title: Macrophage inflammatory protein-1alpha mediates the development of neuropathic pain following peripheral nerve injury through interleukin-1beta up-regulation.
abstract: In the present study, we investigated the role of the macrophage inflammatory protein-1alpha (MIP-1alpha) in the pathogenesis of neuropathic pain following partial sciatic nerve ligation (PSL) in mice. MIP-1alpha mRNA and its protein were dramatically up-regulated after PSL, and MIP-1alpha 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-1alpha (2ng). Intraneural (20ng) and perineural (100ng) injection of recombinant MIP-1alpha elicited tactile allodynia and thermal hyperalgesia in sham-operated limb. MIP-1alpha 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 (0.2nmol) of siRNA against CCR1 and CCR5. On the other hand, PSL-induced thermal hyperalgesia was prevented by siRNA against CCR5, but not CCR1. Interleukin-1beta (IL-1beta) 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-1beta (2ng). PSL-induced IL-1beta up-regulation was suppressed by anti-MIP-1alpha and siRNA against CCR1 and CCR5. Perineural injection of nicotine (20nmol), a macrophage suppressor, prevented PSL-induced neuropathic pain and suppressed MIP-1alpha and IL-1beta expressions. In conclusion, we propose a novel critical molecule MIP-1alpha derived from macrophages and Schwann cells that appears to play a crucial role in the development of neuropathic pain induced by PSL.
authors.affiliation: Department of Pharmacology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-0012, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Kiguchi
authors.forename: Takehiko
authors.initials: T
authors.lastname: Maeda
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Yohji
authors.initials: Y
authors.lastname: Fukazawa
authors.forename: Shiroh
authors.initials: S
authors.lastname: Kishioka
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism*; D006930:Hyperalgesia / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018722:Nicotinic Agonists / Q000494:pharmacology; D010523:Peripheral Nervous System Diseases / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D054389:Receptors, CCR1 / Q000235:genetics / Q000378:metabolism; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D012583:Schwann Cells / Q000276:immunology / Q000378:metabolism; D020426:Sciatic Neuropathy / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D000906:Antibodies; C496534:Ccl3 protein, mouse; C515301:Ccr1 protein, mouse; D054405:Chemokine CCL3; D053583:Interleukin-1beta; D018722:Nicotinic Agonists; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054389:Receptors, CCR1; D019713:Receptors, CCR5