3P049 Effects of cyclosporin A, a P-glycoprotein inhibitor, on antinociception in rats induced by a new μ-opioid receptor agonist with pirerazine moiety

To assess the role of P-glycoprotein (P-gp) in the blood-brain barrier (BBB) transport of opioids, effects of cyclosporin A (CsA), a P-gp inhibitor, on opioid-induced inhibition of tail-flick response (TFR) had been examined. Results had shown that the magnitude of inhibition of TFR of rats produced by the s. c. administration of either loperamide or difenoxin, both compounds having a piperidine moiety in their structures, was significantly increased by CsA. In the present investigation, the effect of CSA on the magnitude of inhibition of TFR of rats produced by the s. c. administration of 4-[4-(2-methoxyphenyl)piperazin-1-yl]-N, N-dimethyl-2, 2-diphenylbutanamide, a new μ-opioid receptor agonist with piperazine moiety, was examined. The magnitude of inhibition of TFR of rats produced by the new compound and loperamide indicate that the new compound is 5- to 10-fold more potent than loperamide. Additionally, the magnitude of the inhibition induced by the s. c. administration of the new compound was significantly increased by the i, p. pretreatment of rats with CsA. Furthermore, in rats pretreated with of CsA, the potency to inhibit the TFR by the new compound was approximately 10-fold higher than that by loperamide. Results indicate that the new compound has a potent antinociceptive effect and its entry into the brain is prevented by P-gp expressed in the BBB.