The Capsaicin Paradox: Pain Relief by an Algesic Agent (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.
Neuropharmacology, 2013
Pha1b toxin is a peptide purified from the venom of the armed spider Phoneutria nigriventer, with markedly antinociceptive action in models of acute and persistent pain in rats. Similarly to ziconotide, its analgesic action is related to inhibition of high voltage activated calcium channels with more selectivity for N-type. In this study we evaluated the effect of Pha1b when injected peripherally or intrathecally in a rat model of spontaneous pain induced by capsaicin. We also investigated the effect of Pha1b on Ca 2þ transients in cultured dorsal root ganglia (DRG) neurons and HEK293 cells expressing the TRPV1 receptor. Intraplantar or intrathecal administered Pha1b reduced both nocifensive behavior and mechanical hypersensitivity induced by capsaicin similarly to that observed with SB366791, a specific TRPV1 antagonist. Peripheral nifedipine and mibefradil did also decrease nociceptive behavior induced by intraplantar capsaicin. In contrast, u-conotoxin MVIIA (a selective N-type Ca 2þ channel blocker) was effective only when administered intrathecally. Pha1b, MVIIA and SB366791 inhibited, with similar potency, the capsaicin-induced Ca 2þ transients in DRG neurons. The simultaneous administration of Pha1b and SB366791 inhibited the capsaicin-induced Ca 2þ transients that were additive suggesting that they act through different targets. Moreover, Pha1b did not inhibit capsaicin-activated currents in patchclamp recordings of HEK293 cells that expressed TRPV1 receptors. Our results show that Pha1b may be effective as a therapeutic strategy for pain and this effect is not related to the inhibition of TRPV1 receptors.
Neuroscience, 2006
Intradermal capsaicin injection produces immediate spontaneous pain behaviors, and a secondary mechanical hypersensitivity (SMH) that is employed in the clinic as a model potentially predictive of human neuropathic pain. Presently, we have characterized capsaicin-induced SMH in rats, and compared pharmacological actions of standard analgesics in this and two nerve injury models, the L5/L6 spinal nerve ligation (SNL) and sciatic nerve chronic constriction injury (CCI) models. Intraplantar capsaicin produced doserelated SMH (enhanced paw withdrawal response to von Frey monofilament stimulation at an area away from injection site) that lasted for over 4 h. While pretreatment with a potent selective transient receptor potential vanilloid receptor-1 (TRPV1) antagonist A-425619 (1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea) prevented development of acute nocifensive (flinching) behavior immediately following capsaicin injection (ED 50 9.4؍ mg/kg), the compound failed to attenuate the SMH when administered 2 h following capsaicin (10 g/10 l). Additional standard analgesics were also tested 3 h following intraplantar capsaicin in the SMH model. Comparison of their potencies in attenuating mechanical hypersensitivity in capsaicin, SNL and CCI models revealed similar ED 50 s for morphine (2.3 mg/kg, 1.6 mg/kg and 3.2 mg/ kg, respectively), gabapentin (33.1 mg/kg, 33.9 mg/kg and 26.3 mg/kg, respectively) and lamotrigine (9.1 mg/kg, 8.9 mg/kg and 15.5 mg/kg, respectively). Duloxetine produced 50-65% effect at the highest tested dose (50 mg/kg), whereas the highest tested doses of morphine (10 mg/kg), gabapentin (85.5 mg/kg) and lamotrigine (30 mg/kg) all produced >70% efficacy in capsaicin SMH, SNL and CCI models. In contrast, celecoxib and ibuprofen showed weak effects in all three models. All standard analgesics generally had weak efficacy in attenuating capsaicin-induced immediate acute flinching behavior when administered before capsaicin. These results provide further support to the suggestions that distinct pharmacological mechanisms underlie capsaicin-induced acute nocifensive and SMH behaviors, and certain neuronal mechanisms underlying neuropathic pain states are also contributory to capsaicin-induced SMH.
