ASIC1 and ASIC3 play different roles in the development of Hyperalgesia after inflammatory muscle injury.
Acid-sensing ion channels (ASICs) respond to acidosis that normally occurs after inflammation. We examined the expression of ASIC1, ASIC2, and ASIC3 mRNAs in lumbar dorsal root ganglion neurons before and 24 hours after carrageenan-induced muscle inflammation. Muscle inflammation causes bilateral increases of ASIC2 and ASIC3 but not ASIC1 (neither ASIC1a nor ASIC1b) mRNA, suggesting differential regulation of ASIC1 versus ASIC2 and ASIC3 mRNA. Similar mRNA increases were observed after inflammation in knockout mice: ASIC2 mRNA increases in ASIC3-/- mice; ASIC2 and ASIC3 mRNAs increase in ASIC1-/- mice. Prior behavioral studies in ASIC3-/- mice showed deficits in secondary hyperalgesia (increased response to noxious stimuli outside the site of injury) but not primary hyperalgesia (increased response to noxious stimuli at the site of injury). In this study, we show that ASIC1-/- mice do not develop primary muscle hyperalgesia but develop secondary paw hyperalgesia. In contrast, and as expected, ASIC3-/- mice develop primary muscle hyperalgesia but do not develop secondary paw hyperalgesia. The pharmacological utility of the nonselective ASIC inhibitor A-317567, given locally, was tested. A-317567 reverses both the primary and the secondary hyperalgesia induced by carrageenan muscle inflammation. Thus, peripherally located ASIC1 and ASIC3 play different roles in the development of hyperalgesia after muscle inflammation.


CONCLUSIONS
This study shows changes in ASIC mRNA expression and behavioral hyperalgesia of C57Bl/6 (wild type), ASIC1-/-, and ASIC3-/- mice before and after the induction of muscle inflammation. A-317567 was effective in reversing hyperalgesia in these animals, suggesting the potential of ASICs as therapeutic targets for muscle inflammatory pain.
Walder
Roxanne Y
RY
Physical Therapy and Rehabilitation Science, Pain Research Program, University of Iowa, Iowa City, Iowa, USA.
Rasmussen
Lynn A
LA
Rainier
Jon D
JD
Light
Alan R
AR
Wemmie
John A
JA
Sluka
Kathleen A
KA
D062565:Acid Sensing Ion Channels; D000818:Animals; D002351:Carrageenan / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005528:Foot / Q000503:physiopathology; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology; D009220:Myositis / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D009281:Naphthalenes / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009619:Nociceptors / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000166:cytology / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics*
C506640:A-317567; C568267:ASIC1 protein, mouse; C568265:ASIC2 protein, mouse; C508378:ASIC3 protein, mouse; D062565:Acid Sensing Ion Channels; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D007546:Isoquinolines; D009281:Naphthalenes; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D015222:Sodium Channels; D002351:Carrageenan