Loperamide (ADL 2-1294), an opioid antihyperalgesic agent with peripheral selectivity

The antihyperalgesic properties of the opiate antidiarrheal agent loperamid e (ADL 2-1294) were investigated in a variety of inflammatory pain models i n rodents. Loperamide exhibited potent affinity and selectivity for the clo ned mu (K-i = 3 nM) compared with the delta (K-i = 48 nM) and kappa (K-i = 1156 nM) human opioid receptors. Loperamide potently stimulated [S-35]guano sine-5'-O-(3-thio)-triphosphate binding (EC50 = 56 nM), and inhibited forsk olin-stimulated cAMP accumulation (IC50 = 25 nM) in Chinese hamster ovary c ells transfected with the human mu opioid receptor. The injection of 0.3 mg of loperamide into the intra-articular space of the inflamed rat knee join t resulted in potent antinociception to knee compression that was antagoniz ed by naloxone, whereas injection into:the contralateral knee joint or via the i.m. route failed to inhibit compression-induced changes in blood press ure. Loperamide potently inhibited late-phase formalin-induced flinching af ter intrapaw injection (A(50) = 6 mu g) but was ineffective against early-p hase flinching or after injection into the paw contralateral to the formali n-treated paw. Local injection of loperamide also produced antinociception against Freund's adjuvant-(ED50= 21 mu g) or tape stripping- (ED50 = 71 mu g) induced hyperalgesia as demonstrated by increased paw pressure threshold s,in the inflamed paw. In all animal models examined, the potency of lopera mide after local administration was comparable to or better than that of mo rphine. Loperamide has potential therapeutic use as a peripherally selectiv e opiate antihyperalgesic agent that lacks many of the side effects general ly associated with administration of centrally acting opiates.