Use of Irreversible Antagonists to Determine the Relative Efficacy of μ-Opioids in a Pigeon Drug Discrimination Procedure: Comparison of β-Funaltrexamine and Clocinnamox

Abstract

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 ␤-funaltrexamine (␤-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 ␤-FNA and C-CAM. Using quantitative analyses according to an extended model of Black and Leff (1983), apparent efficacy () and affinity (K A ) of each opioid was determined, as well as the degree of receptor inactivation (q) produced by each dose of each antagonist. ␤-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 values suggest a rank order of efficacy of etorphine Ͼ sufentanil ϭ l-methadone Ͼ fentanyl ϭ morphine. Marked differences in the profiles of antagonism produced by ␤-FNA and C-CAM were also apparent, as C-CAM, but not ␤-FNA, produced insurmountable antagonism. The q values for each antagonist were consistent with these data in indicating that C-CAM and ␤-FNA can inactivate nearly 100 and 75% of the receptor population, respectively. In tests conducted in pigeons chronically treated with morphine, doses of ␤-FNA that produced parallel, rightward shifts in untreated pigeons flattened the morphine dose-effect curve in morphine-treated pigeons. These results indicate that ␤-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 ␤-FNA.

Buprenorphine/naloxone reduces the reinforcing and subjective effects of heroin in heroin-dependent volunteers

“…The exact relation of these apparent K A estimates determined in humans to those obtained in non-human species is presently unknown due to the differences in dose measurement units. For example, apparent K A estimates for morphine range from 11 to 68 mg/kg in laboratory animals (Barrett et al 2003;Pitts et al 1998;Walker et al 1995Walker et al , 1998Zernig and Issaevitch 1995;Zernig et al 1994). Interestingly, the efficacy estimates for heroin in the present study (range 13-20) were comparable to those obtained for morphine in these same rodent and monkey studies (range 9-38).…”

“…These efficacy estimates are important for drug classification because relative efficacy can only be determined in a functional assay. Furthermore, these results demonstrate that similar apparent agonist affinity and efficacy estimates for heroin (morphine) are calculated whether buprenorphine/naloxone combination (present study), buprenorphine alone Walker et al 1995), or clocinnamox (Barrett et al 2003;Pitts et al 1998;Walker et al 1998;Zernig et al 1994) is used as the insurmountable antagonist. The data collected in the present study provide support for the validity and generalizability of the data collected in laboratory animals.…”

“…For example, buprenorphine was used in previous antinociceptive studies to estimate the K A and efficacy of morphine in rhesus monkeys (Walker et al 1995) and rodents (Raffa et al 1982;Tallarida and Cowan 1982). More recently, clocinnamox and β-FNA have been used to obtain affinity and efficacy estimates for heroin as well as fentanyl, alfentanil, etonitazene, etorphine, L-methadone, morphine, buprenorphine, and nalbuphine in a variety of behavioral assays in laboratory animals (Adams et al 1990; Barrett et al 2003;Negus et al 2003;Pitts et al 1998;Walker et al 1995Walker et al , 1998Zernig et al 1994). …”

The Competitive N-Methyl-d-aspartate Receptor Antagonist (-)-6-Phosphonomethyl-deca-hydroisoquinoline-3-carboxylic Acid (LY235959) Potentiates the Antinociceptive Effects of Opioids That Vary in Efficacy at the μ-Opioid Receptor

“…The purpose of the present study was to assess the effects of LY235959 in combination with MOR agonists other than morphine that vary along the dimension of efficacy. There are several published experimental results that demonstrate differences in relative efficacy among the MOR agonists chosen for the present study (Zimmerman et al, 1987;Adams et al, 1990;Barrett et al, 2003). In vitro studies using various cell and isolated tissue preparations are concordant with these behavioral studies and support the arguments that methadone has higher efficacy (Ivarsson and Neil, 1989), levorphanol has similar efficacy (Emmerson et al, 1996), and buprenorphine and butorphanol have lower efficacy (Toll, 1995;Emmerson et al, 1996;Selley et al, 1997) than morphine.…”

Evaluation of morphine‐like effects of the mixed mu/delta agonist morphine‐6‐O‐sulfate in rats: Drug discrimination and physical dependence

“…Doses were calculated as those of the free bases. The doses and preinjection intervals for morphine, M6S, M3A6S, fentanyl, and salvinorin A were selected from pilot studies or from previously published reports . For M6S, a maximal dose of 5.6 mg/kg was studied since previous experiments in our lab determined this was the highest dose achievable in rodents without observing adverse sedative effects which would likely limit behavioral performance in the planned studies .…”