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Discrimination of a single dose of morphine followed by naltrexone: substitution of other agonists for morphine and other antagonists for naltrexone in a rat model of acute dependence.
J Pharmacol Exp Ther 2003; 304(3):1033-41JP

Abstract

Rats were trained to discriminate 4-h pretreatment with 10 mg/kg morphine and 15-min pretreatment with 0.3 mg/kg naltrexone (morphine-->naltrexone) from pretreatment with saline and 0.3 mg/kg naltrexone (saline-->naltrexone). The discrimination seems to derive from interoceptive stimuli from antagonist-precipitated withdrawal from acute morphine dependence. The purpose of this study was to extend pharmacological characterization of the discrimination by testing opioid agonists other than morphine and antagonists other than naltrexone. Of seven mu-opioid agonists tested in place of morphine, only two (heroin and levorphanol) substituted completely for it; trials completed on the morphine-->naltrexone-appropriate lever increased as a function of agonist and naltrexone dose. Agonists with intrinsic efficacy higher (etorphine, fentanyl, and methadone) or lower (buprenorphine and meperidine) than that of morphine substituted only partially. However, when naltrexone was administered during continuous infusion of fentanyl or methadone via s.c. osmotic pump, rats responded as if they had received morphine-->naltrexone; discriminative responding correlated with global withdrawal scores. Rats responded primarily on the saline-->naltrexone-appropriate lever when naltrexone was administered after pretreatment with dextrorphan, the dextrorotatory isomer of levorphanol, or kappa-opioid agonists (5-alpha,7-alpha,8-beta)-(+)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl]-benzeneacetamide (U69,593) and spiradoline. Antagonists with no intrinsic efficacy at mu-opioid receptors (naloxone and diprenorphine) substituted completely for naltrexone, whereas those with some efficacy (nalorphine and levallorphan) substituted partially. Thus, morphine-->naltrexone-like stimulus control of behavior by drugs administered acutely requires pretreatment with certain mu-opioid agonists and a pure antagonist, is independent of agonist efficacy, and is stereoselective. Interoceptive stimuli from naltrexone-precipitated opioid withdrawal are more similar across morphine-like agonists during chronic dependence than they are during acute dependence.

Authors+Show Affiliations

Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. sholtzm@emory.edu

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12604679

Citation

Holtzman, Stephen G.. "Discrimination of a Single Dose of Morphine Followed By Naltrexone: Substitution of Other Agonists for Morphine and Other Antagonists for Naltrexone in a Rat Model of Acute Dependence." The Journal of Pharmacology and Experimental Therapeutics, vol. 304, no. 3, 2003, pp. 1033-41.
Holtzman SG. Discrimination of a single dose of morphine followed by naltrexone: substitution of other agonists for morphine and other antagonists for naltrexone in a rat model of acute dependence. J Pharmacol Exp Ther. 2003;304(3):1033-41.
Holtzman, S. G. (2003). Discrimination of a single dose of morphine followed by naltrexone: substitution of other agonists for morphine and other antagonists for naltrexone in a rat model of acute dependence. The Journal of Pharmacology and Experimental Therapeutics, 304(3), pp. 1033-41.
Holtzman SG. Discrimination of a Single Dose of Morphine Followed By Naltrexone: Substitution of Other Agonists for Morphine and Other Antagonists for Naltrexone in a Rat Model of Acute Dependence. J Pharmacol Exp Ther. 2003;304(3):1033-41. PubMed PMID: 12604679.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discrimination of a single dose of morphine followed by naltrexone: substitution of other agonists for morphine and other antagonists for naltrexone in a rat model of acute dependence. A1 - Holtzman,Stephen G, PY - 2003/2/27/pubmed PY - 2003/4/22/medline PY - 2003/2/27/entrez SP - 1033 EP - 41 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 304 IS - 3 N2 - Rats were trained to discriminate 4-h pretreatment with 10 mg/kg morphine and 15-min pretreatment with 0.3 mg/kg naltrexone (morphine-->naltrexone) from pretreatment with saline and 0.3 mg/kg naltrexone (saline-->naltrexone). The discrimination seems to derive from interoceptive stimuli from antagonist-precipitated withdrawal from acute morphine dependence. The purpose of this study was to extend pharmacological characterization of the discrimination by testing opioid agonists other than morphine and antagonists other than naltrexone. Of seven mu-opioid agonists tested in place of morphine, only two (heroin and levorphanol) substituted completely for it; trials completed on the morphine-->naltrexone-appropriate lever increased as a function of agonist and naltrexone dose. Agonists with intrinsic efficacy higher (etorphine, fentanyl, and methadone) or lower (buprenorphine and meperidine) than that of morphine substituted only partially. However, when naltrexone was administered during continuous infusion of fentanyl or methadone via s.c. osmotic pump, rats responded as if they had received morphine-->naltrexone; discriminative responding correlated with global withdrawal scores. Rats responded primarily on the saline-->naltrexone-appropriate lever when naltrexone was administered after pretreatment with dextrorphan, the dextrorotatory isomer of levorphanol, or kappa-opioid agonists (5-alpha,7-alpha,8-beta)-(+)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl]-benzeneacetamide (U69,593) and spiradoline. Antagonists with no intrinsic efficacy at mu-opioid receptors (naloxone and diprenorphine) substituted completely for naltrexone, whereas those with some efficacy (nalorphine and levallorphan) substituted partially. Thus, morphine-->naltrexone-like stimulus control of behavior by drugs administered acutely requires pretreatment with certain mu-opioid agonists and a pure antagonist, is independent of agonist efficacy, and is stereoselective. Interoceptive stimuli from naltrexone-precipitated opioid withdrawal are more similar across morphine-like agonists during chronic dependence than they are during acute dependence. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/12604679/Discrimination_of_a_single_dose_of_morphine_followed_by_naltrexone:_substitution_of_other_agonists_for_morphine_and_other_antagonists_for_naltrexone_in_a_rat_model_of_acute_dependence_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12604679 DB - PRIME DP - Unbound Medicine ER -