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Journal of Pharmacology and Experimental Therapeutics

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Abstract

Effects of opioid agonists selective for mu, kappa and delta opioid receptors on schedule-controlled responding in rhesus monkeys: antagonism by quadazocine.

S S Negus, T F Burke, F Medzihradsky and J H Woods
Journal of Pharmacology and Experimental Therapeutics November 1993, 267 (2) 896-903;
S S Negus
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T F Burke
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F Medzihradsky
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J H Woods
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Abstract

Rhesus monkeys were trained to respond under a fixed-ratio 30 schedule of food reinforcement. The mu opioid agonists alfentanil and fentanyl, the kappa opioid agonists ethylketocyclazocine (EKC) and U69,593, the delta opioid agonist BW373U86 [(+-)-4-((R*)-a-((2S*5R*)-4-allyl-2,5-dimethyl-1-piperazinal)-3-h ydroxy- benzyl)-N,N-diethylbenzamide dihydrochloride] and the nonopioid, noncompetitive N-methyl-D-aspartate antagonist ketamine all produced a dose-dependent decrease in rates of responding. Quadazocine (0.1-10 mg/kg) antagonized the rate-decreasing effects of all the opioid agonists, but not of ketamine. The in vivo apparent pA2 values (95% CL) for quadazocine in combination with each agonist were: alfentanil, 7.7 (7.6-7.8); fentanyl, 7.7 (7.6-7.8); EKC, 6.3 (5.9-6.7); U69,593, 6.5 (5.9-7.0); and BW373U86, 5.5 (5.3-5.8). Additionally, antagonist effects of individual doses of quadazocine in combination with each agonist were evaluated by using in vivo apparent pKB analysis, and pKB values were found to be similar to the more rigorously determined pA2 values. The relative pA2 and pKB values of quadazocine in antagonizing the rate-decreasing effects of mu, kappa and delta opioid agonists corresponded to the relative potency of quadazocine in displacing the specific binding of the mu agonist [3H]Tyr-D-Ala-Gly-(Me)-Phe-Gly-ol (IC50 = 0.080 nM), the kappa agonist [3H]U69,593 (IC50 = 0.52 nM) and the delta agonist [D-Pen2,D-Pen5]-[3H]enkephalin (IC50 = 4.6 nM) from binding sites in membranes from monkey brain cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

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Journal of Pharmacology and Experimental Therapeutics
Vol. 267, Issue 2
1 Nov 1993
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Abstract

Effects of opioid agonists selective for mu, kappa and delta opioid receptors on schedule-controlled responding in rhesus monkeys: antagonism by quadazocine.

S S Negus, T F Burke, F Medzihradsky and J H Woods
Journal of Pharmacology and Experimental Therapeutics November 1, 1993, 267 (2) 896-903;

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Abstract

Effects of opioid agonists selective for mu, kappa and delta opioid receptors on schedule-controlled responding in rhesus monkeys: antagonism by quadazocine.

S S Negus, T F Burke, F Medzihradsky and J H Woods
Journal of Pharmacology and Experimental Therapeutics November 1, 1993, 267 (2) 896-903;
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