Naltrexone-sensitizing effects of centrally administered morphine and opioid peptides

Rats were trained to lever-press on a multiple-trial, fixed-interval, 3-min schedule of food-reinforcement; each trial consisted of a 10-min time-out and a 9.5-min response period. Naltrexone, injected s.c. prior to each trial, reduced response rates in a dose-related fashion, with an ED 50 of 21 mg/kg. Four-hour pretreatment with i.c.v. morphine (3.0–30 μg) produced leftward shifts of the naltrexone dose-effect curve of up to 3 orders of magnitude. The selective μ agonist, [D-Ala 2,NMePhe 4,Gly-ol 5]enkephalin (DAGO; 0.1–0.3 μg i.c.v.), sensitized animals to the rate-decreasing effects of naltrexone by more than 2 orders of magnitude. Pretreatment with the selective κ agonist, dynorphin A-(1–17) (30 μg i.c.v.) or the selective δ agonist, [D-Pen 2, D-Pen 5]enkephalin (DPDPE; 30–100 μg i.c.m.) induced moderate sensitization with leftward shifts of 1.0–1.5 log units. Thus, the naltrexone-sensitizing effect of acute opioid pretreatment is centrally mediated, consistent with the hypothesis that the phenomenon is related to the initiation of opioid physical dependence. Further, the effect appears to be mediated predominately by μ-opioid receptors, because μ agonists consistently produced the largest sensitization to naltrexone.