Opioid receptor antagonists discriminate between presynaptic mu and delta receptors and the adenylate cyclase-coupled opioid receptor complex in the brain.
The present study addressed the question as to whether or not' interacting mu and delta opioid receptors, which may constitute an opioid receptor complex-inhibitory coupled to adenylate cyclase in rat neostriatum, display different antagonistic properties than the classical (noncomplexed) mu and delta receptors. In concentrations that antagonized the presynaptic inhibitory effect of [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO) on [3H]norepinephrine release from rat neocortical slices, the cyclic somatostatin-related mu opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 did not affect the inhibition of dopamine-sensitive adenylate cyclase caused by DAMGO in neostriatal slices. The delta opioid receptor antagonist naltrindole appeared to be about 200-fold more effective as an antagonist against inhibitory effect of [D-Ser2(O-tert-butyl),Leu5]enkephalyl-Thr6 on [14C]acetylcholine release from neostriatal slices than against the inhibitory effect of DAMGO on [3H]norepinephrine release from neocortical slices, in agreement with the involvement of presynaptic delta and mu receptors, respectively. However, regarding the inhibitory effect of DAMGO and [D-Ser2(O-tert-butyl),Leu5] enkephalyl-Thr6 on adenylate cyclase activity in neostriatal slices, naltrindole not only displayed a very low affinity but also only 10-fold delta-selectivity. In striking contrast to D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 and naltrindole, naloxone did not discriminate between the neurotransmitter release-and adenylate cyclase-inhibitory effects of DAMGO and [D-Ser2(O-tert-butyl), Leu5]enkephalyl-Thr6.(ABSTRACT TRUNCATED AT 250 WORDS)
Schoffelmeer
A N
AN
Department of Pharmacology, Free University, Medical Faculty, Amsterdam, The Netherlands.
De Vries
T J
TJ
Hogenboom
F
F
Hruby
V J
VJ
Portoghese
P S
PS
Mulder
A H
AH
D000109:Acetylcholine / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009019:Morphinans / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / 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; D000262:Adenylyl Cyclases; C055382:naltrindole; D000109:Acetylcholine; D009638:Norepinephrine