MECHANISM OF DICLOFENAC ANALGESIA - DIRECT BLOCKADE OF INFLAMMATORY SENSITIZATION

Indomethacin, a typical cyclo-oxygenase inhibitor, acts as an analgesic by preventing the hyperalgesia induced by prostaglandins during inflammation. Analgesics of the dipyrone type directly block the sensitization of nociceptors. In the present investigation, the analgesic effect of diclofenac was compared with that of indomethacin in two algesimetric tests which permit discrimination between the two types of analgesic: the rat knee joint incapacitation and the rat paw hyperalgesia tests. The analgesics were given either pre- or posttreatment relative to the induction of hyperalgesia with carrageenin or prostaglandin E(2). In both tests intraperitoneal pretreatment with indomethacin was equally or slightly more potent than diclofenac. Posttreatment with diclofenac was more effective than posttreatment with indomethacin. This was particularly evident in the paw hyperalgesia test in which posttreatment with indomethacin was not effective while diclofenac caused dose-dependent analgesia. When nociception was induced by PGE(2) in both tests, the administration of indomethacin directly into the knee joint or rat paw had no effect while diclofenac continued to cause dose-dependent analgesia. Thus, diclofenac has a direct effect on ongoing hyperalgesia in addition to its ability to block cyclo-oxygenase, Naloxone and N-methyl-nalorphine did not affect diclofenac analgesia, thus indicating that the analgesic effect of the latter is independent of a central or peripheral opioid effect. Local administration of agents which inhibit the formation of nitric oxide (N-G-monomethyl-L-arginine) or inhibit the activation of guanylate cyclase by nitric oxide (methylene blue) abolished diclofenac-induced analgesia. Thus, the present results indicate that the principal analgesic action of diclofenac is not associated with the prevention of Sensitization but is due to the functional down-regulation of sensitized, peripheral pain receptors. This functional down-regulation seems to be the result of stimulation of the cGMP system via the arginine-nitric oxide pathway, a mechanism of analgesic action postulated for peripheral analgesics which directly block ongoing hyperalgesia.