Potentiation of opioid analgesia in dopamine2 receptor knock-out mice: evidence for a tonically active anti-opioid system.

Dopamine systems are intimately involved with opioid actions. Pharmacological studies suggest an important modulatory effect of dopamine and its receptors on opioid analgesia. We have now examined these interactions in a knock-out model in which the dopamine(2) (D(2)) receptor has been disrupted. Loss of D(2) receptors enhances, in a dose-dependent manner, the analgesic actions 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/nociceptin analgesia. Antisense studies using a probe targeting the D(2) receptor revealed results similar to those observed in the knock-out model. The modulatory actions of D(2) receptors were independent of final sigma receptor systems because the final sigma agonist (+)-pentazocine lowered opioid analgesia in all mice, including the D(2) knock-out group. Thus, dopamine D(2) receptors represent an additional, significant modulatory system that inhibits analgesic responses to mu and kappa opioids.