nalbuphine and enadoline

Squirrel monkeys were trained to discriminate i.m. injections of the kappa-opioid receptor agonist enadoline (0.0017 mg/kg) from saline in a two-lever drug-discrimination procedure. Enadoline produced a reliable discriminative stimulus that was reproduced by the kappa-selective agonists PD 117302, U 50,488, GR 89686A, (-)-spiradoline, ICI 204448, and EMD 61753, and by the mixed-action kappa/mu-agonists bremazocine and ethylketocyclazocine. The discriminative stimulus effects of enadoline were not reproduced by the mu-selective agonist morphine, the delta-selective agonist BW373U86, the mixed-action opioids nalbuphine and nalorphine, or by the less active enantiomers of enadoline and spiradoline PD 129829 and (+)-spiradoline, respectively. The selective mu-opioid antagonist beta-funaltrexamine (10.0 mg/kg) did not appreciably alter the dose-effect function for enadoline in any subject. However, the nonselective and kappa-selective opioid antagonists quadazocine (0.03-3.0 mg/kg) and nor-BNI (3-10 mg/kg), and the mixed-action opioid nalbuphine (0.3-30 mg/kg) served to surmountably antagonize enadoline's discriminative stimulus effects. The antagonist effects of nor-BNI were long-lasting and did not distinguish between drugs purported to act at different kappa-receptor subtypes. The present results bolster the view that common discriminative stimulus effects of enadoline and other opioids are mediated by kappa-agonist actions that are surmountably antagonized by nor-BNI in a long-lasting manner. The enadoline-antagonist effects of nalbuphine support the idea that it acts with low efficacy at kappa-opioid receptors.

Topics: Animals; Benzofurans; Discrimination Learning; Dose-Response Relationship, Drug; Male; Nalbuphine; Naltrexone; Narcotic Antagonists; Pyrroles; Pyrrolidines; Receptors, Opioid, kappa; Receptors, Opioid, mu; Saimiri; Thiophenes

The binding characteristics of the kappa opioid ligands [3H]U69,593 and [3H]bremazocine, the mu opioid ligand [3H][D-ala2,N-Me-Phe4,glycol5]enkephalin and the delta opioid ligand [3H]p-Cl-[D-pen2,5]enkephalin were studied in rhesus monkey brain membranes in saturation binding experiments and were followed by competition binding experiments with a variety of peptidic and nonpeptidic opioid ligands. The [3H]U69,593 sites appeared to be a subset of kappa opioid receptors (kappa-1 receptors: Kd, 1.2 nM; Bmax, 66 fmol/mg). [3H]Bremazocine (in the presence of mu and delta receptor-masking agents), bound to a larger population of kappa receptors (kappa-all: Kd, 0.39 nM; Bmax, 227 fmol/mg), which presumably included the aforementioned kappa-1 sites. Competition binding experiments revealed that the presently defined kappa-1 sites were similar to previously reported sites in other mammalian species, particularly in terms of the higher kappa-1 selectivity observed with arylacetamide (e.g., U50,488) vs. benzomorphan kappa agonists (e.g., ethylketocyclazocine). The kappa-selective antagonist norbinaltorphimine (nor-BNI) displayed a very small (2.3-fold) selectivity for kappa-1 vs. kappa-all sites. This led to the prediction that in rhesus monkeys (n = 3), systemically administered nor-BNI (10 mg/kg s.c.) should have a very moderate degree of antagonist selectivity for the antinociceptive effects of a putative kappa-1-agonist, the arylacetamide U50,488 (0.1-3.2 mg/kg s.c.), vs. those of the benzomorphan kappa agonist ethylketocyclazocine (0.01-056 mg/kg s.c.). This prediction was confirmed in vivo because nor-BNI (10 mg/kg) caused a robust and long lasting (up to 21 days) antagonism of the antinociceptive effects of U50,488 and a small but significant antagonism of ethylketocyclazocine. The arylacetamide congener Cl-977 (enadoline), which displayed an 11-fold kappa-1 vs. kappa-all binding selectivity, was not sensitive to nor-BNI pretreatment. This indicates that the kappa subtype-binding profile of an agonist is not necessarily predictive of its sensitivity to nor-BNI in vivo. Overall, the present results suggest that at least two functional kappa receptor populations may be present in rhesus monkey brain.

