title: Peripheral neurosteroids enhance P2X receptor-induced mechanical allodynia via a sigma-1 receptor-mediated mechanism.
abstract: The role of peripheral neurosteroids and their related mechanisms on nociception have not been thoroughly investigated. Based on emerging evidence in the literature indicating that neurosteroids and their main target receptors, i.e., sigma-1, GABAA and NMDA, affect P2X-induced changes in neuronal activity, this study was designed to investigate the effect of peripherally injected dehydroepiandrosterone sulphate (DHEAS) and pregnenolone sulfate (PREGS) on P2X receptor-mediated mechanical allodynia in rats. Intraplantar injection of either neurosteroids alone did not produced any detectable changes in paw withdrawal frequency to the innocuous mechanical stimulation in naïve rats. However, When DHEAS or PREGS were co-injected with a sub-effective dose of αβmeATP, mechanical allodynia was developed and this was dose dependently blocked by pre-injection of the P2X antagonist, TNP-ATP. These results demonstrates that DHEAS and PREGS potentiate the activity of P2X receptors which results in the enhancement of αβmeATP-induced mechanical allodynia. In order to investigate the potential role of peripheral sigma-1, GABAA and NMDA receptors in this facilitatory action, we pretreated animals with BD-1047 (a sigma-1 antagonist), muscimol (a GABAA agonist) or MK-801 (a NMDA antagonist) prior to DHEAS or PREGS+αβmeATP injection. Only BD-1047 effectively prevented the facilitatory effects induced by neurosteroids on αβmeATP-induced mechanical allodynia. Collectively, we have shown that peripheral neurosteroids potentiate P2X-induced mechanical allodynia and that this action is mediated by sigma-1, but not by GABAA nor NMDA, receptors.
authors.affiliation: Department of Veterinary Physiology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Soon-Gu
authors.initials: SG
authors.lastname: Kwon
authors.affiliation: Pain Cognitive Function Research Center, Department of Brain and Cognitive Sciences College of Natural Sciences, Seoul National University, Seoul, Republic of Korea; Department of Neurobiology and Physiology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
authors.forename: Seo-Yeon
authors.initials: SY
authors.lastname: Yoon
authors.affiliation: Department of Maxillofacial Tissue Regeneration, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Dae-Hyun
authors.initials: DH
authors.lastname: Roh
authors.affiliation: Department of Veterinary Physiology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Sheu-Ran
authors.initials: SR
authors.lastname: Choi
authors.affiliation: Department of Veterinary Physiology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Hoon-Seong
authors.initials: HS
authors.lastname: Choi
authors.affiliation: KM Fundamental Research Division, Korea Institute of Oriental Medicine, Daejeon 305-811, Republic of Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Moon
authors.affiliation: KM Fundamental Research Division, Korea Institute of Oriental Medicine, Daejeon 305-811, Republic of Korea.
authors.forename: Suk-Yun
authors.initials: SY
authors.lastname: Kang
authors.affiliation: Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN 55108, USA.
authors.forename: Alvin J
authors.initials: AJ
authors.lastname: Beitz
authors.affiliation: Department of Veterinary Physiology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea. Electronic address: jhl1101@snu.ac.kr.
authors.forename: Jang-Hern
authors.initials: JH
authors.lastname: Lee
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D019314:Dehydroepiandrosterone Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005029:Ethylenediamines / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D010147:Pain Measurement; D011284:Pregnenolone / Q000633:toxicity; D058911:Purinergic P2X Receptor Agonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058469:Receptors, Purinergic P2X / Q000378:metabolism*; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors
chemical_list: D005029:Ethylenediamines; D058911:Purinergic P2X Receptor Agonists; D058469:Receptors, Purinergic P2X; D017480:Receptors, sigma; C018370:pregnenolone sulfate; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; D019314:Dehydroepiandrosterone Sulfate; C045674:2',3'-O-(2,4,6-trinitro-cyclohexadienylidine)adenosine 5'-triphosphate; D011284:Pregnenolone; D000255:Adenosine Triphosphate
keywords: Dehydroepiandrosterone sulphate; Mechanical allodynia; Neurosteroid; P2X; Pregnenolone sulfate; Sigma-1 receptor