Vol. 283, Issue 2, 557-565, 1997

The Role of Dopaminergic Systems in Opioid Receptor Desensitization in Nucleus Accumbens and Caudate Putamen of Rat After Chronic Morphine Treatment¹

Florence Noble² and Brian M. Cox

Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland

Morphine treatment of rats (60-70 mg/kg/day, 7 days) reduced  opioid receptor-mediated inhibition of adenylyl cyclase activity in caudate putamen without any change in regulation by µ receptors. Earlier studies suggested that dopamine D₁ and µ opioid receptors that regulate adenylyl cyclase are expressed preferentially by striato-nigral neurons, whereas adenosine A_2a and ₁ opioid receptors are expressed preferentially by striato-pallidal neurons. Chronic morphine treatment also resulted in a reduction of dopamine D₂ receptor-mediated inhibition of A_2a 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 ₁ and ₂ opioid inhibition of adenylyl cyclase, with no change in the inhibitory activity of a µ agonist. The inhibitory activity of the D₂ agonist quinelorane against adenosine A_2a-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 A_2a receptor-expressing striato-pallidal neurons. D₂ receptor activation appears to play an important role in the desensitization of  receptors, because concurrent administration of the D₂ antagonist eticlopride with morphine prevented the densitization of  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.