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.
Malmberg
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Department of Anesthesiology, University of California, San Diego, La Jolla.
Yaksh
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D000698:Analgesia; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016308:Enkephalin, Leucine-2-Alanine / Q000494:pharmacology; D004745:Enkephalins / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D007278:Injections, Spinal; D008297:Male; D009019:Morphinans / Q000494:pharmacology*; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000187:drug effects*
D004745:Enkephalins; D007211:Indoles; D009019:Morphinans; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009271:Naltrexone; D016308:Enkephalin, Leucine-2-Alanine; D009020:Morphine; C055382:naltrindole