title: Involvement of matrix metalloproteinase-9 in the development of morphine tolerance.
abstract: Matrix metalloproteinase-9 (MMP-9) is involved in tissue remodeling or neural plasticity in various clinical states (e.g. inflammation, neuropathic pain). We focused on the effect of MMP-9 on development of morphine tolerance after repeated morphine treatment. To develop morphine tolerance, mice were given morphine (10mg/kg; s.c.) once daily for 5 days. The antinociceptive effect of morphine was measured by the tail flick method. Development of morphine tolerance was significantly inhibited by daily treatment of the non-specific MMP inhibitor GM6001 (5 μg/mouse, i.c.v.). A MMP-9 inhibitor (5 μg/mouse, i.c.v.) partially, yet significantly, inhibited the development of morphine tolerance. Intrathecal treatment of a MMP-9 inhibitor did not affect morphine tolerance. In MMP-9((-/-)) mice, the development of morphine tolerance was partially, yet significantly, inhibited compared with wild-type mice. MMP-9 protein expression levels in the midbrain gradually increased 12h to 24h after morphine treatment on day 1, but were unchanged on days 3-5. In the spinal cord, MMP-9 protein expression levels were unchanged. In gelatin zymography analyses, MMP-9 activity in the midbrain gradually increased 12 to 24h after morphine treatment. Increment in MMP-9 activity in the midbrain was also observed on days 3-5. Our findings suggest that persistent MMP-9 activation observed after the transient increment in MMP-9 expression from the early phase of morphine treatment may contribute to the development of morphine tolerance.
authors.affiliation: Department of Clinical Pharmacy, Kobe Gakuin University, School of Pharmaceutical Sciences, 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nakamoto
authors.forename: Shintaro
authors.initials: S
authors.lastname: Kawasaki
authors.forename: Takuro
authors.initials: T
authors.lastname: Kobori
authors.forename: Wakako
authors.initials: W
authors.lastname: Fujita-Hamabe
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizoguchi
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamada
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
authors.forename: Shogo
authors.initials: S
authors.lastname: Tokuyama
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology; D004361:Drug Tolerance; D057967:Infusions, Intraventricular; D007278:Injections, Spinal; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008636:Mesencephalon / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010147:Pain Measurement; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D009419:Nerve Tissue Proteins; D011480:Protease Inhibitors; D009020:Morphine; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse