Reversal of acid-induced and inflammatory pain by the selective ASIC3 inhibitor, APETx2.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Karczewski
Jerzy
J
Departments of Pain Research and Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. jerzy_karczewski@merck.com
Spencer
Robert H
RH
Garsky
Victor M
VM
Liang
Annie
A
Leitl
Michael D
MD
Cato
Matthew J
MJ
Cook
Sean P
SP
Kane
Stefanie
S
Urban
Mark O
MO
D062565:Acid Sensing Ion Channels; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D003064:Cnidarian Venoms / Q000008:administration & dosage / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000633:toxicity; D006863:Hydrogen-Ion Concentration; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000378:metabolism*; D012965:Sodium Chloride / Q000633:toxicity
C501880:APETx2 protein, Anthopleura elegantissima; C568269:ASIC3 protein, rat; D062565:Acid Sensing Ion Channels; D000700:Analgesics; D003064:Cnidarian Venoms; D009419:Nerve Tissue Proteins; D015222:Sodium Channels; D012965:Sodium Chloride; D005620:Freund's Adjuvant