arvanil), in particular, were described in several publications and patents to behave as potent anti-hyperalgesic compounds in experimental models of chronic and inflammatory pain, and to activate both "capsaicin receptors", i.e. the transient receptor potential of vanilloid type-1 (TRPV1) channel, and, either directly or indirectly, cannabinoid receptors of type-1. Here we report the biochemical and pharmacological characterization of a so far neglected NAVAM, N-palmitoylvanillamide (palvanil), and propose its possible use instead of capsaicin, as a possible topical analgesic. Palvanil exhibited a kinetics of activation of human recombinant TRPV1-mediated intracellular calcium elevation significantly slower than that of capsaicin (t 1/2 = 21 s and 8 s, respectively at 1 M). Slow kinetics of TRPV1 agonists were previously found to be associated with stronger potencies as TRPV1 desensitizing agents, which in turn are usually associated with lower pungency and stronger anti-hyperalgesic activity. Accordingly, palvanil desensitized the human recombinant TRPV1 to the effect of capsaicin (10 nM) with significantly higher potency than capsaicin (IC 50 = 0.8 nM and 3.8 nM, respectively), this effect reaching its maximum more rapidly (50 and 250 min, respectively). Palvanil was also more potent than capsaicin at desensitizing the stimulatory effect of TRPV1 by low pH together with anandamide, which mimics conditions occurring during inflammation. In the eye-wiping assay carried out in mice, palvanil was not pungent and instead caused a strong and long-lasting inhibition of capsaicin-induced eye-wiping. Finally, intraplantar palvanil inhibited the second phase of the nociceptive response to formalin in mice. In conclusion, palvanil appears to be a non-pungent analogue of capsaicin with stronger desensitizing effects on TRPV1 and hence potentially higher anti-hyperalgesic activity.