Acid-Induced Pain and Its Modulation in Humans

• Published in: The Journal of neuroscience Vol. 24; no. 48; pp. 10974 - 10979
• Main Authors: Jones, Nicholas G, Slater, Rebeccah, Cadiou, Herve, McNaughton, Peter, McMahon, Stephen B
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 01.12.2004; Society for Neuroscience
• Subjects: Acid Sensing Ion Channels; Administration, Cutaneous; Adult; Amiloride - administration & dosage; Amiloride - therapeutic use; Analgesics - administration & dosage; Analgesics - therapeutic use; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Behavioral/Systems/Cognitive; Capsaicin - toxicity; Diclofenac - administration & dosage; Diclofenac - therapeutic use; Female; Forearm; Hot Temperature; Humans; Hydrochloric Acid - toxicity; Hydrogen-Ion Concentration; Hyperalgesia - chemically induced; Hyperalgesia - physiopathology; Ibuprofen - administration & dosage; Ibuprofen - therapeutic use; Injections, Subcutaneous; Ion Channels - physiology; Iontophoresis; Male; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - physiology; Middle Aged; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - physiology; Pain - chemically induced; Pain - drug therapy; Pain - physiopathology; Pain - prevention & control; Pain Measurement; Pain Threshold - drug effects; Pain Threshold - physiology; Refractory Period, Electrophysiological; Single-Blind Method; Sodium Channels - physiology; TRPV Cation Channels
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.2619-04.2004

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.