Vol. 304, Issue 3, 1033-1041, March 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

Stephen G. Holtzman

Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia

Rats were trained to discriminate 4-h pretreatment with 10 mg/kg morphine and 15-min pretreatment with 0.3 mg/kg naltrexone (morphinenaltrexone) from pretreatment with saline and 0.3 mg/kg naltrexone (salinenaltrexone). 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 µ-opioid agonists tested in place of morphine, only two (heroin and levorphanol) substituted completely for it; trials completed on the morphinenaltrexone-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 morphinenaltrexone; discriminative responding correlated with global withdrawal scores. Rats responded primarily on the salinenaltrexone-appropriate lever when naltrexone was administered after pretreatment with dextrorphan, the dextrorotatory isomer of levorphanol, or -opioid agonists (5-,7-,8-)-(+)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl]-benzeneacetamide (U69,593) and spiradoline. Antagonists with no intrinsic efficacy at µ-opioid receptors (naloxone and diprenorphine) substituted completely for naltrexone, whereas those with some efficacy (nalorphine and levallorphan) substituted partially. Thus, morphinenaltrexone-like stimulus control of behavior by drugs administered acutely requires pretreatment with certain µ-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.