Role of dopamine D3 receptors in basal nociception regulation and in morphine-induced tolerance and withdrawal

Repeated administration of opioids such as morphine leads to the development of tolerance to their pain-relieving effects as well as to physical dependence. Although the association between the dopamine system and the molecular mechanisms of morphine-induced antinociceptive tolerance has been studied, the possible interaction between morphine-induced tolerance and D3 receptors has not been investigated. In the present study, male mice lacking the dopamine D3 receptor gene were used to investigate the function of D3 receptors in the development of morphine-induced tolerance and withdrawal. Compared with wild-type (WT) mice, the dopamine D3 receptor knockout (D3R KO) mice showed pronounced hypoalgesia. The D3R KO mice clearly developed lower morphine-induced tolerance and showed attenuated withdrawal signs compared with the WT mice. These results suggest that D3 receptors regulate basal nociception and are involved in the development of morphine-induced tolerance and withdrawal.

► D3R regulates basal pain threshold.
► D3R KO mice exhibited enhanced acute analgesic effects of morphine and clearly developed a lower morphine tolerance.
► D3R KO mice showed significantly lower in the general withdrawal score than that of WT mice.