RT Journal Article
SR Electronic
T1 Intracranial Self-Stimulation in Rats: Sensitization to an Opioid Antagonist Following Acute or Chronic Treatment with MuOpioid Agonists
,
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 188
OP 199
VO 281
IS 1
A1 Keith W. Easterling
A1 Stephen G. Holtzman
YR 1997
UL http://jpet.aspetjournals.org/content/281/1/188.abstract
AB Acute mu opioid agonist pretreatment (4 hr) dose-dependently sensitizes rats responding for food reinforcement to the rate-decreasing effects of naltrexone (NTX). In the present study, adult rats were trained to respond in an intracranial self-stimulation autotitration procedure in which responding resulted in electrical stimulation of the medial forebrain bundle that decreased in frequency until reset to the initial value. In an acute sensitization experiment, pretreatment (4 hr) doses of 3.0 and 10 mg/kg morphine reduced the ED25 value for the intracranial self-stimulation rate-decreasing effect of NTX from 28.2 mg/kg to 0.29 and 0.02 mg/kg, respectively. All mu-selective opioid agonists tested, fentanyl > levorphanol > methadone > morphine > meperidine (listed in order of decreasing potency), produced similar large increases in sensitivity to NTX. Acute sensitization was not induced by the kappa-selective opioid agonist spiradoline, the dextrorotary enantiomer of levorphanol, dextrorphan, or the nonopioid drugs d-amphetamine and pentobarbital. Pretreatment with morphine for 10 days by continuous subcutaneous infusion (15 mg/kg/day) reduced the ED25 value of NTX from 28.2 to 0.002 ± 1.48 mg/kg. The correlation of decreases in ED25 values for the rate-decreasing effect of NTX after both acute and chronic morphine administration is consistent with the theory that acute agonist-induced sensitization reflects receptor-mediated changes occurring early in the development of physical dependence. The American Society for Pharmacology and Experimental Therapeutics