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The Journal of Neuroscience, January 28, 2004, 24(4):819-827; doi:10.1523/JNEUROSCI.1263-03.2004

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Development/Plasticity/Repair
Semaphorin3A Inhibits Nerve Growth Factor-Induced Sprouting of Nociceptive Afferents in Adult Rat Spinal Cord

Xiao-Qing Tang,¹ Darrell L. Tanelian,² and George M. Smith¹

¹Department of Physiology, Spinal Cord and Brain Injury Research Center, University of Kentucky Chandler Medical Center, Lexington, Kentucky 40536-0298, and ²Medical City Dallas Hospital, Dallas, Texas 75230

Increased expression of NGF after spinal cord injury induces sprouting of primary nociceptive axons. Exogenous application of NGF also results in extensive sprouting of these axons and causes chronic pain in uninjured animals. During development, semaphorin3A is thought to act as a repulsive guidance cue for NGF-responsive nociceptive afferents, restricting their projections to the superficial dorsal horn. We investigated the ability of semaphorin3A to selectively reduce NGF-induced sprouting and neuropathic pain in adult rats. The chemorepulsive effect of virus-mediated semaphorin3A expression was shown to counteract the sprouting induced by NGF in a dose-dependent manner, both in vitro and in adult rat spinal cords. Coexpression of semaphorin3A and NGF at moderate to low concentrations within the adult spinal cord reduced sprouting of calcitonin gene-related peptide and substance P-containing axons compared with GFP and NGF coexpression controls. At high expression levels of NGF, there was no difference in sprouting between the semaphorin3A-treated and control groups. The distribution of endogenous primary nociceptive afferents in the spinal cord appeared to be unaffected by semaphorin3A treatment in these experiments. Behavioral assessment shows that semaphorin3A coexpression with NGF led to decreased mechanical allodynia but no significant reductions in thermal hyperalgesia. These findings demonstrate directly that mature sensory afferents maintain their responsiveness to semaphorin3A, suggesting that this molecule might be used therapeutically to control aberrant sensory sprouting involved in pain or autonomic dysfunction.

Key words: semaphorin3A; nerve growth factor; nociceptive afferents; sprouting; gene therapy; spinal cord; pain

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Received April 28, 2003; revised November 11, 2003; accepted November 25, 2003.

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