A spinal mechanism of action is involved in the antinociception produced by the capsaicin analogue NE 19550 (olvanil)

Abstract

We have studied the effect of NE 19550 (olvanil, N-(4-hydroxy-3-methoxyphenyl) methyl-9Z-octadecenamide), a capsaicin analogue with approximately equipotent antinociceptive activity in vivo compared with capsaicin, on nociceptive responses recorded from spinal dorsal horn neurones in vivo and from a spinal ventral root in vitro. In adult rats anaesthetized with halothane, antinociceptive doses of olvanil (20-40 mumol/kg, s.c.) reduced C-fibre responses evoked in wide dynamic range, lumbar dorsal horn neurones, by peripheral transcutaneous electrical stimulation. Intradermal injection of olvanil, localized to a discrete region of the peripheral receptive field, did not activate C-fibres nor change C-fibre evoked activation of dorsal horn neurones. Spinal intrathecal administration of olvanil attenuated C-fibre evoked responses and, at the highest concentration, significantly reduced A beta-fibre evoked activity. In the neonatal rat spinal cord/tail preparation maintained in vitro, superfusion of the cord with olvanil (500 nM-5 microM) did not evoke a depolarization but responses to peripheral noxious stimulation were attenuated. In a similar in vitro preparation of the neonatal rat spinal cord, the release of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) was measured in spinal cord superfusates. Capsaicin (2-10 microM) evoked a large release of CGRP-LI but olvanil (2-10 microM) produced only a small or undetectable release. Following the administration of each substance, however, the release of CGRP-LI evoked by a depolarizing potassium stimulus was significantly attenuated. These data indicate that C-fibre input to the dorsal horn was attenuated by acute systemic doses of olvanil that were antinociceptive in behavioural tests. This effect was unlikely to be due to impairment of C-fibre function by a peripheral locus of action but was more consistent with an action in the spinal cord in which the reduced release of a neurotransmitter substance from afferent nerve terminals may play a prominent role.

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

“…As noted previously, one or both of these compounds may differ from capsaicin in potency, thermoregulatory effects, peptide release, blood pressure lowering, and pungency. Although there are several reasons why olvanil and GL-NVA may give different physiological responses than capsaicin, such as the possibility that capsaicin acts peripherally whereas olvanil acts centrally (Dickenson et al, 1990), our data suggest that the differences between these two nonpungent analogs and capsaicin may be accounted for by either the presence and distribution of different receptor subtypes and /or by the slower rate of activation of the currents evoked by GLNVA and olvanil.…”

“…There is no question that olvanil inhibits Na ϩ channels because it blocks evoked responses from A␤-fibers (Dickenson et al, 1990). The comparatively slower activation kinetics seen in most neurons with olvanil cannot be attributed to different K 1/2 values, because on average they were the same as the capsaicin values (Fig.…”

“…That is, olvanil was less potent than capsaicin in its ability to activate nociceptors. Also 2-10 M capsaicin, but not 2-10 M olvanil, evoked the release of peptides from rat spinal cord (Dickenson et al, 1990). In contrast, olvanil was found to be 10 times more potent than capsaicin in increasing blood flow in rabbit skin (Hughes et al, 1992).…”

“…For example, in whole-nerve recordings from rat spinal cord the response evoked by 2 M capsaicin was mimicked by 500 M olvanil (Dickenson et al, 1990;. That is, olvanil was less potent than capsaicin in its ability to activate nociceptors.…”

Differential Activation and Desensitization of Sensory Neurons by Resiniferatoxin

“…Such differences are evident not only in comparisons between vanilloids of the RTX and capsaicin classes, but also within each class. Thus, the vanilloid analog olvanil differentially induces desensitization compared with capsaicin (Dickenson et al, 1990;Dray et al, 1990). The dissection of patterns of biological response can be explained most readily by receptor subtypes, although it is also clear that differences in pharmacokinetics can complicate interpretation (Maggi et al, 1990).…”