Clocinnamox Distinguishes Opioid Agonists According to Relative Efficacy in Normal and Morphine-Treated Rats Trained to Discriminate Morphine

Walker, Ellen A.; Young, Alice M.

doi:10.1124/jpet.302.1.101

Cited by 17 publications

(6 citation statements)

References 29 publications

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“…Furthermore, had higher doses of morphine produced complete substitution, the rightward shift in the dose-effect curve would have been greater than that observed under acute conditions. Such data are consistent with a recent report in rats trained to discriminate morphine from saline, in which chronic opioid treatment enhanced the potency and effectiveness of C-CAM (Walker and Young, 2002). Thus, when there is a relatively small receptor reserve, such as during chronic morphine treatment, ␤-FNA and C-CAM display similar profiles of action.…”

Section: Discussionsupporting

confidence: 92%

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

Barrett

Smith²,

Picker³

2003

J Pharmacol Exp Ther

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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.

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Section: Discussionsupporting

confidence: 92%

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

Barrett

Smith²,

Picker³

2003

J Pharmacol Exp Ther

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“…Morphine was effectively established as a discriminative stimulus with equivalent potency and efficacy in male and female C57Bl/6 mice using a two-choice drug-discrimination procedure. To the best of our knowledge, this report is the first morphine-discrimination study in an inbred mouse strain and is consistent with previous studies in other species, such as rats, pigeons, and monkeys (Maguire, Yang, & France, 2013; Platt, Grech, Rowlett, & Spealman, 1999; Walker, Picker, Granger, & Dykstra, 2004; Walker & Young, 2002). Previously, sex differences in the discriminative stimulus effects of morphine have been studied in rats.…”

Section: Discussionsupporting

confidence: 90%

Discriminative stimulus effects of morphine and oxycodone in the absence and presence of acetic acid in male and female C57Bl/6 mice.

Neelakantan

Ward

Walker

2015

Experimental and Clinical Psychopharmacology

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The use of prescription opioids for clinical management of pain remains problematic because of concerns about addiction associated with opioid use. Another difficulty in pain management is the increasing evidence for sex differences in pain behavior and opioid-induced behavioral effects. However, few studies have documented the abuse potential of prescription opioids as a function of pain in rodents, with significant gaps in the literature pertaining to sex differences in the interaction between pain and opioid effects. The present study evaluated the effects of an experimentally induced acute pain state (acetic acid injections) on the potency of morphine and oxycodone to produce discriminative stimulus effects in male and female C57Bl/6 mice trained to discriminate 3.2 mg/kg morphine from saline. Acetic acid injections attenuated the stimulus potency of morphine by 2.2-fold but not the stimulus potency of oxycodone in male mice. Acetic acid injections did not alter the discriminative stimulus effects of either morphine or oxycodone in female mice. The antinociceptive effects of the 2 opioids were evaluated using the acetic acid-induced stretching test. For antinociceptive effects, morphine was 2.0-fold less potent relative to oxycodone in male mice, whereas morphine and oxycodone were equipotent in female mice. Taken together, these results indicate that acetic acid-induced acute pain differentially modulates the discriminative stimulus effects of morphine in male and female mice and that this change may be related to the variable antinociceptive effectiveness of these opioids across sexes.

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“…Thus, depending on the immediate pharmacologic history of morphine-treated monkeys, buprenorphine was an antagonist or an agonist, whereas nalbuphine was only an agonist, suggesting that buprenorphine has lower efficacy than nalbuphine. While these results are consistent with previous studies in rhesus monkeys (Woods and Gmerek, 1985;Walker et al, 1995), they differ from studies reporting that buprenorphine has higher efficacy than nalbuphine in rats (Zimmerman et al, 1987;Morgan and Picker, 1998;Walker and Young, 2002). It is not clear whether these apparent differences in rank order efficacy are species specific or due to methodological differences across studies.…”

Section: Discussioncontrasting

confidence: 54%

Relative Efficacy of Buprenorphine, Nalbuphine and Morphine in Opioid-Treated Rhesus Monkeys Discriminating Naltrexone

Sell

McMahon

2003

J Pharmacol Exp Ther

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Efficacy is one determinant of whether a drug is an agonist or an antagonist under a particular set of conditions. Relative efficacy among the opioid receptor (MOR) ligands buprenorphine, nalbuphine, and morphine was examined in monkeys dependent on morphine (3.2 mg/kg/day) or L-␣-acetylmethadol (LAAM) (1.0 mg/kg twice daily) and that discriminated naltrexone (0.0178 mg/kg) from saline. In morphine-treated monkeys, buprenorphine and not nalbuphine substituted for naltrexone. When administered before naltrexone in morphine-treated monkeys, morphine and nalbuphine shifted the naltrexone dose-effect curve to the right, while buprenorphine shifted the naltrexone dose-effect curve to the left. Under conditions of acute morphine deprivation, naltrexone-lever responding was slightly attenuated by buprenorphine and markedly attenuated by nalbuphine and morphine. In LAAM-treated monkeys, buprenorphine substituted completely for naltrexone in only one monkey, while nalbuphine and morphine failed to substitute in any monkey. When administered before naltrexone in LAAMtreated monkeys, buprenorphine, nalbuphine, and morphine dose dependently shifted the naltrexone dose-effect curve to the right, with the exception of one monkey in which buprenorphine shifted the naltrexone dose-effect curve to the left. These results demonstrate that a low efficacy MOR ligand can exert agonist or antagonist actions in the same animal depending on immediate pharmacologic history. The qualitatively different effects of buprenorphine in morphine-and LAAM-treated monkeys might be related to magnitude of dependence insofar as dependence can determine the efficacy required for agonist activity. Thus, buprenorphine has markedly different effects across different levels of opioid dependence.

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Clocinnamox Distinguishes Opioid Agonists According to Relative Efficacy in Normal and Morphine-Treated Rats Trained to Discriminate Morphine

Cited by 17 publications

References 29 publications

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

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

Discriminative stimulus effects of morphine and oxycodone in the absence and presence of acetic acid in male and female C57Bl/6 mice.

Relative Efficacy of Buprenorphine, Nalbuphine and Morphine in Opioid-Treated Rhesus Monkeys Discriminating Naltrexone

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