Differential effects of mu-, delta- and kappa-opioid receptor agonists on the discriminative stimulus properties of cocaine in rats.
The effects of selective mu-, delta- and kappa-opioid receptor agonists on the discriminative stimulus properties of cocaine were examined in rats trained to discriminate between cocaine (10 mg/kg) and saline. Cocaine produced a dose-related increase in cocaine-appropriate responses in all of the rats. In generalization tests, neither morphine (mu-opioid receptor agonist) nor N-methyl-N-7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-11-4-benzofu ranacetamide (U50,488H: kappa-opioid receptor agonist) generalized to the discriminative stimulus properties of cocaine. On the other hand, the newly synthesized non-peptide selective delta-opioid receptor agonist 2-methyl-4a alpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a alpha-octahydro-quinolino(2,3,3,-g)isoquinoline (TAN-67) partially generalized (56.7% cocaine-appropriate responses) to the discriminative stimulus properties of cocaine. Intracerebroventricular (i.c.v.) administration of [D-Ala2]deltorphin II (peptide delta 2-opioid receptor agonist) completely generalized, while neither [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO: mu-opioid receptor agonist) nor [D-Pen2,D-Pen5]enkephalin (DPDPE; delta 1-opioid receptor agonist) generalized to the discriminative stimulus properties of cocaine. These results suggest that the discriminative stimulus properties of cocaine may be partially mediated by delta-opioid (especially delta 2-opioid) receptors. In combination tests, pretreatment with morphine (3.0 mg/kg) and TAN-67 (3.0 and 10 mg/kg) significantly potentiated the discriminative stimulus properties cocaine. In contrast, pretreatment with U50,488H (2.0 and 4.0 mg/kg) scarcely shifted the discriminative stimulus properties of cocaine. Furthermore, the potentiating effect of 3.0 mg/kg morphine on the discriminative stimulus properties of cocaine was attenuated by 2.0 mg/kg U50,488H. In contrast, the potentiating effect of 10 mg/kg TAN-67 on the discriminative stimulus properties of cocaine was not reversed by either 2.0 or 4.0 mg/kg U50,488H. These results suggest that mu-, delta- and kappa-opioid receptor agonists modulate the discriminative stimulus properties of cocaine through different mechanisms, perhaps through different effects on the dopaminergic system.
Suzuki
T
T
Department of Pharmacology, School of Pharmacy, Hoshi University, Tokyo, Japan.
Mori
T
T
Tsuji
M
M
Maeda
J
J
Kishimoto
Y
Y
Misawa
M
M
Nagase
H
H
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000633:toxicity*; D004193:Discrimination Learning / Q000187:drug effects*; D004192:Discrimination, Psychological / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000008:administration & dosage / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000633:toxicity; D009294:Narcotics / Q000008:administration & dosage / Q000633:toxicity*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017465:Receptors, Opioid, delta / Q000819:agonists*; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D019966:Substance-Related Disorders
D000700:Analgesics; D004745:Enkephalins; D009294:Narcotics; D011759:Pyrrolidines; D011804:Quinolines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C094142:TAN 67; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; D020881:Enkephalin, D-Penicillamine (2,5)-; D003042:Cocaine