Involvement of matrix metalloproteinase-9 in the development of morphine tolerance

Kazuo Nakamoto, Shintaro Kawasaki, Takuro Kobori, Wakako Fujita-Hamabe, Hiroyuki Mizoguchi, Kiyofumi Yamada, Toshitaka Nabeshima, Shogo Tokuyama

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 (10 mg/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 12 h to 24 h 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 24 h 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.

Original languageEnglish
Pages (from-to)86-92
Number of pages7
JournalEuropean Journal of Pharmacology
Volume683
Issue number1-3
DOIs
Publication statusPublished - 15-05-2012

All Science Journal Classification (ASJC) codes

  • Pharmacology

Fingerprint Dive into the research topics of 'Involvement of matrix metalloproteinase-9 in the development of morphine tolerance'. Together they form a unique fingerprint.

  • Cite this

    Nakamoto, K., Kawasaki, S., Kobori, T., Fujita-Hamabe, W., Mizoguchi, H., Yamada, K., Nabeshima, T., & Tokuyama, S. (2012). Involvement of matrix metalloproteinase-9 in the development of morphine tolerance. European Journal of Pharmacology, 683(1-3), 86-92. https://doi.org/10.1016/j.ejphar.2012.03.006