ANTINOCICEPTION INDUCED BY CIVAMIDE, AN ORALLY-ACTIVE CAPSAICIN ANALOG

The antinociceptive effects of a novel capsaicin analogue, civamide (c is-8-methyl-N-vanillyl-6-nonenamide), given orally to adult rats were examined. In the formalin test, civamide significantly suppressed the flinch response, particularly phase 2, in a dose-dependent fashion (20 -200 mg/kg). This inhibitory effect started 1 h after application, and was maintained for 4-7 days. A competitive capsaicin antagonist, caps azepine (15 mg/kg, s.c.), reversed the antinociceptive action of civam ide (200 mg/kg) on the formalin test when it was given either 5 min or 55 min after oral civamide delivery. In contrast, capsazepine deliver ed 2 days after civamide had no effect upon the depressed formalin res ponse. Civamide produced a significant increase in the response latenc y on the thermal paw withdrawal lest which persisted for 2-3 days. Civ amide produced a modest, but statistically significant, reversal of lo w tactile thresholds otherwise observed in the Chung neuropathic rats. Morbidity (approximately 10%) was observed which was secondary to bro nchial constriction occurring with gastric reflux. Civamide at the dos es given did not produce motor dysfunction. Neither calcitonin gene-re lated peptide (CGRP) nor substance P (SP) concentrations in dorsal or ventral spinal cord were altered by civamide (200 mg/kg) up to 5 days, whereas CGRP, but not SP, in dorsal root ganglia (DRG) and sciatic ne rves was modestly reduced at 1 day after the delivery. These data sugg est that an orally bioavailable capsaicin analogue, civamide, possesse d analgesic activity with respect to several noxious stimuli, includin g inflammation-induced hyperalgesia, noxious thermal stimulation and n erve injury-induced tactile allodynia. The rapid onset and lack of cha nge in the peptide levels in dorsal spinal cord suggests that the anal gesic action of civamide is primarily a result of desensitization at t he afferent terminals. The antinociception of civamide is probably med iated by at least two mechanisms: (i) an acute receptor occupancy depe ndent effect; and (ii) a persistent and receptor independent effect wh ich is initiated by the acute exposure to the drug. (C) 1997 Internati onal Association for the Study of Pain. Published by Elsevier Science B.V.