Journal article
Selective targeting of ASIC3 using artificial miRNAs inhibits primary and secondary hyperalgesia after muscle inflammation
Pain (Amsterdam), Vol.152(10), pp.2348-2356
10/2011
DOI: 10.1016/j.pain.2011.06.027
PMCID: PMC3476729
PMID: 21843914
Abstract
Artificial miRNAs targeting mouse acid-sensing ion channel 3 (ASIC3) reduce pH sensitivity of heteromeric ASIC1/3 channels, ASIC3 protein, and mRNA expression, and prevent the development of hyperalgesia after muscle inflammation.
Acid-sensing ion channels (ASICs) are activated by acidic pH and may play a significant role in the development of hyperalgesia. Earlier studies show ASIC3 is important for induction of hyperalgesia after muscle insult using ASIC3−/− mice. ASIC3−/− mice lack ASIC3 throughout the body, and the distribution and composition of ASICs could be different from wild-type mice. We therefore tested whether knockdown of ASIC3 in primary afferents innervating muscle of adult wild-type mice prevented development of hyperalgesia to muscle inflammation. We cloned and characterized artificial miRNAs (miR-ASIC3) directed against mouse ASIC3 (mASIC3) to downregulate ASIC3 expression in vitro and in vivo. In CHO-K1 cells transfected with mASIC3 cDNA in culture, the miR-ASIC3 constructs inhibited protein expression of mASIC3 and acidic pH-evoked currents and had no effect on protein expression or acidic pH-evoked currents of ASIC1a. When miR-ASIC3 was used in vivo, delivered into the muscle of mice using a herpes simplex viral vector, both muscle and paw mechanical hyperalgesia were reduced after carrageenan-induced muscle inflammation. ASIC3 mRNA in DRG and protein levels in muscle were decreased in vivo by miR-ASIC3. In CHO-K1 cells co-transfected with ASIC1a and ASIC3, miR-ASIC3 reduced the amplitude of acidic pH-evoked currents, suggesting an overall inhibition in the surface expression of heteromeric ASIC3-containing channels. Our results show, for the first time, that reducing ASIC3 in vivo in primary afferent fibers innervating muscle prevents the development of inflammatory hyperalgesia in wild-type mice, and thus, may have applications in the treatment of musculoskeletal pain in humans.
Details
- Title: Subtitle
- Selective targeting of ASIC3 using artificial miRNAs inhibits primary and secondary hyperalgesia after muscle inflammation
- Creators
- Roxanne Y Walder - Physical Therapy and Rehabilitation Sciences Graduate Program, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USAMamta Gautam - Physical Therapy and Rehabilitation Sciences Graduate Program, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USASteven P Wilson - Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USAChristopher J Benson - Department of Internal Medicine, Pain Research Program, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USAKathleen A Sluka - Physical Therapy and Rehabilitation Sciences Graduate Program, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USA
- Resource Type
- Journal article
- Publication Details
- Pain (Amsterdam), Vol.152(10), pp.2348-2356
- DOI
- 10.1016/j.pain.2011.06.027
- PMID
- 21843914
- PMCID
- PMC3476729
- NLM abbreviation
- Pain
- ISSN
- 0304-3959
- eISSN
- 1872-6623
- Publisher
- Elsevier B.V
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health; DOI: 10.13039/100000069, name: National Institute of Arthritis and Musculoskeletal and Skin Diseases, award: R01AR053509, R01AR053509S1
- Language
- English
- Date published
- 10/2011
- Academic Unit
- Iowa Neuroscience Institute; Cardiovascular Medicine; Nursing; Physical Therapy and Rehabilitation Science; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984040387402771
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