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The Journal of Neuroscience, December 12, 2007, 27(50):13680-13690; doi:10.1523/JNEUROSCI.2203-07.2007
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Cellular/Molecular
TRPM8 Mechanism of Cold Allodynia after Chronic Nerve Injury
Hong Xing,1 * Meng Chen,1 * Jennifer Ling,1 Weihong Tan,2 andJianguo G. Gu1 1Department of Oral and Maxillofacial Surgery, McKnight Brain Institute and College of Dentistry, University of Florida, Gainesville, Florida 32610, and 2Department of Chemistry, Shands Cancer Center, University of Florida Genetics Institute, and McKnight Brain Institute, University of Florida, Gainesville, Florida 32611-7200
Correspondence should be addressed to Dr. Jianguo G. Gu, Department of Oral and Maxillofacial Surgery, McKnight Brain Institute and College of Dentistry, University of Florida, Box 100416, Gainesville, FL 32610. Email: jgu{at}dental.ufl.edu
The cold- and menthol-sensitive receptor TRPM8 (transient receptor potential melastatin 8) has been suggested to play a role in cold allodynia, an intractable pain seen clinically. We studied how TRPM8 is involved in cold allodynia using rats with chronic constrictive nerve injury (CCI), a neuropathic pain model manifesting cold allodynia in hindlimbs. We found that cold allodynic response in the CCI animals was significantly attenuated by capsazepine, a blocker for both TRPM8 and TRPV1 (transient receptor potential vanilloid 1) receptors, but not by the selective TRPV1 antagonist I-RTX (5-iodoresiniferatoxin). In L5 dorsal root ganglion (DRG) sections of the CCI rats, immunostaining showed an increase in the percentage of TRPM8-immunoreactive neurons when compared with the sham group. Using the Ca2+-imaging technique and neurons acutely dissociated from the L5 DRGs, we found that CCI resulted in a significant increase in the percentage of menthol- and cold-sensitive neurons and also a substantial enhancement in the responsiveness of these neurons to both menthol and innocuous cold. These changes occurred in capsaicin-sensitive neurons, a subpopulation of nociceptive-like neurons. Using patch-clamp recordings, we found that membrane currents evoked by both menthol and innocuous cold were significantly enhanced in the CCI group compared with the sham group. By retrograde labeling afferent neurons that target hindlimb skin, we showed that the skin neurons expressed TRPM8 receptors, that the percentage of menthol-sensitive/cold-sensitive/capsaicin-sensitive neurons increased, and that the menthol- and cold-evoked responses were significantly enhanced in capsaicin-sensitive neurons after CCI. Together, the gain of TRPM8-mediated cold sensitivity on nociceptive afferent neurons provides a mechanism of cold allodynia.
Key words: TRPM8; cold allodynia; pain; chronic nerve injury; calcium imaging; patch-clamp recording
Received May 14, 2007; revised Sept. 17, 2007; accepted Sept. 17, 2007.
Correspondence should be addressed to Dr. Jianguo G. Gu, Department of Oral and Maxillofacial Surgery, McKnight Brain Institute and College of Dentistry, University of Florida, Box 100416, Gainesville, FL 32610. Email: jgu{at}dental.ufl.edu
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