Prolonged Morphine Treatment Targets δ Opioid Receptors to Neuronal Plasma Membranes and Enhances δ-Mediated Antinociception

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Abstract
Opioid receptors are known to undergo complex regulatory changes in response to ligand exposure. In the present study, we examined the effect of morphine on the in vitro and in vivo density and trafficking of δ opioid receptors (δORs). Prolonged exposure (48 hr) of cortical neurons in culture to morphine (10 μm) resulted in a robust increase in the internalization of Fluo-deltorphin, a highly selective fluorescent δOR agonist. This effect was μ-mediated because it was entirely blocked by the selective μ opioid receptor antagonistd-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2and was reproduced using the selective μ agonist fentanyl citrate. Immunogold electron microscopy revealed a marked increase in the cell surface density of δORs in neurons exposed to morphine, indicating that the increase in Fluo-deltorphin internalization was caused by increased receptor availability. Prolonged morphine exposure had no effect on δOR protein levels, as assessed by immunocytochemistry and Western blotting, suggesting that the increase in bioavailable δORs was caused by recruitment of reserve receptors from intracellular stores and not from receptor neosynthesis. Complementaryin vivo studies demonstrated that chronic treatment of adult rats with morphine (5–15 mg/kg, s.c., every 12 hr) similarly augmented targeting of δORs to neuronal plasma membranes in the dorsal horn of the spinal cord. Furthermore, this treatment markedly potentiated intrathecald-[Ala2]deltorphin II-induced antinociception. Taken together, these results demonstrate that prolonged stimulation of neurons with morphine markedly increases recruitment of intracellular δORs to the cell surface, both in vitro and in vivo. We propose that this type of receptor subtype cross-mobilization may widen the transduction repertoire of G-protein-coupled receptors and offer new therapeutic strategies.

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