INTRACELLULAR MESSENGERS CONTRIBUTING TO PERSISTENT NOCICEPTION AND HYPERALGESIA INDUCED BY L-GLUTAMATE AND SUBSTANCE-P IN THE RAT FORMALINPAIN MODEL

The contribution of the intracellular messengers nitric oxide, arachid onic acid and protein kinase C to persistent nociception in response t o tissue injury in rats was examined following the subcutaneous inject ion of formalin into the hindpaw. Formalin injury-induced nociceptive behaviours were reduced by intrathecal pretreatment with inhibitors of nitric oxide synthase (N-G-nitro-L-arginine methyl ester, L-NAME), ar achidonic acid (dexamethasone) or protein kinase C [protein kinase C ( 19-26) and 1-95-(isoquinolinesulphonyl)-2-methylpiperazine dihydrochlo ride, H-7]. Each of these agents affected the tonic, but not the acute , phase of the formalin response. Furthermore, none of these agents af fected mechanical or thermal flexion reflex thresholds in rats not inj ected with formalin. Conversely, formalin-induced nociceptive response s were enhanced by stimulators of nitric oxide (sodium nitroprusside), arachidonic acid metabolism (arachidonic acid) or protein kinase C [( +/-)-1 -oleoyl-2-acetyl-glycerol], and were slightly reduced by inosit ol trisphosphate. Mechanical flexion reflexes were also reduced by ara chidonic acid, while thermal flexion reflexes were reduced after treat ment with sodium nitroprusside, arachidonic acid or [(+/-)-1-oleoyl-2- acetyl-glycerol]. The enhancement of formalin nociceptive behaviours ( hyperalgesia) in rats treated with L-glutamate or substance P was reve rsed by pretreatment with inhibitors of nitric oxide (L-NAME), arachid onic acid (dexamethasone) or protein kinase C (H-7). The results sugge st that central sensitization and persistent nociception following for malin-induced tissue injury, and the hyperalgesia in the formalin test induced by L-glutamate and substance P, are dependent on the intracel lular messengers nitric oxide, arachidonic acid and protein kinase C.