Chronic intrathecal morphine administration produces homologous mu receptor/G-protein desensitization specifically in spinal cord

Previous studies have shown that chronic i.v. treatment with morphine or heroin decreased mu opioid receptor activation of G-proteins in specific brain regions. The present study examined the effect of intrathecal (i.t.) morphine administration on receptor/G-protein coupling in the spinal cord. In spinal cord membranes, [³⁵S]GTPγS binding was stimulated by agonists of several G-protein-coupled receptors, including mu opioid (DAMGO), delta opioid (DPDPE), GABA_B (baclofen), cannabinoid CB₁ (WIN 55,212-2), muscarinic cholinergic (carbachol) and adenosine A₁ (PIA). [³⁵S]GTPγS autoradiography revealed that most of this agonist activation of G-proteins was localized to laminae I and II of dorsal horn. To determine the effects of chronic morphine on these receptor activities, rats were treated for 7 days with 0.11 mg/kg/day i.t. morphine, and receptor activation of G-proteins was determined by [³⁵S]GTPγS autoradiography of brain and spinal cord. In spinal cord sections, chronic morphine treatment decreased DAMGO-stimulated [³⁵S]GTPγS binding in laminae I and II at all levels of spinal cord examined. There were no effects of morphine treatment on [³⁵S]GTPγS stimulation in spinal cord by other receptor systems examined (Adenosine A₁ and GABA_B), and no significant effects of chronic i.t. morphine treatment were observed in brain sections. These data show that homologous desensitization of mu receptor/G-protein coupling occurs specifically in spinal cord following chronic morphine administration.