Neuropathic pain is a common cause of pain after nerve injury, but its molecular basis is poorly understood. In a post-genechip microarray effort to identify new target genes contributing to neuropathic pain development, we report here the characterization of a novel neuropathic pain contributor, thrombospondin-4 (TSP4), using a neuropathic pain model of spinal nerve ligation injury. TSP4 is mainly expressed in astrocytes and significantly upregulated in the injury side of dorsal spinal cord that correlates with the development of neuropathic pain states. TSP4 blockade either by intrathecal antibodies, antisense oligodeoxynucleotides, or inactivation of the TSP4 gene reverses or prevents behavioral hypersensitivities. Intrathecal injection of TSP4 protein into naïve rats is sufficient to enhance the frequency of excitatory postsynaptic currents in spinal dorsal horn neurons, suggesting an increased excitatory pre-synaptic input, and cause similar behavioral hypersensitivities. Together, these findings support that injury-induced spinal TSP4 may contribute to spinal pre-synaptic hypersensitivity and neuropathic pain states. Development of TSP4 antagonists has the therapeutic potential for target-specific neuropathic pain management.

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Background: Factors mediating orofacial neuropathic pain are not well defined. Results: Trigeminal nerve injury-induced calcium channel ␣ 2 ␦ 1 protein up-regulation in trigeminal ganglia and spinal complex correlated with enhanced spinal presynaptic neurotransmission, excitatory synaptogenesis, and orofacial pain states. Conclusion: This neuroplasticity may mediate orofacial neuropathic pain states by enhancing dorsal horn excitatory synaptic neurotransmission. Significance: This reveals a mechanism underlying orofacial neuropathic pain states.

Thrombospondin-4 (TSP4) belongs to a family of large oligomeric, extracellular matrix glycoproteins that mediate interactions between cells and interactions of cells with underlying matrix components. Recent evidence shows that TSP4 may contribute to the generation of neuropathic pain. However, there is no systematic examination of TSP4 expression in the DRGs after injury. We therefore investigated whether TSP4 protein level is changed in DRGs after injury following spinal nerve ligation (SNL) and spared nerve injury (SNI) in rats using western blot, immunohistochemistry, and immunocytochemistry. After nerve ligation, TSP4 protein level is up-regulated in the axotomized somata of the L5 DRG. There is substantial additional TSP4 in the non-neuronal compartment of the L5 DRG that does not co-stain for markers of satellite glia, microglia, or Schwann cells and appears to be in the interstitial space. Evidence of intracellular overexpression of TSP4 persists in neurons dissociated from the L5 DRG after SNL. These findings indicate that following peripheral nerve injury, TSP4 protein expression is elevated in the cytoplasm of axotomized sensory neurons and in the surrounding interstitial space.

This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.