Potentiation of opioid analgesia in dopamine(2) receptor knock-out mice: Evidence for a tonically active anti-opioid system

Dopamine systems are intimately involved with opioid actions. Pharmacologic al studies suggest an important modulatory effect of dopamine and Its recep tors on opioid analgesia. We have now examined these interactions in a knoc k-out model in which the dopamine(2) (D-2), receptor has been disrupted. Lo ss of D-2 receptors, enhances, in a dose-dependent manner, the analgesic ac tions of the mu analgesic morphine, the kappa (1) agonist U50,488H and the kappa (3) analgesic naloxone, benzoylhydrazone. The responses to the delta opioid analgesic [D-Pen(2),D-Pen(5)]enkephalin were unaffected in the knock -out animals. Loss of D-2 receptors also potentiated, spinal orphanin FQ/no ciceptin analgesia. Antisense studies using a probe targeting the D-2 recep tor revealed results similar to those observed in the knock-out model. The modulatory actions of D-2 receptors were independent of a receptor systems because the sigma agonist (+)-pentazocine lowered opioid analgesia in all m ice, including the D-2 knock-out group. Thus, dopamine D-2 receptors repres ent an additional, significant modulatory system that inhibits analgesic re sponses to mu and kappa opioids.