Differential desensitization of μ‐ and δ‐ opioid receptors in selected neural pathways following chronic morphine treatment

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Abstract
1 Morphine produces a plethora of pharmacological effects and its chronic administration induces several side-effects. The cellular mechanisms by which opiates induce these side-effects are not fully understood. Several studies suggest that regulation of adenylyl cyclase activity by opioids and other transmitters plays an important role in the control of neural function. 2 The aim of this study was to evaluate desensitization of μ- and δ- opioid receptors, defined as a reduced ability of opioid agonists to inhibit adenylyl cyclase activity, in four different brain structures known to be involved in opiate drug actions: caudate putamen, nucleus accumbens, thalamus and periaqueductal gray (PAG). Opiate regulation of adenylyl cyclase in these regions has been studied in control and morphine-dependent rats. 3 The chronic morphine treatment used in the present study (subcutaneous administration of 15.4 mg morphine/rat/day for 6 days via osmotic pump) induced significant physical dependence as indicated by naloxone-precipitated withdrawal symptoms. 4 Basal adenylyl cyclase in the four brain regions was not modified by this chronic morphine treatment. In the PAG and the thalamus, a desensitization of μ- and δ-opioid receptors was observed, characterized by a reduced ability of Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol (DAMGO; μ), Tyr-D-Pen-Gly-Phe-D-Pen(DPDPE; δ) and [D-Ala2]-deltorphin-II (DT-II; μ) to inhibit adenylyl cyclase, activity following chronic morphine treatment. 5 The opioid receptor desensitization in PAG and thalamus appeared to be heterologous since the metabotropic glutamate receptor agonists, L-AP4 and glutamate, and the 5-hydroxytryptamine (5-HT)1A receptor agonist, R(+)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), also showed reduced inhibition of adenylyl cyclase activity following chronic morphine treatment. 6 In the nucleus accumbens and the caudate putamen, desensitization of δ-opioid receptor-mediated inhibition without modification of μ-opioid receptor-mediated inhibition was observed. An indirect mechanism probably involving dopaminergic systems is proposed to explain the desensitization of δ-mediated responses and the lack of μ-opioid receptor desensitization after chronic morphine treatment in caudate putamen and nucleus accumbens. 7 These results suggest that adaptive responses occurring during chronic morphine administration are not identical in all opiate-sensitive neural populations.