Regulation of morphine tolerance by alternative Splicing

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The utility of morphine in the treatment of chronic pain is limited by the rapid development of tolerance. In contrast to its analgesic effects, tolerance does not develop to morphine-induced itch. Whereas the analgesic properties of morphine are mediated by the mu-opioid receptor (MOR1), morphine-induced itch is mediated by the C-terminal splice variant MOR1D. Our previous work has established that, high-efficacy agonists such as fentanyl or sufentanil stimulate a GRK2/3-dependent phosphorylation of threonin 370 (T370), serin 375 (S375), threonin (T376) und threonin (T379) within the C-terminus of the MOR1 receptor, while morphine induces a selective and GRK5-dependent S375 phosphorylation without causing a rapid endocytosis of the receptor. In contrast, morphine promotes a robust phosphorylation and internalization of the MOR1D receptor. We have also shown that in vivo tolerance to high-efficacy agonists develops at a much slower rate than morphine tolerance. The specific aims of the research grant proposal are: 1) to determine morphine tolerance in a novel MOR1D knock in mouse, 2) to elucidate the phosphorylation and internalization of the MOR1D receptor in vivo and in vitro, 3) to examine the mechanisms of opioid dependence in MOR1D knock in mice (gain of function model) and in S375A knock in mice (loss of function model), 4) to examine the role of opioid receptor internalization and desensitization in pathological pain. These studies will provide novel insights into the agonist-selective regulation of endogenous mu-opioid receptors and its functional consequences.