The role of dopaminergic systems in opioid receptor desensitization in nucleus accumbens and caudate putamen of rat after chronic morphine treatment.

Morphine treatment of rats (60-70 mg/kg/day, 7 days) reduced delta opioid receptor-mediated inhibition of adenylyl cyclase activity in caudate putamen without any change in regulation by mu receptors. Earlier studies suggested that dopamine D1 and mu opioid receptors that regulate adenylyl cyclase are expressed preferentially by striato-nigral neurons, whereas adenosine A2a and delta1 opioid receptors are expressed preferentially by striato-pallidal neurons. Chronic morphine treatment also resulted in a reduction of dopamine D2 receptor-mediated inhibition of A2a receptor-stimulated adenylyl cyclase. Treatment with a D2 receptor antagonist (eticlopride; 1 mg/kg/day) for 7 days reduced D1 receptor stimulation of adenylyl cyclase. In contrast, chronic treatment with a D1 receptor antagonist R(+)-7-chloro-8-dihydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine HCL (SCH 23390; 2.5 mg/kg/day) resulted in a reduction of delta1 and delta2 opioid inhibition of adenylyl cyclase, with no change in the inhibitory activity of a mu agonist. The inhibitory activity of the D2 agonist quinelorane against adenosine A2a-activated enzyme was also reduced by this treatment. Thus chronic D1 blockade, like chronic morphine treatment, appears to cause a selective impairment of the regulation of adenylyl cyclase in A2a receptor-expressing striato-pallidal neurons. D2 receptor activation appears to play an important role in the desensitization of delta receptors, because concurrent administration of the D2 antagonist eticlopride with morphine prevented the densitization of delta and D2 receptors. Similar results were obtained in nucleus accumbens, which suggests a role for D2 receptor desensitization in the adaptive response of this brain region to chronic morphine.