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

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.