Pharmacological blockade or genetic knockout of the NOP receptor potentiates the rewarding effect of morphine in rats

The Nociceptin/OrphaninFQ (NOP) system is believed to be involved in drug abuse and addiction. We have recently demonstrated that activation of the NOP receptor, by systemic administration of the NOP receptor agonist Ro65-6570, attenuated the rewarding effect of various opioids in conditioned place preference (CPP) in rats and this attenuating effect was reversed by the NOP receptor antagonist J-113397. The present study demonstrates that co-administration of J-113397 (4.64 mg/kg, i.p.) during conditioning, facilitates morphine-induced CPP. Moreover, we found that NOP receptor knockout rats (oprl1(-/-)) are more sensitive to the rewarding effect of morphine than wildtype control rats. Thus, pharmacological or genetic inactivation of the NOP system rendered rats more susceptible to the rewarding effect of morphine. These findings support the suggestion that the endogenous NOP system attenuates the rewarding effect of opioids and therefore offers a therapeutic target for the treatment of drug abuse and addiction.