OPIOID PHARMACOLOGY OF THE ANTINOCICEPTIVE EFFECTS OF LOPERAMIDE IN MICE

Loperamide (0.1-3.2 mg/kg i.p.) produced dose-dependent and complete s uppression of writhing in the acetic acid-induced writhing assay in mi ce. Naltrexone (NTX; 0.1-10.0 mg/kg s.c.) and its N-methylated derivat ive quaternary naltrexone (QNTX; 1.0 and 10.0 mg/kg s.c.) were roughly equipotent in antagonizing the antinociceptive effects of loperamide. In contrast, NTX was approximately 100-fold more potent than QNTX in antagonizing the antinociceptive effects of the classical mu agonist m orphine. Furthermore, the antinociceptive effects of loperamide were n ot antagonized by central administration of the selective mu antagonis t D-Phe Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP; 300 ng i.c.v.), or by systemic administration of either the kappa selective antagonist nor- binaltorphimine (nor-BNI; 32.0 mg/kg s.c.), or the delta antagonist na ltrindole (NTI; 10.0 mg/kg s.c.). These doses of CTAP, nor-BNI and NTI were effective antagonists of morphine, the kappa agonist U69,593 and the delta agonist BW 373U86 piperazinal)-3-hydroxybenzyl)-N,N-diethyl benzamide dihydrochloride], respectively. These results indicate that the antinociceptive effects of loperamide in mice are mediated, at lea st in part, by opioid receptors; however, these receptors are distinct from the opioid receptors mediating the effects of morphine, U69,593 and BW 373U86. These results are consistent with the hypothesis that l operamide produces its antinociceptive effects by acting, at least in part, at peripheral opioid receptors.