title: Spinal sigma-1 receptors activate NADPH oxidase 2 leading to the induction of pain hypersensitivity in mice and mechanical allodynia in neuropathic rats.
abstract: We have recently demonstrated that spinal sigma-1 receptors (Sig-1Rs) mediate pain hypersensitivity in mice and neuropathic pain in rats. In this study, we examine the role of NADPH oxidase 2 (Nox2)-induced reactive oxygen species (ROS) on Sig-1R-induced pain hypersensitivity and the induction of chronic neuropathic pain. Neuropathic pain was produced by chronic constriction injury (CCI) of the right sciatic nerve in rats. Mechanical allodynia and thermal hyperalgesia were evaluated in mice and CCI-rats. Western blotting and dihydroethidium (DHE) staining were performed to assess the changes in Nox2 activation and ROS production in spinal cord, respectively. Direct activation of spinal Sig-1Rs with the Sig-1R agonist, PRE084 induced mechanical allodynia and thermal hyperalgesia, which were dose-dependently attenuated by pretreatment with the ROS scavenger, NAC or the Nox inhibitor, apocynin. PRE084 also induced an increase in Nox2 activation and ROS production, which were attenuated by pretreatment with the Sig-1R antagonist, BD1047 or apocynin. CCI-induced nerve injury produced an increase in Nox2 activation and ROS production in the spinal cord, all of which were attenuated by intrathecal administration with BD1047 during the induction phase of neuropathic pain. Furthermore, administration with BD1047 or apocynin reversed CCI-induced mechanical allodynia during the induction phase, but not the maintenance phase. These findings demonstrate that spinal Sig-1Rs modulate Nox2 activation and ROS production in the spinal cord, and ultimately contribute to the Sig-1R-induced pain hypersensitivity and the peripheral nerve injury-induced induction of chronic neuropathic pain.
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Sheu-Ran
authors.initials: SR
authors.lastname: Choi
authors.forename: Dae-Hyun
authors.initials: DH
authors.lastname: Roh
authors.forename: Seo-Yeon
authors.initials: SY
authors.lastname: Yoon
authors.forename: Suk-Yun
authors.initials: SY
authors.lastname: Kang
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Moon
authors.forename: Soon-Gu
authors.initials: SG
authors.lastname: Kwon
authors.forename: Hoon-Seong
authors.initials: HS
authors.lastname: Choi
authors.forename: Ho-Jae
authors.initials: HJ
authors.lastname: Han
authors.forename: Alvin J
authors.initials: AJ
authors.lastname: Beitz
authors.forename: Seog-Bae
authors.initials: SB
authors.lastname: Oh
authors.forename: Jang-Hern
authors.initials: JH
authors.lastname: Lee
mesh_terms: D000818:Animals; D005029:Ethylenediamines / Q000494:pharmacology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D009025:Morpholines / Q000494:pharmacology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D009437:Neuralgia / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D017480:Receptors, sigma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism; D014110:Touch; D000097605:Sigma-1 Receptor
chemical_list: D005029:Ethylenediamines; D008562:Membrane Glycoproteins; D009025:Morpholines; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D017382:Reactive Oxygen Species; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; C488842:Cybb protein, mouse; C500593:Cybb protein, rat
keywords: 2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate hydrochloride; 4′-hydroxy-3′-methoxyacetophenone; BD1047; CCI; Chronic constriction injury; N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide; N-acetyl-l-cysteine; N-methyl-D-aspartate; NAC; NADPH oxidase; NADPH oxidase 2; NMDA; Neuropathic pain; PRE084; PWF; PWL; ROS; Reactive Oxygen Species; Sig-1Rs; Sigma-1 receptor; Sigma-1 receptors; apocynin; chronic constriction injury; nicotinamide adenine dinucleotide phosphate oxidase; pNR1; paw withdrawal frequency; paw withdrawal latency; phosphorylation of the NMDA receptor NR1 subunit; reactive oxygen species