title: Role of peripheral sigma-1 receptors in ischaemic pain: Potential interactions with ASIC and P2X receptors.
abstract: BACKGROUND
  The role of peripheral sigma-1 receptors (Sig-1Rs) in normal nociception and in pathologically induced pain conditions has not been thoroughly investigated. Since there is mounting evidence that Sig-1Rs modulate ischaemia-induced pathological conditions, we investigated the role of Sig-1Rs in ischaemia-induced mechanical allodynia (MA) and addressed their possible interaction with acid-sensing ion channels (ASICs) and P2X receptors at the ischaemic site.
  
  
  METHODS
  We used a rodent model of hindlimb thrombus-induced ischaemic pain (TIIP) to investigate their role. Western blot was performed to observe changes in Sig-1R expression in peripheral nervous tissues. MA was measured after intraplantar (i.pl.) injections of antagonists for the Sig-1, ASIC and P2X receptors in TIIP rats or agonists of each receptor in naïve rats.
  
  
  RESULTS
  Sig-1R expression significantly increased in skin, sciatic nerve and dorsal root ganglia at 3 days post-TIIP surgery. I.pl. injections of the Sig-1R antagonist, BD-1047 on post-operative days 0-3 significantly attenuated the development of MA during the induction phase, but had no effect on MA when given during the maintenance phase (days 3-6 post-surgery). BD-1047 synergistically increased amiloride (an ASICs blocker)- and TNP-ATP (a P2X antagonist)-induced analgesic effects in TIIP rats. In naïve rats, i.pl. injection of Sig-1R agonist PRE-084 alone did not produce MA; but it did induce MA when co-administered with either an acidic pH solution or a sub-effective dose of αβmeATP.
  
  
  CONCLUSIONS
  Peripheral Sig-1Rs contribute to the induction of ischaemia-induced MA via facilitation of ASICs and P2X receptors. Thus, peripheral Sig-1Rs represent a novel therapeutic target for the treatment of ischaemic pain.
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, Korea.
authors.forename: S G
authors.initials: SG
authors.lastname: Kwon
authors.affiliation: Department of Maxillofacial Tissue Regeneration, School of Dentistry, Kyung Hee University, Seoul, Korea.
authors.forename: D H
authors.initials: DH
authors.lastname: Roh
authors.affiliation: Pain Cognitive Function Research Center, Department of Brain and Cognitive Sciences College of Natural Sciences, Seoul National University, Korea.|Dental Research Institute and Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Korea.
authors.forename: S Y
authors.initials: SY
authors.lastname: Yoon
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, Korea.
authors.forename: S R
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, Korea.
authors.forename: H S
authors.initials: HS
authors.lastname: Choi
authors.affiliation: KM Fundamental Research Division, Korea Institute of Oriental Medicine, Daejeon, Korea.
authors.forename: J Y
authors.initials: JY
authors.lastname: Moon
authors.affiliation: KM Fundamental Research Division, Korea Institute of Oriental Medicine, Daejeon, Korea.
authors.forename: S Y
authors.initials: SY
authors.lastname: Kang
authors.affiliation: Department of Physiology, Institute of Brain Research, Chungnam National University Medical School, Daejeon, Korea.
authors.forename: H W
authors.initials: HW
authors.lastname: Kim
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, Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Han
authors.affiliation: Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Beitz
authors.affiliation: Pain Cognitive Function Research Center, Department of Brain and Cognitive Sciences College of Natural Sciences, Seoul National University, Korea.|Dental Research Institute and Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Korea.
authors.forename: S B
authors.initials: SB
authors.lastname: Oh
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, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Lee
mesh_terms: D062565:Acid Sensing Ion Channels / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives; D000818:Animals; D005029:Ethylenediamines; D006614:Hindlimb / Q000098:blood supply; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism*; D007511:Ischemia / Q000150:complications* / Q000378:metabolism; D008297:Male; D009025:Morpholines; D010146:Pain / Q000209:etiology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058469:Receptors, Purinergic P2X / Q000502:physiology*; D017480:Receptors, sigma / Q000502:physiology*; D000097605:Sigma-1 Receptor
chemical_list: D062565:Acid Sensing Ion Channels; D000255:Adenosine Triphosphate; D005029:Ethylenediamines; D009025:Morpholines; D058469:Receptors, Purinergic P2X; 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; C045674:2',3'-O-(2,4,6-trinitro-cyclohexadienylidine)adenosine 5'-triphosphate