Differential naltrexone antagonism of hydromorphone and pentazocine effects in human volunteers.

Naltrexone is more potent in blocking mu receptor activity than kappa receptor activity. This study examined the interactions of naltrexone with the mu agonist, hydromorphone, and with the mixed agonist-antagonist, pentazocine, to assess the apparent receptor mechanisms of their effects. After oral, 2-hr pretreatment with placebo or naltrexone (12.5 or 25 mg), a within-session cumulative dosing procedure (four intramuscular injections at 1-hr intervals) was used to assess the effects of hydromorphone (0, 0.75, 1.5 and 3 mg) and pentazocine (0, 15, 30 and 60 mg) vs. saline placebo. Subjective, physiological and behavioral effects were studied in six substance abusers. Hydromorphone significantly increased ratings on subjective measures typical of mu agonists, increased blood pressure and heart rate and decreased pupil diameter and respiratory rate; pretreatment with naltrexone (12.5 and 25 mg) blocked these effects. Pentazocine produced mu-like subjective effects, miosis and increases in blood pressure and heart rate. Naltrexone (12.5 mg) pretreatment decreased the mu-like subjective effects and miosis produced by pentazocine but increased kappa-like effects such as ratings of bad effects and Addiction Research Center Inventory LSD scale scores. Naltrexone (25 mg) blocked both the mu-like and kappa-like subjective effects of pentazocine. There was incomplete blockade of the cardiovascular effects of pentazocine. Thus, differential blockade of mu-like and kappa-like opioid effects by naltrexone was demonstrated in human subjects. Furthermore, the results suggest that mu agonist activity may suppress kappa-like effects such a dysphoria.