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The Journal of Neuroscience, May 19, 2004, 24(20):4832-4839; doi:10.1523/JNEUROSCI.0300-04.2004

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Development/Plasticity/Repair
Altered Sodium Channel Expression in Second-Order Spinal Sensory Neurons Contributes to Pain after Peripheral Nerve Injury

Bryan C. Hains, Carl Y. Saab, Joshua P. Klein, Matthew J. Craner, and Stephen G. Waxman

Department of Neurology and the Paralyzed Veterans of America–Eastern Paralyzed Veterans Association Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, and Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516

Peripheral nerve injury is known to upregulate the rapidly repriming Na_v1.3 sodium channel within first-order spinal sensory neurons. In this study, we hypothesized that (1) after peripheral nerve injury, second-order dorsal horn neurons abnormally express Na_v1.3, which (2) contributes to the responsiveness of these dorsal horn neurons and to pain-related behaviors. To test these hypotheses, adult rats underwent chronic constriction injury (CCI) of the sciatic nerve. Ten days after CCI, allodynia and hyperalgesia were evident. In situ hybridization, quantitative reverse transcription-PCR, and immunocytochemical analysis revealed upregulation of Na_v1.3 in dorsal horn nociceptive neurons but not in astrocytes or microglia, and unit recordings demonstrated hyperresponsiveness of dorsal horn sensory neurons. Intrathecal antisense oligodeoxynucleotides targeting Na_v1.3 decreased the expression of Na_v1.3 mRNA and protein, reduced the hyperresponsiveness of dorsal horn neurons, and attenuated pain-related behaviors after CCI, all of which returned after cessation of antisense delivery. These results demonstrate for the first time that sodium channel expression is altered within higher-order spinal sensory neurons after peripheral nerve injury and suggest a link between misexpression of the Na_v1.3 sodium channel and central mechanisms that contribute to neuropathic pain after peripheral nerve injury.

Key words: ion channel; sensitization; neuropathy; dorsal horn; wide dynamic range; pain

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Received Jan 27, 2004; revised March 1, 2004; accepted March 1, 2004.

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