ENHANCEMENT OF A KAPPA-OPIOID RECEPTOR AGONIST-INDUCED ANALGESIA BY L-TYROSINE AND L-TRYPTOPHAN

The effects of the methyl esters of L-tyrosine (L-Tyr-OMe) and L-trypt ophan (L-Trp-OMe) on the analgesic action of yl-N-[2-(1-pyrrolidin)cyc lohexyl]-benzeneacetamide methane sulfonate (U-50,488H), a kappa-opioi d receptor agonist, were determined in male Swiss-Webster mice using t he tail-flick test. Intraperitoneal injections of U-50,488H produced a dose-dependent analgesic response. The analgesic response to all dose s of U-50,488H was potentiated by L-Tyr-OMe at 200 mg/kg injected intr aperitoneally 30 min prior to the injection of U-50,488H. The effect o f various doses of L-Tyr-OMe (50, 100 and 200 mg/kg) on the analgesia produced by 20 mg/kg of U-50,488H was also determined. The lowest dose (50 mg/kg) of L-Tyr-OMe did not modify U-50,488H-induced analgesia bu t the two higher doses enhanced it significantly. L-Tyr-OMe by itself at all the doses tested had no effect on the tail-flick latency. L-Trp -OMe (200 mg/kg) enhanced the analgesic action of 10 and 20 mg/kg dose s of U-50,488H but not that induced by a 5 mg/kg dose. The analgesia i nduced by 20 mg/kg of U-50,488H was potentiated by L-Trp-OMe at 100 an d 200 mg/kg but not by a 50 mg/kg dose. L-Trp-OMe by itself also did n ot alter the tail-flick latency. Previously, the studies in this labor atory have shown that L-Tyr-OMe potentiates morphine, a mu-opioid rece ptor agonist-induced analgesia. Taken together with the present data, it is dear that compounds like L-Tyr-OMe and L-Trp-OMe which by themse lves have little action on nociception can enhance opioid-induced anal gesia. Such a combination may decrease the requirement of the dose of the opioids and thus decrease the side effects associated with their u se.