buprenorphine and tifluadom

The present study was designed to explore the nature of the interaction between mu and kappa opioid agonists in the rat drug discrimination procedure. In rats trained to discriminate the kappa agonist U50,488 (5.6 mg/kg) from water, the other kappa agonist bremazocine substituted completely for the U50,488 training stimulus, and the additional kappa agonist tifluadom substituted in three of five of rats tested. In contrast, the mu agonists morphine, fentanyl, and buprenorphine produced primarily vehicle-appropriate responding. When morphine, fentanyl, and buprenorphine were combined with the training dose of U50,488, all three mu agonists reduced U50,488-appropriate responding. In rats trained to discriminate the mu agonist morphine (10.0 mg/kg) from saline, the other mu agonists morphine and buprenorphine all substituted in a dose-dependent manner for the morphine training stimulus, whereas U50,488, bremazocine, and tifluadom produced primarily vehicle-appropriate responding. When combined with the training dose of morphine, bremazocine antagonized morphine's discriminative stimulus effects, whereas U50,488 and tifluadom had no effect. The barbiturate pentobarbital neither substituted for, nor antagonized, the discriminative stimulus effects of either U50,488 or morphine. These results suggest that mu agonists and kappa agonists produce interacting effects in the drug discrimination procedure in rats.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzodiazepines; Benzomorphans; Buprenorphine; Discrimination, Psychological; Dose-Response Relationship, Drug; Drug Interactions; Fentanyl; Male; Morphine; Pentobarbital; Pyrrolidines; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu

1. When U50 was given to rats over 5 d by twice-daily s.c. injection (but not when delivered by osmotic minipump), buprenorphine and naloxone each precipitated strong, qualitatively distinct, behavioral syndromes. 2. The same dose of buprenorphine provoked similar behaviors in rats given chronic U50 and chronic TIF (analogous s.c. injection protocols), suggestive of neuroadaptation to kappa agonists as a class. This adaptation clearly contrasts with that to chronic mu agonists. 3. The buprenorphine-induced syndrome was characterized by oral stereotypies which had an onset of about 5 min and a duration greater than 4 hr. The intensity was dependent on the dose of agonist injected. 4. The naloxone-induced syndrome was characterized by repetitive yawning and writhing. 5. If oral stereotypy, yawning and writhing are considered to represent an abstinence syndrome, then it will be necessary to use multiple or more selective kappa antagonists to fully unveil kappa dependence in the rat. 6. The present data indicate a strong trend toward the parallel development of tolerance in rats given a similar course of chronic U50 injections as those tested for physical dependence.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Adaptation, Physiological; Animals; Behavior, Animal; Benzodiazepines; Buprenorphine; Male; Naloxone; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Stereotyped Behavior

The effect of the irreversible opioid receptor antagonist, beta-funaltrexamine (beta-FNA), on antinociception produced by mu- and kappa-receptor agonists was studied in the rat. beta-FNA, 20 to 80 mg kg-1, s.c., given 24 h before testing, produced a dose-related antagonism of the effects of morphine in the paw pressure, hotplate and tail-flick tests. Following the 80 mg kg-1 dose, the degree of antagonism of morphine was stable for up to 48 h after dosing, but was reduced by 5 days and had disappeared by 8 days. In the paw pressure test, beta-FNA, 40 mg kg-1, s.c., antagonized the effects of fentanyl, buprenorphine, tifluadom, ethylketocyclazocine and proxorphan; it was without effect against the highly selective kappa-agonist, U-50,488. In light of these results, the possible opioid receptor selectivities of both the agonists and beta-FNA are reassessed.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzodiazepines; Buprenorphine; Cyclazocine; Ethylketocyclazocine; Fentanyl; Male; Naltrexone; Pain; Pyrrolidines; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu