Capsaicin causes prolonged inhibition of voltage-activated calcium currents in adult rat dorsal root ganglion neurons in culture

Docherty, R. J.; Robertson, B. E.; Bevan, Stuart

doi:10.1016/0306-4522(91)90137-d

Cited by 96 publications

(54 citation statements)

References 17 publications

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“…Our findings that activation of TRPA1 produced an initial 'depolarization block' and an extensive and sustained inhibition of voltage-gated calcium and sodium currents in DRG neurons provide a mechanism for the antinociceptive effect of spinal TRPA1 activation. This is in line with previous studies, showing that activation of TRPV1 produces a sustained inhibition of voltage-gated calcium and sodium channels [35][36][37][38][39] in sensory neurons as well as spinal antinociception 30,31,48 . On the basis of these studies, a model for TRPA1-mediated inhibition of synaptic transmission emerges, in which sodium and calcium influx through TRPA1 produces an initial depolarization-induced inactivation of voltage-gated sodium channels and a sustained inhibition of voltage-gated sodium and calcium currents, reducing action potential-dependent neurotransmitter release (Fig.…”

Section: Discussionsupporting

confidence: 93%

“…It is noteworthy that APAP has not been replaced therapeutically by any analogue that is not metabolized to reactive molecules. This would support the idea that the effect of APAP is mediated by 35,36 . Cation influx through TRPA1 also depolarizes the membrane and produces a sustained inhibition of voltage-gated sodium channels (naV), thereby reducing neuronal excitability and action potential-dependent neurotransmitter release.…”

Section: Discussionsupporting

confidence: 80%

“…We next considered the possibility that activation of TRPA1 expressed on the central terminals of nociceptive DRG neurons inhibits the activity of voltage-gated calcium or sodium channels, thereby modifying synaptic transmission. Such mechanisms have previously been shown to operate following TRPV1 activation [35][36][37][38][39] . To assess the involvement of voltage-gated channels, we initially examined the effect of activation of TRPA1 on action potential properties and the excitability of DRG neurons in the current-clamp configuration.…”

Section: The Antinociceptive Effect Of Apap Requires Trpa1mentioning

confidence: 92%

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TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ9-tetrahydrocannabiorcol

et al. 2011

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TRPA1 is a unique sensor of noxious stimuli and, hence, a potential drug target for analgesics. Here we show that the antinociceptive effects of spinal and systemic administration of acetaminophen (paracetamol) are lost in Trpa1 − / − mice. The electrophilic metabolites N-acetylp-benzoquinoneimine and p-benzoquinone, but not acetaminophen itself, activate mouse and human TRPA1. These metabolites also activate native TRPA1 and, as a consequence, reduce voltage-gated calcium and sodium currents in primary sensory neurons. The N-acetyl-pbenzoquinoneimine metabolite l-cysteinyl-S-acetaminophen was detected in the mouse spinal cord after systemic acetaminophen administration. In the hot-plate test, intrathecal administration of N-acetyl-p-benzoquinoneimine, p-benzoquinone and the electrophilic TRPA1 activator cinnamaldehyde produced antinociception that was lost in Trpa1 − / − mice. Intrathecal injection of a non-electrophilic cannabinoid, ∆ 9 -tetrahydrocannabiorcol, also produced TRPA1-dependent antinociception in this test. our study provides a molecular mechanism for the antinociceptive effect of acetaminophen and discloses spinal TRPA1 activation as a potential pharmacological strategy to alleviate pain.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 80%

Section: The Antinociceptive Effect Of Apap Requires Trpa1mentioning

confidence: 92%

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TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ9-tetrahydrocannabiorcol

et al. 2011

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“…Desensitization occurs with repeated administration of capsaicin, is a receptor-mediated process, and involves Ca 2ϩ -and calmodulin-dependent processes and phosphorylation of the cation channel (Winter et al, 1995;Wood and Docherty, 1997). Capsaicin induces release of substance P and calcitonin gene-related peptide from both peripheral and central terminals of sensory neurons, and desensitization inhibits such release (Holzer, 1991); such inhibition may result from inhibition of voltage-gated Ca 2ϩ -currents (Docherty et al, 1991;Winter et al, 1995). Neurotoxicity is partially osmotic and partially due to Ca 2ϩ entry with activation of Ca 2ϩ -sensitive proteases (Wood et al, 1989;Winter et al, 1995).…”

