S14080, A PERIPHERAL ANALGESIC ACTING BY RELEASE OF AN ENDOGENOUS CIRCULATING OPIOID-LIKE SUBSTANCE

1 The oral administration of a benzothiazolinone derivative (benzoyl-6 dihydro-2,3 benzothiazole), S14080, caused dose-dependent antinociception in the rat paw pressure test, which represents a model of mechanical hyperalgesia. S14080 had no significant effect on the inflammatory oedema induced by carrageenin or on the tail flick test, nor did it possess a notable antipyretic effect. 2 Post-treatment with S14080 dose-dependently antagonized the hyperalgesia induced by prostaglandin El, bradykinin, dopamine and by the hyperalgesic cytokines reported to be released by carrageenin (tumour necrosis factor alpha, interleukin-1 and interleukin-8). 3 The blockade of prostaglandin E(2)-induced paw hyperalgesia by oral pretreatment of the rats with S14080 was abolished by prior intraplantar administration of either naloxone or NorBNI which are non-specific and specific kappa opioid antagonists, respectively. 4 Adrenalectomy abolished the oral antinociceptive effect of S14080. 5 Five consecutive daily injections of S14080 did not produce tolerance such as that seen with the central antinociceptive action of morphine. 6 As with peripherally acting opiates, the antinociceptive activity of S14080 was abolished by the intraplantar injection of agents which inhibit either arginine synthetase (N-G-monomethyl-L-arginine) or the activation of guanylate cyclase (methylene blue). 7 We conclude that S14080 is a new type of peripheral antinociceptive which, in rats, acts mainly by releasing an endogenous, opioid-like substance from the adrenal glands.