Isobolographic and dose-response analyses of the interaction between intrathecal mu and delta agonists: effects of naltrindole and its benzofuran analog (NTB)

AB Malmberg and TL Yaksh

Department of Anesthesiology, University of California, San Diego, La Jolla.

Intrathecal administration of DPDPE, PL017, DAMGO, morphine and DADLE produced a dose-dependent increase in hot plate response latency, with the order of potency (ED50 nmol) being: DAMGO (0.17) > DADLE (0.70) > or = PL017 (1.2) > morphine (15) > DPDPE (130). Characteristics of the spinal mu and delta interaction were determined independently by two methods. 1) In the presence of a fixed dose of DPDPE (150 nmol), there was a left shift in the dose-response curve of the mu agonist, with the magnitude of the shifts being greater than those anticipated from a simple additive interaction: PL017 (31-fold) > or = DAMGO (20-fold) > morphine (6.5-fold) > 4-fold (theoretical additive shift). 2) With an isobolographic analysis, a statistically significant nonlinearity was observed, suggesting a multiplicative interaction upon coadministration of the delta-selective ligand DPDPE together with all the tested mu- selective agonists. Examining antagonist activity, mu agonists were antagonized in a dose-dependent fashion by naloxone and naltrindole- benzofuran analog, whereas DPDPE was reversed by all three antagonists used, naltrindole, naltrindole-benzofuran analog and naloxone. The synergic effect produced by the coadministration of PL017 and DPDPE, was reversed in a dose-dependent fashion by all three antagonists, suggesting that the interaction requires the concurrent agonist occupancy of mu and delta receptors.

Volume 263, Issue 1, pp. 264-275, 10/01/1992
Copyright © 1992 by American Society for Pharmacology and Experimental Therapeutics

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