Antinociception induced by civamide, an orally active capsaicin analogue

The antinociceptive effects of a novel capsaicin analogue, civamide (cis-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, capsazepine (15 mg/kg, s.c.), reversed the antinociceptive action of civamide (200 mg/kg) on the formalin test when it was given either 5 min or 55 min after oral civamide delivery. In contrast, capsazepine delivered 2 days after civamide had no effect upon the depressed formalin response. Civamide produced a significant increase in the response latency on the thermal paw withdrawal test, which persisted for 2-3 days. Civamide produced a modest, but statistically significant, reversal of low tactile thresholds otherwise observed in the Chung neuropathic rats. Morbidity (approximately 10%) was observed which was secondary to bronchial constriction occurring with gastric reflux. Civamide at the doses given did not produce motor dysfunction. Neither calcitonin gene-related 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 nerves was modestly reduced at 1 day after the delivery. These data suggest that an orally bioavailable capsaicin analogue, civamide, possessed analgesic activity with respect to several noxious stimuli, including inflammation-induced hyperalgesia, noxious thermal stimulation and nerve injury-induced tactile allodynia. The rapid onset and lack of change in the peptide levels in dorsal spinal cord suggests that the analgesic action of civamide is primarily a result of desensitization at the afferent terminals. The antinociception of civamide is probably mediated by at least two mechanisms: (i) an acute receptor occupancy dependent effect; and (ii) a persistent and receptor independent effect which is initiated by the acute exposure to the drug.