Section: Capsaicinmentioning

confidence: 99%

Topical and Peripherally Acting Analgesics

2003

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“…It is established that capsaicin blocks voltage-dependent Na ϩ , K ϩ , and Ca 2ϩ channels (Marsh et al, 1987;Docherty et al, 1991;Kehl, 1994), which will prevent the generation of trains of action potentials. Despite these "local anesthetic" effects, capsaicin is pungent, meaning that action potentials are transmitted to the higher centers and that in primary nociceptors, depolarization precedes inhibition.…”

Section: Speculations Regarding the Basis Of Pungency Of Capsaicin Anmentioning

confidence: 99%

The Responses of Rat Trigeminal Ganglion Neurons to Capsaicin and Two Nonpungent Vanilloid Receptor Agonists, Olvanil and Glyceryl Nonamide

Liu

Chen

et al. 1997

J. Neurosci.

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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 Ϫ60 mV, capsaicin, olvanil, and GLNVA were found to activate one or two kinetically distinct inward currents. Two inward currents were also activated when extracellular Ca 2ϩ was replaced with Ba 2ϩ and also when intracellular chloride was replaced by aspartate. The reversal potentials of the rapidly and slowly activating currents were 15.3 Ϯ 6 and Ϫ4.0 Ϯ 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 kinetics of the currents evoked by 1 M olvanil and 30 M GLNVA are considerably slower than those evoked by 1 M capsaicin. Measurements of the peak current, Ip, versus agonist concentration were fit to the Hill equation to yield values of the half maximal concentrations (K 1/2 ), and the Hill coefficients (n). For capsaicin, olvanil, and GLNVA, K 1/2 ϭ 0.68, 0.59, and 27.0 M; and n ϭ 1.38, 1.32, and 1.24, respectively.We propose that olvanil and GLNVA are nonpungent because they activate different subtypes of receptors and/or because of their activation kinetics (compared with capsaicin) are, on average, slower than the rate they inhibit action potentials from polymodal nociceptors. Key words: pain; taste; vanilloid receptors; pungent; olvanil; capsaicinCapsaicin, the pungent ingredient in chili pepper, produces pain and inflammation when placed on skin or mucus membranes (Holzer, 1991;Szolcanyi et al., 1991). These effects result from the activation of cation-selective channels in polymodal nociceptors causing peptides and transmitters to be released from their peripheral and central terminals. The selectivity of capsaicin for polymodal nociceptors, coupled with the fact that on repeated applications it produces a long-lasting desensitization of these neurons, has made it useful clinically as an anti-nociceptive and -inflammatory compound. a One disadvantage of using capsaicin clinically is that its initial contact with skin produces marked pain and inflammation that sometimes prevents continuance. To reduce these initial responses, protocols were developed in which the capsaicin concentration, the interstimulus interval, and the delivery vehicle were varied systematically (Craft and Porreca, 1992). Another approach was to synthesize analogs of capsaicin with properties that will not cause marked pain on the initial application. This latter approach has followed the pioneering structure activity work of Szolcsanyi and Jansco-Gabor (1975a,b), who found that analogs with longer acyl chains or with altered phenolic hydroxy groups were less pun...

show abstract

Capsaicin causes prolonged inhibition of voltage-activated calcium currents in adult rat dorsal root ganglion neurons in culture

Cited by 96 publications

References 17 publications

TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ9-tetrahydrocannabiorcol

TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ9-tetrahydrocannabiorcol

Topical and Peripherally Acting Analgesics

The Responses of Rat Trigeminal Ganglion Neurons to Capsaicin and Two Nonpungent Vanilloid Receptor Agonists, Olvanil and Glyceryl Nonamide

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