title: Acidic pH facilitates peripheral αβmeATP-mediated nociception in rats: differential roles of P2X, P2Y, ASIC and TRPV1 receptors in ATP-induced mechanical allodynia and thermal hyperalgesia.
abstract: Peripheral ischemia is commonly associated with an increase in tissue ATP concentration and a decrease in tissue pH. Although in vitro data suggest that low tissue pH can affect ATP-binding affinities to P2 receptors, the mechanistic relationship between ATP and low pH on peripheral nociception has not been fully examined. This study was designed to investigate the potential role of an acidified environment on intraplantar αβmeATP-induced peripheral pain responses in rats. The mechanical allodynia (MA) produced by injection of αβmeATP was significantly increased in animals that received the drug diluted in pH 4.0 saline compared to those that received the drug diluted in pH 7.0 saline. Moreover, animals injected with αβmeATP (100 nmol) in pH 4.0 saline developed thermal hyperalgesia (TH), which did not occur in animals treated with αβmeATP diluted in pH 7.0 saline. To elucidate which receptors were involved in this pH-related facilitation of αβmeATP-induced MA and TH, rats were pretreated with PPADS (P2 antagonist), TNP-ATP (P2X antagonist), MRS2179 (P2Y1 antagonist), AMG9810 (TRPV1 antagonist) or amiloride (ASIC blocker). Both PPADS and TNP-ATP dose-dependently blocked pH-facilitated MA, while TH was significantly reduced by pre-treatment with MRS2179 or AMG9810. Moreover, amiloride injection significantly reduced low pH-induced facilitation of αβmeATP-mediated MA, but not TH. These results demonstrate that low tissue pH facilitates ATP-mediated MA via the activation of P2X receptors and ASICs, whereas TH induced by ATP under low pH conditions is mediated by the P2Y1 receptor and TRPV1, but not ASIC. Thus distinct mechanisms are responsible for the development of MA and TH under conditions of tissue acidosis and increased ATP.
authors.affiliation: Yuhan Research Institute, Giheung-gu, Yongin-si, Gyeonggi-do, Republic of Korea.
authors.forename: Hyoung-Sig
authors.initials: HS
authors.lastname: Seo
authors.forename: Dae-Hyun
authors.initials: DH
authors.lastname: Roh
authors.forename: Soon-Gu
authors.initials: SG
authors.lastname: Kwon
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: Sheu-Ran
authors.initials: SR
authors.lastname: Choi
authors.forename: Alvin J
authors.initials: AJ
authors.lastname: Beitz
authors.forename: Jang-Hern
authors.initials: JH
authors.lastname: Lee
mesh_terms: D062565:Acid Sensing Ion Channels; D000255:Adenosine Triphosphate / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000704:Analysis of Variance; D000818:Animals; D006358:Hot Temperature; D006863:Hydrogen-Ion Concentration; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010147:Pain Measurement; D058748:Pain Perception / Q000187:drug effects / Q000502:physiology; D010812:Physical Stimulation; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D058469:Receptors, Purinergic P2X / Q000378:metabolism*; D058470:Receptors, Purinergic P2Y / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D062565:Acid Sensing Ion Channels; D009419:Nerve Tissue Proteins; D058469:Receptors, Purinergic P2X; D058470:Receptors, Purinergic P2Y; D015222:Sodium Channels; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D000255:Adenosine Triphosphate; C002630:alpha,beta-methyleneadenosine 5'-triphosphate