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Macrophage inflammatory protein-1α mediates the development of neuropathic pain following peripheral nerve injury through interleukin-1β up-regulation

Kiguchi, Norikazu; Maeda, Takehiko; Kobayashi, Yuka; Fukazawa, Yohji; Kishioka, Shiroh*

doi: 10.1016/j.pain.2010.02.025
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In the present study, we investigated the role of the macrophage inflammatory protein-1α (MIP-1α) in the pathogenesis of neuropathic pain following partial sciatic nerve ligation (PSL) in mice. MIP-1α mRNA and its protein were dramatically up-regulated after PSL, and MIP-1α was localized on macrophages and Schwann cells in the injured sciatic nerve (SCN). PSL-induced long-lasting tactile allodynia and thermal hyperalgesia were prevented by the perineural injection of anti-MIP-1α (2 ng). Intraneural (20 ng) and perineural (100 ng) injection of recombinant MIP-1α elicited tactile allodynia and thermal hyperalgesia in sham-operated limb. MIP-1α receptors (CCR1 and CCR5) mRNA and their proteins were also up-regulated in the SCN after PSL, and were localized on macrophages and Schwann cells. PSL-induced tactile allodynia was attenuated by perineural injection (0.2 nmol) of siRNA against CCR1 and CCR5. On the other hand, PSL-induced thermal hyperalgesia was prevented by siRNA against CCR5, but not CCR1. Interleukin-1β (IL-1β) mRNA and its precursor protein in macrophages and Schwann cells were also up-regulated in the SCN after PSL, and PSL-induced neuropathic pain was prevented by the perineural injection of anti-IL-1β (2 ng). PSL-induced IL-1β up-regulation was suppressed by anti-MIP-1α and siRNA against CCR1 and CCR5. Perineural injection of nicotine (20 nmol), a macrophage suppressor, prevented PSL-induced neuropathic pain and suppressed MIP-1α and IL-1β expressions. In conclusion, we propose a novel critical molecule MIP-1α derived from macrophages and Schwann cells that appears to play a crucial role in the development of neuropathic pain induced by PSL.

Department of Pharmacology, Wakayama Medical University, 811–1 Kimiidera, Wakayama 641–0012, Japan

*Corresponding author. Tel.: +81 73 441 0629; fax: +81 73 446 3806.

E-mail address:kishioka@wakayama-med.ac.jp

Submitted July 6, 2009; revised February 10, 2010; accepted February 13, 2010.

© 2010 Lippincott Williams & Wilkins, Inc.
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