The role of spinal cord vanilloid (TRPV1) receptors in pain modulation
Physiological Research, 2008
Transient receptor potential vanilloid 1 (TRPV1) receptor is a nonselective cation channel activated by capsaicin, a pungent substance from chili peppers. It is considered to act as an integrator of various physical and chemical nociceptive stimuli, as it can be gated by noxious heat (>43 oC), low pH (protons) and also by recently described endogenous lipids. The structure and function of TRPV1 receptors was vigorously studied, especially since its cloning in 1997. However, most of the research was pointed towards the role of TRPV1 receptors in the peripheral tissues. Mounting evidence now suggests that TRPV1 receptors on the central branches of dorsal root ganglion neurons in the spinal cord may play an important role in modulation of pain and nociceptive transmission. The aim of this short review was to summarize the knowledge about TRPV1 receptors in the spinal cord dorsal horn, preferentially from morphological and electrophysiological studies on spinal cord slices and from i...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1997
Capsaicin, the pungent ingredient in hot pepper, activates and subsequently desensitizes a subset of polymodal nociceptors. Because its initial application to skin produces pain, nonpungent analogs such as olvanil and glyceryl nonivamide (GLNVA) were synthesized to enhance its clinical use. To explore how these nonpungent analogs differ from capsaicin, whole-cell patch-clamp recordings were performed on cultured rat trigeminal ganglion neurons. In neurons held at -60 mV, capsaicin, olvanil, and GLNVA were found to activate one or two kinetically distinct inward currents. Two inward currents were also activated when extracellular Ca2+ was replaced with Ba2+ and also when intracellular chloride was replaced by aspartate. The reversal potentials of the rapidly and slowly activating currents were 15.3 +/- 6 and -4.0 +/- 2.5 mV, respectively. These data provide strong evidence for subtypes of vanilloid receptors. One difference among these agonists is that, on average, the activation kin...
TRPV1 Receptors in the CNS Play a Key Role in Broad-Spectrum Analgesia of TRPV1 Antagonists
The Journal of Neuroscience, 2006
Vanilloid receptor type 1 (TRPV1) is a ligand-gated nonselective cation channel that is considered to be an important integrator of various pain stimuli such as endogenous lipids, capsaicin, heat, and low pH. In addition to expression in primary afferents, TRPV1 is also expressed in the CNS. To test the hypothesis that the CNS plays a differential role in the effect of TRPV1 antagonists in various types of pain, the analgesic effects of two TRPV1 antagonists with similarin vitropotency but different CNS penetration were comparedin vivo. Oral administration of either A-784168 (1-[3-(trifluoromethyl)pyridin-2-yl]-N-[4-(trifluoromethylsulfonyl)phenyl]-1,2,3,6-tetrahydropyridine-4-carboxamide) (good CNS penetration) or A-795614 (N-1H-indazol-4-yl-N′-[(1R)-5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl]urea) (poor CNS penetration) blocked capsaicin-induced acute pain with the same potency. In complete Freund's adjuvant (CFA)-induced chronic inflammatory pain, oral administration of eithe...
Capsaicinoids in the treatment of neuropathic pain: a review
Therapeutic advances in neurological disorders, 2014
The treatment of neuropathic pain is difficult. Oral pharmaceuticals have significant side effects, and treatment efficacy tends to be modest. The use of topical analgesics reduces the potential for systemic side effects and allows direct application of medications to the area of pain. The natural spicy substance, capsaicin, has historically been known for its topical use. Capsaicin, once applied to the skin, causes a brief initial sensitization followed by a prolonged desensitization of the local pain nerves. This occurs through stimulation of the transient receptor potential vanilloid-1 (TRPV1) expressing pain nerve fibers. While low-dose capsaicin has not resulted in good efficacy, the larger dose 8% topical capsaicin has had some of the best data currently available in the treatment of post-herpetic neuralgia (PHN) and other neuropathic conditions. This paper discusses the data currently existing for capsaicin 8% in the treatment of PHN. It further reviews data for the low-dose ...
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.