title: TRPM2 contributes to inflammatory and neuropathic pain through the aggravation of pronociceptive inflammatory responses in mice.
abstract: Accumulating evidence suggests that neuroimmune interactions contribute to pathological pain. Transient receptor potential melastatin 2 (TRPM2) is a nonselective Ca²⁺-permeable cation channel that acts as a sensor for reactive oxygen species. TRPM2 is expressed abundantly in immune cells and is important in inflammatory processes. The results of the present study show that TRPM2 plays a crucial role in inflammatory and neuropathic pain. While wild-type and TRPM2 knock-out mice showed no difference in their basal sensitivity to mechanical and thermal stimulation, nocifensive behaviors in the formalin test were reduced in TRPM2 knock-out mice. In carrageenan-induced inflammatory pain and sciatic nerve injury-induced neuropathic pain models, mechanical allodynia and thermal hyperalgesia were attenuated in TRPM2 knock-out mice. Carrageenan-induced inflammation and sciatic nerve injury increased the expression of TRPM2 mRNA in the inflamed paw and around the injured sciatic nerve, respectively. TRPM2 deficiency diminished the infiltration of neutrophils and the production of chemokine (C-X-C motif) ligand-2 (CXCL2), a major chemokine that recruits neutrophils, but did not alter the recruitment of F4/80-positive macrophages in the inflamed paw or around the injured sciatic nerve. Microglial activation after nerve injury was suppressed in the spinal cord of TRPM2 knock-out mice. Furthermore, CXCL2 production and inducible nitric oxide synthase induction were diminished in cultured macrophages and microglia derived from TRPM2 knock-out mice. Together, these results suggest that TRPM2 expressed in macrophages and microglia aggravates peripheral and spinal pronociceptive inflammatory responses and contributes to the pathogenesis of inflammatory and neuropathic pain.
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Kayo
authors.initials: K
authors.lastname: Haraguchi
authors.forename: Ai
authors.initials: A
authors.lastname: Kawamoto
authors.forename: Kouichi
authors.initials: K
authors.lastname: Isami
authors.forename: Sanae
authors.initials: S
authors.lastname: Maeda
authors.forename: Ayaka
authors.initials: A
authors.lastname: Kusano
authors.forename: Kayoko
authors.initials: K
authors.lastname: Asakura
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shirakawa
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Shuji
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009437:Neuralgia / Q000378:metabolism* / Q000473:pathology*; D059225:Nociception / Q000502:physiology*; D010147:Pain Measurement / Q000379:methods*; D050053:TRPM Cation Channels / Q000502:physiology*
chemical_list: D018836:Inflammation Mediators; D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse