title: Involvement of NCAM and FGF receptor signaling in the development of analgesic tolerance to morphine.
abstract: This study examined the involvement of neural cell adhesion molecule (NCAM), a member of the immunoglobulin superfamily, in the development of tolerance to morphine. Furthermore, we focused on fibroblast growth factor (FGF) receptor and protein kinase C (PKC)-α as part of the intracellular signal transduction pathways underlying NCAM stimulation. The development of analgesic tolerance to morphine was gradually observed during daily treatment of morphine (10mg/kg, s.c.) for 5 days. Morphine treatment gradually and significantly decreased the NCAM expression levels. However it returned to normal levels immediately after re-treatment of morphine. Treatment of AS-ODN against NCAM completely inhibited analgesic tolerance to morphine. Protein expression levels of PKC-α were significantly increased by repeated morphine treatment in a NCAM-AS-ODN-reversible manner. Interestingly, alterations of protein interactions between NCAM and FGF receptor were observed under repeated morphine treatment. In addition, SU5402 (2 μg/mouse, i.c.v.), an inhibitor of FGF receptor, completely abolished the development of analgesic tolerance to morphine. Furthermore, κ-opioid receptor stimulation using U-50,488H, a κ-opioid receptor agonist, or establishment of formalin-induced chronic pain can completely suppress these changes in protein expression levels of NCAM and PKC-α and inhibit development of analgesic tolerance to morphine. These findings suggest that NCAM and its interaction with FGF receptor in the mechanism of up-regulation of PKC-α may contribute to the development of analgesic tolerance to morphine. Chronic pain or κ-opioid receptor stimulation could modulate these phenomena and suppress the development of analgesic tolerance to morphine.
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-0045, Japan.
authors.forename: Wakako
authors.initials: W
authors.lastname: Fujita-Hamabe
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nakamoto
authors.forename: Shogo
authors.initials: S
authors.lastname: Tokuyama
mesh_terms: D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001483:Base Sequence; D059350:Chronic Pain / Q000188:drug therapy / Q000378:metabolism; D004361:Drug Tolerance; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology* / Q000627:therapeutic use; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D051571:Protein Kinase C-alpha / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
chemical_list: D000700:Analgesics; D019006:Neural Cell Adhesion Molecules; D016376:Oligonucleotides, Antisense; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D017468:Receptors, Fibroblast Growth Factor; D017473:Receptors, Opioid, kappa; C105686:SU 5402; D009020:Morphine; D051571:Protein Kinase C-alpha