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.
Hua
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Department of Anesthesiology, University of California, San Diego, La Jolla 92093-0818, USA.
Chen
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Hwang
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Yaksh
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D000284:Administration, Oral; D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D006358:Hot Temperature; D008297:Male; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013373:Substance P / Q000378:metabolism
D000700:Analgesics; D013373:Substance P; D015740:Calcitonin Gene-Related Peptide; C071423:capsazepine; D002211:Capsaicin