Topics: Analgesics, Opioid; Animals; Benzofurans; Brain Chemistry; Butorphanol; Dose-Response Relationship, Drug; Hot Temperature; Macaca mulatta; Nalbuphine; Naltrexone; Pyrrolidines; Radioligand Assay; Receptors, Opioid, kappa

The discriminative stimulus effects of enadoline were characterized in pigeons responding under a fixed-ratio 20 schedule of food presentation and discriminating between intramuscular injections of the kappa opioid agonist enadoline and saline. Cumulative doses of enadoline dose-dependently increased drug-key responding with the training dose of enadoline (0.178 mg/kg) producing > or = 90% drug key responding (% DR). In time course studies, doses of enadoline larger than 0.32 mg/kg produced > or = 90% DR for more than 40 min. Naltrexone antagonized both the discriminative stimulus and the rate-decreasing effects of enadoline (pA2 = 6.79 and 6.73, respectively); in some pigeons, naltrexone produced an unsurmountable antagonism of the enadoline discriminative stimulus. Substitution tests using the kappa agonists U-50,488, spiradoline, U-69,593 and ethylketocyclazocine resulted in > or = 90% DR in most, but not all, pigeons; at larger doses, all compounds markedly decreased response rates. Up to rate-decreasing doses, nalorphine, dynorphin A(1-13) amide (DYN), nalbuphine, butorphanol, morphine and ketamine failed to occasion > or = 90% DR; nalbuphine, nalorphine, butorphanol, but not DYN, antagonized the discriminative stimulus and the rate-decreasing effects of enadoline. This study established stimulus control with enadoline in pigeons and results from substitution studies in these pigeons support the view that the enadoline discriminative stimulus is mediated by kappa opioid receptors; these results further demonstrate that nalbuphine and butorphanol have kappa antagonist actions in pigeons. The negative results obtained with DYN are in contrast to previous demonstrations of kappa agonist effects for DYN and might provide support for the hypothesized importance of nonopioid systems in the effects of this peptide.

Topics: Animals; Benzofurans; Butorphanol; Columbidae; Discrimination Learning; Dose-Response Relationship, Drug; Dynorphins; Nalbuphine; Naltrexone; Pyrrolidines; Receptors, Opioid, kappa

Nalmefene [17-N-cyclopropylmethyl-3,14-beta-dihydroxy-4,5-alpha-epoxy-6- methylenemorphinan hydrochloride (also NIH 10365)], a 6-methylene derivative of naltrexone, was compared to naltrexone for its behavioral effects in rhesus monkeys. Nalmefene had opioid antagonist actions under all conditions, having a potency similar to that of naltrexone. In morphine-treated monkeys, discriminating between 0.01 mg/kg of naltrexone and saline, nalmefene substituted completely for naltrexone at doses larger than 0.001 mg/kg. The onset of discriminative stimulus effects was similar for nalmefene and naltrexone. A dose of 0.032 mg/kg of either antagonist occasioned > or = 90% naltrexone-level responding beginning 6 to 8 min after s.c. administration; the effects of this dose of either antagonist persisted for more than 1 hr. Like the parent compound naltrexone, nalmefene also antagonized the discriminative stimulus effects of opioid agonists. Nalmefene prevented the discriminative stimulus effects of morphine in monkeys acutely deprived of morphine and antagonized the discriminative stimulus effects of nalbuphine in a separate group of monkeys discriminating between nalbuphine and saline. At the dose of naltrexone and nalmefene that produced an equivalent antagonism of morphine when the antagonist was administered 0.25 hr before morphine (0.01 mg/kg), the duration of antagonist action was < 4 hr and > 6 hr, respectively. Nalmefene also attenuated the antinociceptive effects of the mu agonist alfentanil and the kappa agonist CI-977 [5R-(5,7,8-beta)-N-methyl- N-[7-(1-pyrrolidinyl)1-oxaspiro[4,5]dec-8-yl]-4-benzofuranaceta mide], being 55 times more potent in attenuating the antinociceptive effects of alfentanil as compared to Cl-977.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Alfentanil; Analgesics; Animals; Behavior, Animal; Benzofurans; Female; Macaca mulatta; Male; Molecular Structure; Nalbuphine; Naltrexone; Narcotic Antagonists; Pyrrolidines