nalbuphine and clocinnamox

High doses of insurmountable antagonists or frequent administration of high doses of agonists are required to alter the potency of opioid agonists to produce discriminative stimuli. In the present study, insurmountable antagonism and repeated agonist treatment were combined to remove or disable a large enough proportion of mu-opioid receptors to alter the potency or maximal effect for four agonists in male Sprague-Dawley rats trained to discriminate 3.2 mg/kg morphine from saline under a fixed-ratio 15 schedule of food reinforcement. All agonists produced 88 to 100% morphine responding and were differentially sensitive to clocinnamox antagonism (fentanyl < morphine < or = buprenorphine = nalbuphine). Repeated treatment with 20 mg/kg per day morphine for 6 days decreased by 2- to 3-fold the potency of fentanyl, morphine, and buprenorphine to produce morphine responding. After morphine treatment, 3.2 mg/kg clocinnamox produced a 7-fold further decrease in morphine potency. Clocinnamox (10 mg/kg) produced a 7- and 12-fold further decrease in morphine and fentanyl potency, respectively, a reduction in the slope of the morphine dose-response curve, and a suppression of the maximal morphine responding for buprenorphine. Repeated treatment with 10 mg/kg per day morphine for 6 days failed to alter the potency of nalbuphine to produce morphine responding. In these morphine-treated rats, doses of 3.2 or 10 mg/kg clocinnamox suppressed the maximal morphine responding. Taken together, these data indicate that combined insurmountable antagonist and repeated agonist treatment produce additive effects at mu-opioid receptors to diminish discriminative stimulus effects in a manner predicted by the relative efficacy of opioid agonists.

Topics: Algorithms; Analgesics, Opioid; Animals; Buprenorphine; Cinnamates; Discrimination, Psychological; Dose-Response Relationship, Drug; Fentanyl; Male; Morphine; Morphine Derivatives; Nalbuphine; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Opioid, mu

Butorphanol and nalbuphine have substantial affinity for mu and kappa-opioid receptor sites, yet their behavioral effects in monkeys are largely consistent with a mu receptor mechanism of action. Using ethylketocyclazocine (EKC) discrimination and diuresis assays in rhesus monkeys (Macaca mulatta), the purpose of the current investigation was to characterize the in vivo kappa-opioid activity of these compounds through the use of an insurmountable mu-opioid receptor antagonist, clocinnamox. Alone, butorphanol (0.001-0.032 mg/kg i.m.) failed to generalize to EKC, and pretreatment with the competitive opioid receptor antagonist quadazocine (0.1 or 0.32 mg/kg i.m.) did not alter this generalization. At 24 h after clocinnamox (0.1 mg/kg i.m.) administration, butorphanol fully generalized to EKC, and this generalization was maintained in two of three monkeys at 72 h. Parallel results were observed in diuresis: butorphanol alone and in the presence of quadazocine (1 mg/kg i.m.) did not alter urine output, and a marked diuretic effect was demonstrated 24 h to 2 weeks after clocinnamox administration. Clocinnamox did not alter the discriminative stimulus or diuretic effects of nalbuphine or of the kappa-opioid receptor agonists EKC or U69593. These results are consistent with an in vivo agonist activity of butorphanol at kappa-opioid receptors that can only be demonstrated when an insurmountable antagonist has substantially eliminated the dominant receptor population through which it exerts its action.

Topics: Analgesics, Opioid; Animals; Azocines; Benzeneacetamides; Butorphanol; Cinnamates; Conditioning, Operant; Discrimination Learning; Diuresis; Dose-Response Relationship, Drug; Ethylketocyclazocine; Female; Injections, Intramuscular; Macaca mulatta; Male; Morphine Derivatives; Nalbuphine; Narcotic Antagonists; Pyrrolidines; Receptors, Opioid, kappa

The effects of CCAM, an insurmountable mu opioid receptor antagonist, were studied on the intravenous self-administration and thermoantinociception of alfentanil and nalbuphine, high- and low-efficacy opioid agonists, respectively, in rhesus monkeys. A single dose of 0.1 mg/kg CCAM IV reduced alfentanil's reinforcing potency in an FR30 TO 45s schedule 10-fold within a 24-h period. The maximum response rates remained essentially unchanged. At 1 mg/kg, CCAM caused a 300-fold shift of the alfentanil dose-response curve and also depressed the maximum response rates. CCAM also blocked insurmountably responding for nalbuphine, which was essentially abolished in two of three animals after a dose of 0.1 mg/kg CCAM and in all animals after 1 mg/kg. The acute insurmountable antagonism of alfentanil and nalbuphine self-administration by CCAM was used to determine the (relative initial) efficacy values of both agonists. Efficacy values, tau, were 391 for alfentanil and 196 for nalbuphine; the apparent in vivo dissociation constants, KA, were 0.16 mg/kg per injection (i.e., 350 nmol/kg per injection) for alfentanil and 0.14 mg/kg (370 nmol/kg per injection) for nalbuphine. In comparison, in a rhesus monkey 50 degrees C warm-water tail withdrawal assay, the tau values were 11 for alfentanil and 0.92 for nalbuphine, and the KA values were 0.2 mg/kg (440 nmol/kg) for alfentanil and 0.15 mg/kg (400 nmol/kg) for nalbuphine. Therefore, it seems that the higher potency of alfentanil and nalbuphine in self-administration as compared to thermal antinocieption in rhesus monkeys is predominantly due to a larger efficacy of the same agonist in self-administration (i.e., a larger receptor pool) rather than differences in apparent in vivo affinity.

Topics: Alfentanil; Animals; Cinnamates; Depression, Chemical; Dose-Response Relationship, Drug; Female; Infusions, Intravenous; Macaca mulatta; Male; Morphine Derivatives; Nalbuphine; Narcotic Antagonists; Pain Measurement; Receptors, Opioid, mu; Self Administration

Experiments tested the hypothesis that loss of agonist potency or effectiveness following irreversible antagonist or chronic agonist treatment may result from affinity changes at mu opioid receptors. Apparent affinity of naltrexone or nalbuphine for mu opioid receptors was measured in vivo in rats treated with either a single dose of the irreversible antagonist clocinnamox or repeated doses of morphine. Apparent affinity of each antagonist was estimated from its potency as an antagonist of discriminative stimulus or rate-decreasing effects of morphine in rats trained to discriminate 3.2 mg/kg morphine and saline. In control rats, apparent pA2 values for naltrexone and nalbuphine were 7.5-7.6 and 5.3, respectively. In clocinnamox-treated rats, apparent pA2 values for naltrexone were 7.2-7.7, suggesting that clocinnamox treatment did not alter affinity of naltrexone for sites through which morphine exerts behavioral effects. In rats treated repeatedly with morphine, apparent pA2 values for nalbuphine were 5.1-5.3, suggesting that repeated morphine treatment did not alter affinity of nalbuphine for these sites. The observation that neither clocinnamox nor repeated morphine treatment altered in vivo affinity estimates for naltrexone or nalbuphine, respectively, suggests that the reductions in agonist potency produced by these treatments do not result from changes in affinity at mu opioid receptors.

Topics: Animals; Behavior, Animal; Cinnamates; Dose-Response Relationship, Drug; Drug Antagonism; Male; Morphine; Morphine Derivatives; Nalbuphine; Narcotic Antagonists; Narcotics; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu