Kappa opioid antagonist effects of the novel kappa antagonist 5'-guanidinonaltrindole (GNTI) in an assay of schedule-controlled behavior in rhesus monkeys.
BACKGROUND
Opioid receptors are divided into three types: kappa, mu, and delta receptors. Receptor-selective antagonists are useful experimental tools for evaluation of opioid receptor-mediated processes. 5'-Guanidinonaltrindole (GNTI) was recently developed as a novel kappa-selective antagonist.


OBJECTIVE
To evaluate the potency, time course, and selectivity of GNTI's opioid antagonist effects in rhesus monkeys in an assay of schedule-controlled responding.


METHODS
Five rhesus monkeys were trained to respond under a fixed ratio 30 schedule of food reinforcement. The rate-decreasing effects of the kappa agonists U50,488 and U69,593, the mu agonist morphine, and the delta agonist SNC80 were examined alone and after pretreatment with GNTI (0.1 and 1.0 mg/kg i.m.; 1 h to 14 days).


RESULTS
U50,488, U69,593, morphine, and SNC80 dose-dependently decreased response rates in this procedure. GNTI produced a dose- and time-dependent antagonism of the rate-decreasing effects of U50,488. The kappa antagonist effects of GNTI had a slow onset and a long duration of action, and peak antagonist effects were observed after 24 h. A higher dose of 3.2 mg/kg GNTI eliminated responding in one monkey and was not studied further. The antagonist effects of GNTI were kappa selective, because 1.0 mg/kg GNTI also antagonized the effects of U69,593, but not those of morphine or SNC80.


CONCLUSIONS
These results suggest that GNTI is a potent and selective kappa antagonist with a slow onset and long duration of action in rhesus monkeys. Relative to the prototype kappa antagonist nor-binaltorphimine, GNTI may have some advantages as a tool for the study of kappa receptor-mediated processes.
Negus
S Stevens
SS
Alcohol and Drug Abuse Research Center, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA. negus@mclean.harvard.edu
Mello
Nancy K
NK
Linsenmayer
David C
DC
Jones
R M
RM
Portoghese
Philip S
PS
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D044482:Benzeneacetamides; D003216:Conditioning, Operant / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006146:Guanidines; D008253:Macaca mulatta; D008297:Male; D009019:Morphinans; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000819:agonists; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors*; D012055:Reinforcement Schedule; D013997:Time Factors
C411465:17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5'-guanidinyl-3,14-dihydroxyindolo(2',3'-6,7)morphinan; D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D001549:Benzamides; D044482:Benzeneacetamides; D006146:Guanidines; D009019:Morphinans; D009292:Narcotic Antagonists; D009294:Narcotics; D010879:Piperazines; D011759:Pyrrolidines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; C045444:U 69593