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The Journal of Neuroscience, April 5, 2006, 26(14):3864-3874; doi:10.1523/JNEUROSCI.5385-05.2006
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Behavioral/Systems/Cognitive
A Transient Receptor Potential Vanilloid 4-Dependent Mechanism of Hyperalgesia Is Engaged by Concerted Action of Inflammatory Mediators
Nicole Alessandri-Haber, Olayinka A. Dina, Elizabeth K. Joseph, David Reichling, andJon D. Levine Department of Oral and Maxillofacial Surgery and Division of Neurosciences, University of California, San Francisco, San Francisco, California 94143-0440
Correspondence should be addressed to Nicole Alessandri-Haber, Department of Oral and Maxillofacial Surgery, Box 0440, University of California, San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0440. Email: haber{at}itsa.ucsf.edu
The transient receptor potential vanilloid 4 (TRPV4) is a primary afferent transducer that plays a crucial role in neuropathic hyperalgesia for osmotic and mechanical stimuli, as well as in inflammatory mediator-induced hyperalgesia for osmotic stimuli. In view of the clinical importance of mechanical hyperalgesia in inflammatory states, the present study investigated the role of TRPV4 in mechanical hyperalgesia induced by inflammatory mediators and the second-messenger pathways involved. Intradermal injection of either the inflammogen carrageenan or a soup of inflammatory mediators enhanced the nocifensive paw-withdrawal reflex elicited by hypotonic or mechanical stimuli in rat. Spinal administration of TRPV4 antisense oligodeoxynucleotide blocked the enhancement without altering baseline nociceptive threshold. Similarly, in TRPV4–/– knock-out mice, inflammatory soup failed to induce any significant mechanical or osmotic hyperalgesia. In vitro investigation showed that inflammatory mediators engage the TRPV4-mediated mechanism of sensitization by direct action on dissociated primary afferent neurons. Additional behavioral observations suggested that multiple mediators are necessary to achieve sufficient activation of the cAMP pathway to engage the TRPV4-dependent mechanism of hyperalgesia. In addition, direct activation of protein kinase A or protein kinase C
, two pathways that mediate inflammation-induced mechanical hyperalgesia, also induced hyperalgesia for both hypotonic and mechanical stimuli that was decreased by TRPV4 antisense and absent in TRPV4–/– mice. We conclude that TRPV4 plays a crucial role in the mechanical hyperalgesia that is generated by the concerted action of inflammatory mediators present in inflamed tissues.
Key words: pain; mechanotransduction; silent nociceptor; dorsal root ganglion; sensory nerve; inflammatory mediators
Received Aug. 11, 2005; revised Feb. 6, 2006; accepted Feb. 28, 2006.
Correspondence should be addressed to Nicole Alessandri-Haber, Department of Oral and Maxillofacial Surgery, Box 0440, University of California, San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0440. Email: haber{at}itsa.ucsf.edu
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