Behavioral effects of the systemically active delta opioid agonist BW373U86 in rhesus monkeys.
The behavioral effects of (+-)-4-((alpha R*)-alpha-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3- hydroxybenzyl)-N,N-diethylbenzamide dihydrochloride (BW373U86), a nonpeptidic, systemically active, delta opioid agonist, were examined in rhesus monkeys. BW373U86, the mu agonist alfentanil and the kappa agonist U69,593 [(5 alpha,7 alpha,8 beta)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro- (4,5)dec-8-yl)benzeneacetamide] all produced a dose-dependent suppression of response rates maintained under a fixed ratio 30 schedule of food presentation. The rate-suppressing effects of BW373U86 lasted 1 to 2 hr and were no longer apparent after 4 hr. The selective delta antagonist naltrindole (NTI) antagonized the effects of BW373U86 with relatively high potency (pKB = 6.5) and the antagonist effects of NTI against BW373U86 lasted approximately 4 hr. NTI was less potent in antagonizing alfentanil (pKB = 5.1) and the highest dose of NTI examined (10.0 mg/kg) did not antagonize U69,593. BW373U86 did not generalize to the discriminative stimulus effects of the mu agonist alfentanil or the kappa agonist ethylketocyclazocine. BW373U86 also did not produce antinociceptive effects in the warm-water tail-withdrawal procedure, significant respiratory depressant effects in monkeys breathing either air or 5% CO2 or reinforcing effects in a self-administration procedure. The highest dose of BW373U86 examined (1.78 mg/kg) produced convulsions in one monkey. The high relative potency of NTI to antagonize the rate-suppressing effects of BW373U86 was consistent with the characterization of BW373U86 as a systemically active, delta-selective agonist in rhesus monkeys. Under the conditions evaluated in the present study, the delta receptors to which BW373U86 binds do not appear to mediate antinociceptive, respiratory depressant or reinforcing effects in monkeys.
Negus
S S
SS
Department of Pharmacology, University of Michigan, Ann Arbor.
Butelman
E R
ER
Chang
K J
KJ
DeCosta
B
B
Winger
G
G
Woods
J H
JH
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001549:Benzamides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005260:Female; D008253:Macaca mulatta; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000819:agonists*; D012119:Respiration / Q000187:drug effects
D000700:Analgesics; D001549:Benzamides; D009292:Narcotic Antagonists; D010879:Piperazines; D017465:Receptors, Opioid, delta; C083877:BW 373U86; D009271:Naltrexone; C055382:naltrindole