TY - JOUR T1 - Loperamide (ADL 2-1294), an Opioid Antihyperalgesic Agent with Peripheral Selectivity JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 494 LP - 502 VL - 289 IS - 1 AU - D. L. DeHaven-Hudkins AU - L. Cortes Burgos AU - J. A. Cassel AU - J. D. Daubert AU - R. N. DeHaven AU - E. Mansson AU - H. Nagasaka AU - G. Yu AU - T. Yaksh Y1 - 1999/04/01 UR - http://jpet.aspetjournals.org/content/289/1/494.abstract N2 - The antihyperalgesic properties of the opiate antidiarrheal agent loperamide (ADL 2-1294) were investigated in a variety of inflammatory pain models in rodents. Loperamide exhibited potent affinity and selectivity for the cloned μ (Ki = 3 nM) compared with the δ (Ki = 48 nM) and κ (Ki = 1156 nM) human opioid receptors. Loperamide potently stimulated [35S]guanosine-5′-O-(3-thio)triphosphate binding (EC50 = 56 nM), and inhibited forskolin-stimulated cAMP accumulation (IC50 = 25 nM) in Chinese hamster ovary cells transfected with the human μ opioid receptor. The injection of 0.3 mg of loperamide into the intra-articular space of the inflamed rat knee joint resulted in potent antinociception to knee compression that was antagonized by naloxone, whereas injection into the contralateral knee joint or via the i.m. route failed to inhibit compression-induced changes in blood pressure. Loperamide potently inhibited late-phase formalin-induced flinching after intrapaw injection (A50 = 6 μg) but was ineffective against early-phase flinching or after injection into the paw contralateral to the formalin-treated paw. Local injection of loperamide also produced antinociception against Freund’s adjuvant- (ED50 = 21 μg) or tape stripping- (ED50 = 71 μg) induced hyperalgesia as demonstrated by increased paw pressure thresholds in the inflamed paw. In all animal models examined, the potency of loperamide after local administration was comparable to or better than that of morphine. Loperamide has potential therapeutic use as a peripherally selective opiate antihyperalgesic agent that lacks many of the side effects generally associated with administration of centrally acting opiates. The American Society for Pharmacology and Experimental Therapeutics ER -