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The Journal of Neuroscience, December 12, 2007, 27(50):13770-13780; doi:10.1523/JNEUROSCI.3822-07.2007

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Cellular/Molecular
Activin Acutely Sensitizes Dorsal Root Ganglion Neurons and Induces Hyperalgesia via PKC-Mediated Potentiation of Transient Receptor Potential Vanilloid I

Weiguo Zhu,¹ Pin Xu,² Fernando X. Cuascut,² Alison K. Hall,² and Gerry S. Oxford¹

¹Stark Neurosciences Research Institute and Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202, and ²Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106

Correspondence should be addressed to Gerry S. Oxford, Stark Neurosciences Research Institute, Indiana University School of Medicine, 950 West Walnut Street, Room 402, Indianapolis, IN 46202. Email: goxford{at}iupui.edu

Pain hypersensitivity is a cardinal sign of tissue damage, but how molecules from peripheral tissues affect sensory neuron physiology is incompletely understood. Previous studies have shown that activin A increases after peripheral injury and is sufficient to induce acute nociceptive behavior and increase pain peptides in sensory ganglia. This study was designed to test the possibility that the enhanced nociceptive responsiveness associated with activin involved sensitization of transient receptor potential vanilloid I (TRPV1) in primary sensory neurons. Activin receptors were found widely distributed among adult sensory neurons, including those that also express the capsaicin receptor. Whole-cell patch-clamp recording from sensory neurons showed that activin acutely sensitized capsaicin responses and depended on activin receptor kinase activity. Pharmacological studies revealed that the activin sensitization of capsaicin responses required PKC signaling, but not PI3K (phosphoinositide 3-kinase), ERK (extracellular signal-regulated protein kinase), PKA, PKC/β, or Src. Furthermore, activin administration caused acute thermal hyperalgesia in wild-type mice, but not in TRPV1-null mice. These data suggest that activin signals through its own receptor, involves PKC signaling to sensitize the TRPV1 channel, and contributes to acute thermal hyperalgesia.

Key words: activin; capsaicin; nociceptor; TRPV1; hyperalgesia; pain

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Received April 18, 2007; revised Sept. 19, 2007; accepted Sept. 19, 2007.

Correspondence should be addressed to Gerry S. Oxford, Stark Neurosciences Research Institute, Indiana University School of Medicine, 950 West Walnut Street, Room 402, Indianapolis, IN 46202. Email: goxford{at}iupui.edu

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