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

Abstract

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 dosedependent 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.

MICAL flavoprotein monooxygenases: Expression during neural development and following spinal cord injuries in the rat

“…The sustained sensitivity of sprouting adult axons to Sema3A in vivo supports the idea that intracellular signaling cues that function downstream of repulsive semaphorins are expressed in adult neurons following injury (Tanelian et al, 1997;Tang et al, 2004). To test this hypothesis, we subjected adult rats to spinal contusion and overhemisection lesions and evaluated MICAL expression in layer V neurons of the motor cortex and in neurons of the red nucleus.…”

“…Second, meningeal fibroblast-derived Sema3A inhibits DRG axon growth in vitro, and antibodies capable of blocking neuropilin function promote axon growth in an in vitro model of the CNS scar Shearer et al, 2003). Third, adult CNS and PNS neurons express neuropilins, plexinAs, CRMPs, and MICALs, and sprouting sensory axons are responsive to Sema3-mediated axon repulsion in vitro and in vivo (Agudo et al, 2005;De Winter et al, 2002b;Gavazzi et al, 2000;Lindholm et al, 2004;Owesson et al, 2000;Pasterkamp et al, 1998aPasterkamp et al, ,b, 2000Reza et al, 1999;Tanelian et al, 1997;Tang et al, 2004;Wang and Strittmatter, 1996). Fourth, conditioning peripheral nerve injuries that allow DRG axons to regenerate centrally do not promote regenerative axon growth through Sema3-expressing scar tissue (Pasterkamp et al, 2001).…”

Plasticity After Spinal Cord Injury: Relevance to Recovery and Approaches to Facilitate It

“…The sprouting of nociceptive axons can be inhibited by expression of the chemorepulsive molecule semaphorin 3A. Co-expression of semaphorin 3A has been shown to reduce NGF-mediated sprouting, autonomic dysreflexia [123], and allodynia [125].…”

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

“…163 One of the apparent issues is that NGF-treated axons far overshoot their targets 164,165 to terminate deep in the dorsal horn. Tang et al 166 have taken advantage of a developmental mechanism of axon repulsion in the spinal grey matter by transfecting ventral cells with semaphorin 3A. This acts to prevent nociceptive axons from penetrating too deeply into the cord, and to partially inhibit the development of abnormal pain.…”

“…This acts to prevent nociceptive axons from penetrating too deeply into the cord, and to partially inhibit the development of abnormal pain. 166 Direct spinal cord trauma leads to the NGF-mediated sprouting of CGRPpositive fibers, which may be partly responsible for the development of autonomic dysreflexia (AD), a severe and life-threatening condition characterized by large and inappropriate elevations in blood pressure: 167,168 in this situation, sequestering NGF improves outcomes in rats and mice. By refining our ability to manipulate guidance cues, it may eventually be possible to extract from NGF its desired effects.…”