Rationale: Lower (0.001-1.0 mg/kg) doses of the opioid antagonist naltrexone produce few behavioral effects in otherwise drug-free rats responding for ICSS, but reduce response rates by up to 75% after a single dose of morphine.
Objectives: The present study represents an effort to verify that other opioid antagonists produce this acute opioid dependence effect, and to characterize their relative pharmacological profiles.
Methods: We implanted bipolar electrodes in the lateral hypothalamus of adult male rats, and then trained them to lever-press on an "autotitration" ICSS schedule, where responding on a "reset" lever allows the rat to control the frequency of stimulation; performance stabilized at approximately 1.5 responses/s.
Results: During twice-weekly test sessions, cumulative doses of five of seven opioid antagonists produced significant response rate decreases (30-80%) in saline-pretreated rats; nalorphine (ED25=15.6 mg/kg)> naltrexone (ED25=13.1 mg/kg)>naloxone (ED25=7.3 mg/kg)>levallorphan (ED25=13.96 mg/kg)>(-)cyclazocine (ED25=0.028 mg/kg). A single MOR pretreatment (10 mg/kg, 4 h) significantly enhanced the rate-decreasing effects of six of the seven agonists tested; by 10-fold (-) cyclazocine>13-fold (nalorphine)>93-fold (levallorphan)>972-fold (naloxone)>2190-fold (naltrexone). The pure non-selective antagonist diprenorphine potently decreased rates after MOR pretreatment (ED25= 0.01 mg/kg), but did not after saline pretreatment. The mixed opioid agonist-antagonist drug nalbuphine (1.0-30 mg/kg) did not affect responding after either saline or MOR.
Conclusions: Antagonists with a high affinity for, and a lack of intrinsic activity at, the micro-opioid receptor precipitate the greatest behavioral changes in rats acutely dependent on MOR.