CLOCINNAMOX INHIBITS THE INTRAVENOUS SELF-ADMINISTRATION OF OPIOID AGONISTS IN RHESUS-MONKEYS - COMPARISON WITH EFFECTS ON OPIOID AGONIST-MEDIATED ANTINOCICEPTION

The effects of CCAM, an insurmountable mu opioid receptor antagonist, were studied on the intravenous self-administration and thermoantinoci ception of alfentanil and nalbuphine, high- and low-efficacy opioid ag onists, respectively, in rhesus monkeys. A single dose of 0.1 mg/kg CC AM IV reduced alfentanil's reinforcing potency in an FR30 TO 45s sched ule 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 respons e rates. CCAM also blocked insurmountably responding for nalbuphine, w hich 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 insurmount able antagonism of alfentanil and nalbuphine self-administration by CC AM was used to determine the (relative initial) efficacy values of bot h agonists. Efficacy values, tau, were 391 for alfentanil and 196 for nalbuphine; the apparent in vivo dissociation constants, K-A, were 0.1 6 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 compari son, in a rhesus monkey 50 degrees C warm-water tail withdrawal assay, the tau values were II for alfentanil and 0.92 for nalbuphine, and th e K-A values were 0.2 mg/kg (440 nmol/kg) for alfentanil and 0.15 mg/k g (400 nmol/kg) for nalbuphine. Therefore, it seems that the higher po tency of alfentanil and nalbuphine in self-administration as compared to thermal antinociception in rhesus monkeys is predominantly due to a larger efficacy of the same agonist in self-administration (i.e., a l arger receptor pool) rather than differences in apparent in vivo affin ity.