Modulation of the potency and efficacy of mu-mediated antinociception by delta agonists in the mouse.
Previous reports have shown that [Leu5]enkephalin or [Met5] enkephalin, endogenous delta receptor agonists, or synthetic analogues of these substances, can respectively produce a positive (i.e., increase) or negative (i.e., decrease) modulation of the antinociceptive potency of mu agonists such as morphine; such modulation is believed to be the result of interactions between delta and mu receptors. In spite of these studies showing modulation of mu agonist potency, it is unclear whether delta agonists can similarly modulate the antinociceptive efficacy of mu agonists. This question was addressed by using several levels of nociceptive stimulus intensity in mice. As the nociceptive stimulus intensity increased, the i.c.v. morphine dose-response line was shown to be displaced progressively to the right with decreasing maximal effect (i.e., decreased efficacy) a pattern typical of partial agonists. In contrast, the antinociceptive potency and efficacy of i.c.v. etorphine was unaffected by increasing the stimulus intensity, suggesting that this compound has higher efficacy than morphine in this nociceptive assay. Coadministration of delta opioid agonists produced leftward ([D-Pen2, D-Pen5] enkephalin) or rightward ([Met5]enkephalin) displacement of the morphine dose-response line (i.e., changes in potency). When the delta agonists were coadministered with morphine under conditions of high stimulus intensity, the maximal antinociceptive effects of i.c.v. morphine were increased or decreased from studies with morphine alone (i.e., change in efficacy). Both changes in potency and efficacy produced by the delta agonists, but not the direct antinociceptive effects of morphine, were blocked by the delta antagonist, ICI 174,864, suggesting that modulation occurred via the delta receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Qi
J N
JN
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson.
Mosberg
H I
HI
Porreca
F
F
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D003061:Codeine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000494:pharmacology; D005048:Etorphine / Q000494:pharmacology*; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009019:Morphinans / Q000494:pharmacology*; D009020:Morphine / Q000494:pharmacology*; D010147:Pain Measurement; D011957:Receptors, Opioid / Q000187:drug effects*; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu
D000700:Analgesics; D004745:Enkephalins; D009019:Morphinans; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D005048:Etorphine; D009020:Morphine; D020881:Enkephalin, D-Penicillamine (2,5)-; D003061:Codeine