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The Journal of Neuroscience, January 30, 2008, 28(5):1046-1057; doi:10.1523/JNEUROSCI.4497-07.2008

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Neurobiology of Disease
Interaction of Transient Receptor Potential Vanilloid 4, Integrin, and Src Tyrosine Kinase in Mechanical Hyperalgesia

Nicole Alessandri-Haber, Olayinka A. Dina, Elizabeth K. Joseph, David B. Reichling, and Jon D. Levine

Departments of Oral and Maxillofacial Surgery and Medicine and Division of Neuroscience, University of California, San Francisco, San Francisco, California 94143-0440

Correspondence should be addressed to Dr. Nicole Alessandri-Haber, Department of Oral and Maxillofacial Surgery and Medicine, Box 0440, University of California, San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0440. Email: Nicole.Haber{at}ucsf.edu

Although the transient receptor potential vanilloid 4 (TRPV4) has been implicated in the process of osmomechanical transduction, it appears to make little contribution to the normal somatosensory detection of mechanical stimuli. However, evidence suggests that it may play an important role in mechanical hyperalgesia. In the present study, we examined the common requirement for TRPV4 in mechanical hyperalgesia associated with diverse pain models and investigated whether the very close association observed between TRPV4 and mechanical hyperalgesia, regardless of etiology, reflects a close functional connection of TRPV4 with other molecules implicated in mechanical transduction. In models of painful peripheral neuropathy associated with vincristine chemotherapy, alcoholism, diabetes, and human immunodeficiency virus/acquired immune deficiency syndrome therapy, mechanical hyperalgesia was markedly reduced by spinal intrathecal administration of oligodeoxynucleotides antisense to TRPV4. Similarly, mechanical hyperalgesia induced by paclitaxel, vincristine, or diabetes was strongly reduced in TRPV4 knock-out mice. We also show that 2β1 integrin and Src tyrosine kinase, which have been implicated in mechanical transduction, are important for the development of mechanical hyperalgesia, and that their contribution requires TRPV4. Furthermore, we establish a direct interaction between TRPV4, 2 integrin, and the Src tyrosine kinase Lyn in sensory neurons. We suggest that TRPV4 plays a role in mechanotransduction, as a component of a molecular complex that functions only in the setting of inflammation or nerve injury.

Key words: sensory nerve; neuropathic pain; dorsal root ganglion; extracellular matrix; primary afferent nociceptors; inflammatory soup

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Received Oct. 2, 2007; revised Nov. 20, 2007; accepted Dec. 15, 2007.

Correspondence should be addressed to Dr. Nicole Alessandri-Haber, Department of Oral and Maxillofacial Surgery and Medicine, Box 0440, University of California, San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0440. Email: Nicole.Haber{at}ucsf.edu

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