The Capsaicin Paradox: Pain Relief by an Algesic Agent

Abstract

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. Central terminal degeneration AP conduction block Axoplasmatic transport block (?) Chemoanalgesia Chemoanalgesia Loss of heat hyperalgesia (?) Depletion of sensory neuropeptides and markers from the spinal cord Mechanical allodynia Intact cutaneous neurogenic inflammation Perineural application Degenerative changes in the peripheral C-fibres Glial reaction Depletion of peripheral axons and nerve endings Loss of some B-type neurones Depletion of sensory neuropeptides and AP conduction block Axoplasmatic transport block markers (phenotypic switch) Transganglionic degeneration Chemo-and thermal analgesia Loss of thermal hyperalgesia Loss of neurogenic inflammation Decreased visceral reflex afferent functions N o t F o r D i s t r i b u t i o n

Disparate changes in the expression of transient receptor potential vanilloid type 1 receptor mRNA and protein in dorsal root ganglion neurons following local capsaicin treatment of the sciatic nerve in the rat

“…Hence, TRPV1 antagonism or procedures, which inhibit the activation of the receptor may produce significant antinociception. Indeed, the local application of capsaicin and some other vanilloids directly onto peripheral nerve trunks has been shown to provide long-lasting and selective chemical and thermal analgesia, confined to the region innervated by the affected nerve (Jancsó et al, , 2008(Jancsó et al, , 2011Gamse et al, 1982;Fitzgerald and Woolf, 1982;Kissin et al, 2002;Knotkova et al, 2008). Despite numerous investigations that have made use of perineural capsaicin treatment (Gamse et al, 1982;Gibson et al, 1982;Chung et al, 1985;Lawson, 1987, 1990;Pini et al, 1990;Jancsó and Ambrus, 1994;Kissin et al, 2002), the mechanism of analgesia induced by perineural capsaicin remained unclear.…”

“…Indeed, recent findings demonstrated a restoration of viscerosensory innervation by neurogenesis following a systemic injection of capsaicin (Czaja et al, 2008), which results in the degeneration of large populations of nodose and DRG neurons (Jancsó et al, 1977(Jancsó et al, , 1985Ritter and Dinh, 1988;Jancsó and Lawson, 1990;Jancsó, 1992;Hiura et al, 2002). However, this possibility seems unlikely, since little if any functional recovery was demonstrated after perineural treatment with capsaicin (Jancsó et al, , 2011Fitzgerald and Woolf, 1982;Jancsó and Lawson, 1990;Jancsó, 1992;Dux et al, 1999;Sántha and Jancsó, 2003).…”

“…By virtue of their dual functional character, these particular nociceptive neurons comprise a unique population of primary afferent neurons, which transmit impulses generated by noxious stimuli and release neuropeptides from their peripheral and central terminals in response to stimulation (Maggi and Meli, 1988;Holzer, 1991;Jancsó, 2009). The chemosensitive primary afferent neurons, which are selectively sensitive to the stimulatory and neurotoxic effects of capsaicin, account for around 50% of the dorsal root ganglion (DRG) cells and 95% of the unmyelinated dorsal root fibers in the rat (Jancsó et al, 1977(Jancsó et al, , 2011Nagy and Hunt, 1983). Previous studies have demonstrated that selective elimination of these nociceptive afferents either from the whole animal or from selected regions of the body by the systemic (neonatal) or localized (perineural) administration of capsaicin and related vanilloids leads to profound antinociceptive and anti-inflammatory effects (Jancsó et al, 1977Fitzgerald and Woolf, 1982;Gamse et al, 1982).…”

Role of Gangliosides in Peripheral Pain Mechanisms

“…The other population is non-peptidergic and specifically binds the isolectin B4 from Bandeiraea simplicifolia [60][61][62]. Capsaicin-/chemosensitive peptidergic primary sensory neurons represent a unique population of nociceptive primary sensory neurons by possessing a dual function: on the one hand, they transmit nociceptive impulses towards the central nervous system (sensory afferent function), on the other hand, by the release of vasoactive neuropeptides, such as CGRP and SP from their peripheral nerve endings, they are involved in local regulation of tissue reactions, e.g., vasodilatation, plasma extravasation, smooth muscle contraction and immune function (local regulatory/sensory-efferent function) [51,55,[63][64][65][66][67]. Importantly, the chemical phenotype(s) of primary sensory neurons cannot be regarded as a fixed property, but, on the contrary, a dynamic, "on-demand" changing character of the neuron.…”

Roles of Glia, Immune Cells and the Thermo-TRP Channels, TRPV1, TRPA1 and TRPM8, in Pathological Pain

“…Quite recently, different clinical applications of vanilloid agonists for anti-nociceptive, antiinflammatory and anti-hyperalgesic effects via TRPV1 channels have been reported [94,95].…”