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Spinal sigma-1 receptors activate NADPH oxidase 2 leading to the induction of pain hypersensitivity in mice and mechanical allodynia in neuropathic rats.
Pharmacol Res. 2013 Aug; 74:56-67.PR

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+Show Affiliations

Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 151-742, South Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23732704

Citation

Choi, Sheu-Ran, et al. "Spinal Sigma-1 Receptors Activate NADPH Oxidase 2 Leading to the Induction of Pain Hypersensitivity in Mice and Mechanical Allodynia in Neuropathic Rats." Pharmacological Research, vol. 74, 2013, pp. 56-67.
Choi SR, Roh DH, Yoon SY, et al. Spinal sigma-1 receptors activate NADPH oxidase 2 leading to the induction of pain hypersensitivity in mice and mechanical allodynia in neuropathic rats. Pharmacol Res. 2013;74:56-67.
Choi, S. R., Roh, D. H., Yoon, S. Y., Kang, S. Y., Moon, J. Y., Kwon, S. G., Choi, H. S., Han, H. J., Beitz, A. J., Oh, S. B., & Lee, J. H. (2013). Spinal sigma-1 receptors activate NADPH oxidase 2 leading to the induction of pain hypersensitivity in mice and mechanical allodynia in neuropathic rats. Pharmacological Research, 74, 56-67. https://doi.org/10.1016/j.phrs.2013.05.004
Choi SR, et al. Spinal Sigma-1 Receptors Activate NADPH Oxidase 2 Leading to the Induction of Pain Hypersensitivity in Mice and Mechanical Allodynia in Neuropathic Rats. Pharmacol Res. 2013;74:56-67. PubMed PMID: 23732704.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Spinal sigma-1 receptors activate NADPH oxidase 2 leading to the induction of pain hypersensitivity in mice and mechanical allodynia in neuropathic rats. AU - Choi,Sheu-Ran, AU - Roh,Dae-Hyun, AU - Yoon,Seo-Yeon, AU - Kang,Suk-Yun, AU - Moon,Ji-Young, AU - Kwon,Soon-Gu, AU - Choi,Hoon-Seong, AU - Han,Ho-Jae, AU - Beitz,Alvin J, AU - Oh,Seog-Bae, AU - Lee,Jang-Hern, Y1 - 2013/06/01/ PY - 2013/02/13/received PY - 2013/05/18/revised PY - 2013/05/26/accepted PY - 2013/6/5/entrez PY - 2013/6/5/pubmed PY - 2014/3/7/medline KW - 2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate hydrochloride KW - 4′-hydroxy-3′-methoxyacetophenone KW - BD1047 KW - CCI KW - Chronic constriction injury KW - N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide KW - N-acetyl-l-cysteine KW - N-methyl-D-aspartate KW - NAC KW - NADPH oxidase KW - NADPH oxidase 2 KW - NMDA KW - Neuropathic pain KW - PRE084 KW - PWF KW - PWL KW - ROS KW - Reactive Oxygen Species KW - Sig-1Rs KW - Sigma-1 receptor KW - Sigma-1 receptors KW - apocynin KW - chronic constriction injury KW - nicotinamide adenine dinucleotide phosphate oxidase KW - pNR1 KW - paw withdrawal frequency KW - paw withdrawal latency KW - phosphorylation of the NMDA receptor NR1 subunit KW - reactive oxygen species SP - 56 EP - 67 JF - Pharmacological research JO - Pharmacol Res VL - 74 N2 - 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. SN - 1096-1186 UR - https://www.unboundmedicine.com/medline/citation/23732704/Spinal_sigma_1_receptors_activate_NADPH_oxidase_2_leading_to_the_induction_of_pain_hypersensitivity_in_mice_and_mechanical_allodynia_in_neuropathic_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1043-6618(13)00096-0 DB - PRIME DP - Unbound Medicine ER -