title: Clocinnamox inhibits the intravenous self-administration of opioid agonists in rhesus monkeys: comparison with effects on opioid agonist-mediated antinociception.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor 48109-0632, USA. gerald.zernig@kfunigraz.ac.at
authors.forename: G
authors.initials: G
authors.lastname: Zernig
authors.forename: J W
authors.initials: JW
authors.lastname: Lewis
authors.forename: J H
authors.initials: JH
authors.lastname: Woods
mesh_terms: D015760:Alfentanil / Q000494:pharmacology*; D000818:Animals; D002934:Cinnamates / Q000494:pharmacology*; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D005260:Female; D007262:Infusions, Intravenous; D008253:Macaca mulatta; D008297:Male; D009022:Morphine Derivatives / Q000494:pharmacology*; D009266:Nalbuphine / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000819:agonists*; D012646:Self Administration
chemical_list: D002934:Cinnamates; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; C076806:clocinnamox; D015760:Alfentanil; D009266:Nalbuphine