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 E2, 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 E2-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 (NG-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.