title: Regulation of opioid receptor trafficking and morphine tolerance by receptor oligomerization.
abstract: The utility of morphine for the treatment of chronic pain is hindered by the development of tolerance to the analgesic effects of the drug. Morphine is unique among opiates in its ability to activate the mu opioid receptor (MOR) without promoting its desensitization and endocytosis. Here we demonstrate that [D-Ala(2)-MePhe(4)-Gly(5)-ol] enkephalin (DAMGO) can facilitate the ability of morphine to stimulate MOR endocytosis. As a consequence, rats treated chronically with both drugs show reduced analgesic tolerance compared to rats treated with morphine alone. These results demonstrate that endocytosis of the MOR can reduce the development of tolerance, and hence suggest an approach for the development of opiate analogs with enhanced efficacy for the treatment of chronic pain.
authors.affiliation: Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, CA 94608, USA.
authors.forename: Li
authors.initials: L
authors.lastname: He
authors.forename: Jamie
authors.initials: J
authors.lastname: Fong
authors.forename: Mark
authors.initials: M
authors.lastname: von Zastrow
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Whistler
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000378:metabolism; D002478:Cells, Cultured; D004361:Drug Tolerance / Q000502:physiology*; D004705:Endocytosis / Q000502:physiology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology*; D017930:Genes, Reporter; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007150:Immunohistochemistry; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D000701:Analgesics, Opioid; D000906:Antibodies; D018343:Receptors, Adrenergic, beta-2; D017450:Receptors, Opioid, mu; D011993:Recombinant Fusion Proteins; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009020:Morphine; D007545:Isoproterenol