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The Journal of Neuroscience, October 26, 2005, 25(43):9893-9901; doi:10.1523/JNEUROSCI.2019-05.2005
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Cellular/Molecular
Transgenic Expression of a Dominant-Negative ASIC3 Subunit Leads to Increased Sensitivity to Mechanical and Inflammatory Stimuli
Jeffrey S. Mogil,1 Nicole M. Breese,2 Marie-France Witty,3 Jennifer Ritchie,1 Marie-Line Rainville,3 Ariel Ase,3 Naima Abbadi,3 Cheryl L. Stucky,2 andPhilippe Séguéla3 1Department of Psychology and Centre for Research on Pain, McGill University, Montreal, Quebec, Canada H3A 1B1, 2Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, and 3Montreal Neurological Institute, Department of Neurology and Neurosurgery, and Centre for Research on Pain, McGill University, Montreal, Quebec, Canada H3A 2B4
Molecular and behavioral evidence suggests that acid-sensing ion channels (ASICs) contribute to pain processing, but an understanding of their precise role remains elusive. Existing ASIC knock-out mouse experiments are complicated by the heteromultimerization of ASIC subunits. Therefore, we have generated transgenic mice that express a dominant-negative form of the ASIC3 subunit that inactivates all native neuronal ASIC-like currents by oligomerization. Using whole-cell patch-clamp recordings, we examined the response properties of acutely isolated dorsal root ganglion neurons to protons (pH 5.0). We found that whereas 33% of the proton-responsive neurons from wild-type mice exhibited an ASIC-like transient response, none of the neurons from the transgenic mice exhibited a transient inward current. Capsaicin-evoked responses mediated by the TRPV1 receptor were unaltered in transgenic mice. Adult male wild-type and transgenic mice were subjected to a battery of behavioral nociceptive assays, including tests of thermal, mechanical, chemical/inflammatory, and muscle pain. The two genotypes were equally sensitive to thermal pain and to thermal hypersensitivity after inflammation. Compared with wild types, however, transgenic mice were more sensitive to a number of modalities, including mechanical pain (von Frey test, tail-clip test), chemical/inflammatory pain (formalin test, 0.6% acetic acid writhing test), mechanical hypersensitivity after zymosan inflammation, and mechanical hypersensitivity after intramuscular injection of hypotonic saline. These data reinforce the hypothesis that ASICs are involved in both mechanical and inflammatory pain, although the increased sensitivity of transgenic mice renders it unlikely that they are direct transducers of nociceptive stimuli.
Key words: acid-sensing ion channels; sensory neurons; dorsal root ganglia; pain; mutant; hyperalgesia
Received May 19, 2005; revised September 8, 2005; accepted September 9, 2005.
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