Involvement of μ ‐ and δ ‐opioid receptor function in the rewarding effect of (±)‐pentazocine

Most opioid receptor agonists have abuse potential, and the rewarding effects of opioids can be reduced in the presence of pain. While each of the enantiomers of pentazocine has a differential pharmacologic profile, (±)‐pentazocine has been used clinically for the treatment of pain. However, little information is available regarding which components of pentazocine are associated with its rewarding effects, and whether the (±)‐pentazocine‐induced rewarding effects can be suppressed under pain. Therefore, the present study was performed to investigate the effects of pain on the acquisition of the rewarding effects of (±)‐pentazocine, and to examine the mechanism of the rewarding effects of (±)‐pentazocine using the conditioned place preference paradigm. (±)‐Pentazocine and (−)‐pentazocine, but not (+)‐pentazocine, produced significant rewarding effects. Even though the rewarding effects induced by (±)‐pentazocine were significantly suppressed under pain induced by formalin, accompanied by increase of preprodynorphin mRNA levels in the nucleus accumbens, a high dose of (±)‐pentazocine produced significant rewarding effects under pain. In the normal condition, (±)‐pentazocine‐induced rewarding effects were blocked by a low dose of naloxone, whereas the rewarding effects induced by high doses of pentazocine under pain were suppressed by naltrindole (a δ ‐opioid receptor antagonist). Interestingly, (±)‐pentazocine did not significantly affect dopamine levels in the nucleus accumbens. These findings suggest that the rewarding effects of (−)‐pentazocine may contribute to the abuse potential of (±)‐pentazocine through μ ‐ as well as δ ‐opioid receptors, without robust activation of the mesolimbic dopaminergic system. We also found that neural adaptations can reduce the abuse potential of (±)‐pentazocine under pain.