Reversal of acid‐induced and inflammatory pain by the selective ASIC3 inhibitor, APETx2
- 9 June 2010
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 161 (4), 950-960
- https://doi.org/10.1111/j.1476-5381.2010.00918.x
Abstract
Inflammatory pain is triggered by activation of pathways leading to the release of mediators such as bradykinin, prostaglandins, interleukins, ATP, growth factors and protons that sensitize peripheral nociceptors. The activation of acid-sensitive ion channels (ASICs) may have particular relevance in the development and maintenance of inflammatory pain. ASIC3 is of particular interest due to its restricted tissue distribution in the nociceptive primary afferent fibres and its high sensitivity to protons. To examine the contribution of ASIC3 to the development and maintenance of muscle pain and inflammatory pain, we studied the in vivo efficacy of a selective ASIC3 inhibitor, APETx2, in rats. Administration of APETx2 into the gastrocnemius muscle prior to the administration of low pH saline prevented the development of mechanical hypersensitivity, whereas APETx2 administration following low-pH saline was ineffective in reversing hypersensitivity. The prevention of mechanical hypersensitivity produced by acid administration was observed whether APETx2 was applied via i.m. or i.t. routes. In the complete Freund's adjuvant (CFA) inflammatory pain model, local administration of APETx2 resulted in a potent and complete reversal of established mechanical hypersensitivity, whereas i.t. application of APETx2 was ineffective. ASIC3 contributed to the development of mechanical hypersensitivity in the acid-induced muscle pain model, whereas ASIC3 contributed to the maintenance of mechanical hypersensitivity in the CFA inflammatory pain model. The contribution of ASIC3 to established hypersensitivity associated with inflammation suggests that this channel may be an effective analgesic target for inflammatory pain states.Keywords
This publication has 35 references indexed in Scilit:
- Guide to Receptors and Channels (GRAC), 5th editionBritish Journal of Pharmacology, 2011
- ASIC1 and ASIC3 Play Different Roles in the Development of Hyperalgesia After Inflammatory Muscle InjuryThe Journal of Pain, 2010
- Guide to Receptors and Channels (GRAC), 4th editionBritish Journal of Pharmacology, 2009
- Central Sensitization: A Generator of Pain Hypersensitivity by Central Neural PlasticityThe Journal of Pain, 2009
- Amiloride derived inhibitors of acid-sensing ion channel-3 (ASIC3)Bioorganic & Medicinal Chemistry Letters, 2009
- ASIC3, a sensor of acidic and primary inflammatory painThe EMBO Journal, 2008
- Role of ASIC3 in the primary and secondary hyperalgesia produced by joint inflammation in micePain, 2008
- Descending facilitatory pathways from the RVM initiate and maintain bilateral hyperalgesia after muscle insultPain, 2008
- ASIC3 in muscle mediates mechanical, but not heat, hyperalgesia associated with muscle inflammationPain, 2007
- Identification of acid-sensing ion channels in boneBiochemical and Biophysical Research Communications, 2005