clocinnamox and beta-funaltrexamine

The use of irreversible antagonists to assess opioid efficacy has proven fruitful for classifying opioids on the basis of high or low efficacy, but few studies have provided quantitative estimates of efficacy. The purpose of this study was to use beta-funaltrexamine (beta-FNA) and clocinnamox (C-CAM) in a drug discrimination procedure to examine the efficacy of fentanyl, morphine, l-methadone, sufentanil, and etorphine. In pigeons trained to discriminate 0.12 mg/kg fentanyl from water, dose-effect curves were determined for each opioid alone and after pretreatment with beta-FNA and C-CAM. Using quantitative analyses according to an extended model of Black and Leff (1983), apparent efficacy (tau) and affinity (KA) of each opioid was determined, as well as the degree of receptor inactivation (q) produced by each dose of each antagonist. beta-FNA and C-CAM produced dose- and time-dependent, rightward shifts in the dose-effect curves of each opioid, and analyses based on dose-ratios and tau values suggest a rank order of efficacy of etorphine > sufentanil = l-methadone > fentanyl = morphine. Marked differences in the profiles of antagonism produced by beta-FNA and C-CAM were also apparent, as C-CAM, but not beta-FNA, produced insurmountable antagonism. The q values for each antagonist were consistent with these data in indicating that C-CAM and beta-FNA can inactivate nearly 100 and 75% of the receptor population, respectively. In tests conducted in pigeons chronically treated with morphine, doses of beta-FNA that produced parallel, rightward shifts in untreated pigeons flattened the morphine dose-effect curve in morphine-treated pigeons. These results indicate that beta-FNA and C-CAM can differentiate opioids with high relative efficacy and yield comparable estimates of efficacy for various opioids. There are, however, limitations in the proportion of the receptor population that can by eliminated by beta-FNA.

Topics: Animals; Cinnamates; Columbidae; Female; Fentanyl; Methadone; Morphine; Morphine Derivatives; Naltrexone; Narcotic Antagonists; Narcotics; Reaction Time; Receptors, Opioid, mu; Sufentanil

The irreversible mu-opioid antagonists beta-funaltrexamine (beta-FNA) and beta-chlornaltrexamine (beta-CNA) are important pharmacological tools but have a kappa-agonist activity and, in the latter case, low selectivity. This work examines whether clocinnamox (C-CAM) and the newer analog, methocinnamox (M-CAM), represent improved long-lasting antagonists for examining mu-opioid-mediated effects in vivo. beta-FNA, beta-CNA, C-CAM, and M-CAM were compared after systemic administration in mice and in vitro. beta-FNA and beta-CNA were effective agonists in the writhing assay, reversible by the kappa-antagonist norbinaltorphimine. Neither C-CAM nor M-CAM had agonist activity in vivo. M-CAM was devoid of agonist action at cloned opioid receptors. All four compounds depressed the dose-effect curve for the mu-agonist morphine in the warm-water tail-withdrawal test 1 h after administration; at 48 h, recovery was evident. In the writhing assay, the dose-effect curve for morphine was shifted in a parallel fashion in the order M-CAM >> C-CAM > beta-CNA > or = beta-FNA. In comparison with their ability to shift the dose-effect curve for bremazocine (kappa) and BW373U86 (delta), beta-CNA was the least mu-selective, followed by C-CAM < beta-FNA < M-CAM. M-CAM (1.8 mg/kg) produced a 74-fold increase in the ED(50) of morphine while showing no effect on bremazocine or BW373U86 dose-response curves. In binding assays, C-CAM and M-CAM were 8-fold selective for mu- over kappa-receptors, whereas beta-FNA and beta-CNA were mu/delta-, but not mu/kappa, selective. However, ex vivo binding assays confirmed the mu-receptor selectivity of M-CAM. M-CAM is thus a potent, long-lasting, and specific antagonist at mu-receptors in vivo that lacks confounding agonist actions.

Topics: Analgesics, Opioid; Animals; Binding, Competitive; Cerebral Cortex; Cinnamates; Guanosine 5'-O-(3-Thiotriphosphate); In Vitro Techniques; Male; Mice; Morphine; Morphine Derivatives; Naltrexone; Narcotic Antagonists; Pain Measurement; Radioligand Assay; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu