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The Journal of Neuroscience, December 1, 2004, 24(48):10974-10979; doi:10.1523/JNEUROSCI.2619-04.2004

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Behavioral/Systems/Cognitive
Acid-Induced Pain and Its Modulation in Humans

Nicholas G. Jones,¹ Rebeccah Slater,¹ Herve Cadiou,² Peter McNaughton,² and Stephen B. McMahon¹

¹Sensory Function Group, Center for Neuroscience, King's College London, London, SE1 1UL, United Kingdom, and ²Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, United Kingdom

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 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°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.

Key words: pain; acid; iontophoresis; ASIC; TRPV1; NSAID

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Received July 1, 2004; revised August 27, 2004; accepted September 30, 2004.

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