title: Acid-induced pain and its modulation in humans.
abstract: Despite the discovery of ion channels that are activated by protons, we still know relatively little about the signaling of acid pain. We used a novel technique, iontophoresis of protons, to investigate acid-induced pain in human volunteers. We found that transdermal iontophoresis of protons consistently caused moderate pain that was dose-dependent. A marked desensitization occurred with persistent stimulation, with a time constant of approximately 3 min. Recovery from desensitization occurred slowly, over many hours. Acid-induced pain was significantly augmented in skin sensitized by acute topical application of capsaicin. However, skin desensitized by repeated capsaicin application showed no significant reduction in acid-induced pain, suggesting that both capsaicin-sensitive and insensitive sensory neurons contribute to acid pain. Furthermore, topical application of non-steroidal anti-inflammatory drugs (NSAIDs) significantly attenuated acid-evoked pain but did not affect the heat pain threshold, suggesting a specific interaction between NSAIDs and peripheral acid sensors. Subcutaneous injection of amiloride (1 mm) also significantly inhibited the pain induced by iontophoresis of acid, suggesting an involvement of acid-sensing ion channel (ASIC) receptors. Conversely, iontophoresis of acid over a wide range of skin temperatures from 4 to 40 degrees C produced only minor changes in the induced pain. Together these data suggest a prominent role for ASIC channels and only a minor role for transient receptor potential vanilloid receptor-1 as mediators of cutaneous acid-induced pain.
authors.affiliation: Sensory Function Group, Center for Neuroscience, King's College London, London, SE1 1UL, United Kingdom. Nicholas.2.jones@kcl.ac.uk
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Jones
authors.forename: Rebeccah
authors.initials: R
authors.lastname: Slater
authors.forename: Herve
authors.initials: H
authors.lastname: Cadiou
authors.forename: Peter
authors.initials: P
authors.lastname: McNaughton
authors.forename: Stephen B
authors.initials: SB
authors.lastname: McMahon
mesh_terms: D062565:Acid Sensing Ion Channels; D000279:Administration, Cutaneous; D000328:Adult; D000584:Amiloride / Q000008:administration & dosage / Q000627:therapeutic use; D000700:Analgesics / Q000008:administration & dosage / Q000627:therapeutic use; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use; D002211:Capsaicin / Q000633:toxicity; D004008:Diclofenac / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D005542:Forearm; D006358:Hot Temperature; D006801:Humans; D006851:Hydrochloric Acid / Q000633:toxicity*; D006863:Hydrogen-Ion Concentration; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology; D007052:Ibuprofen / Q000008:administration & dosage / Q000627:therapeutic use; D007279:Injections, Subcutaneous; D007473:Ion Channels / Q000502:physiology*; D007478:Iontophoresis; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D010146:Pain / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D012032:Refractory Period, Electrophysiological; D016037:Single-Blind Method; D015222:Sodium Channels / Q000502:physiology*; D050916:TRPV Cation Channels
chemical_list: D062565:Acid Sensing Ion Channels; D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007473:Ion Channels; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D015222:Sodium Channels; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D004008:Diclofenac; D000584:Amiloride; D006851:Hydrochloric Acid; D002211:Capsaicin; D007052:Ibuprofen