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The Journal of Neuroscience, December 24, 2008, 28(52):14062-14073; doi:10.1523/JNEUROSCI.3795-08.2008

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Cellular/Molecular
Nociceptors Are Interleukin-1β Sensors

Alexander M. Binshtok,¹ Haibin Wang,¹ Katharina Zimmermann,² Fumimasa Amaya,¹ Daniel Vardeh,¹ Lin Shi,¹ Gary J. Brenner,¹ Ru-Rong Ji,³ Bruce P. Bean,⁴ Clifford J. Woolf,¹ and Tarek A. Samad^1,5

¹Neural Plasticity Research Group, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, ²Department of Cardiology, Howard Hughes Medical Institute, and Department of Neurobiology, Harvard Medical School, Children's Hospital, Boston, Massachusetts 02115, ³Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, ⁴Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and ⁵Pain Molecular Neurobiology Group, Neuroscience Discovery, Wyeth Research, Princeton, New Jersey 08852

Correspondence should be addressed to Tarek A. Samad, Pain Molecular Neurobiology Group, Neuroscience Discovery, Wyeth Research, 865 Ridge Road, Princeton, NJ 08852. Email: samadt{at}wyeth.com

A cardinal feature of inflammation is heightened pain sensitivity at the site of the inflamed tissue. This results from the local release by immune and injured cells of nociceptor sensitizers, including prostaglandin E₂, bradykinin, and nerve growth factor, that reduce the threshold and increase the excitability of the peripheral terminals of nociceptors so that they now respond to innocuous stimuli: the phenomenon of peripheral sensitization. We show here that the proinflammatory cytokine interleukin-1β (IL-1β), in addition to producing inflammation and inducing synthesis of several nociceptor sensitizers, also rapidly and directly activates nociceptors to generate action potentials and induce pain hypersensitivity. IL-1β acts in a p38 mitogen-activated protein kinase (p38 MAP kinase)-dependent manner, to increase the excitability of nociceptors by relieving resting slow inactivation of tetrodotoxin-resistant voltage-gated sodium channels and also enhances persistent TTX-resistant current near threshold. By acting as an IL-1β sensor, nociceptors can directly signal the presence of ongoing tissue inflammation.

Key words: nociception; inflammation; interleukin; excitability; sodium channel; dorsal root ganglion

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Received Aug. 11, 2008; revised Oct. 31, 2008; accepted Nov. 8, 2008.

Correspondence should be addressed to Tarek A. Samad, Pain Molecular Neurobiology Group, Neuroscience Discovery, Wyeth Research, 865 Ridge Road, Princeton, NJ 08852. Email: samadt{at}wyeth.com

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