Regulation of Wnt Signaling by Nociceptive Input in Animal Models

Abstract

BackgroundCentral sensitization-associated synaptic plasticity in the spinal cord dorsal horn (SCDH) critically contributes to the development of chronic pain, but understanding of the underlying molecular pathways is still incomplete. Emerging evidence suggests that Wnt signaling plays a crucial role in regulation of synaptic plasticity. Little is known about the potential function of the Wnt signaling cascades in chronic pain development.ResultsFluorescent immunostaining results indicate that β-catenin, an essential protein in the canonical Wnt signaling pathway, is expressed in the superficial layers of the mouse SCDH with enrichment at synapses in lamina II. In addition, Wnt3a, a prototypic Wnt ligand that activates the canonical pathway, is also enriched in the superficial layers. Immunoblotting analysis indicates that both Wnt3a a β-catenin are up-regulated in the SCDH of various mouse pain models created by hind-paw injection of capsaicin, intrathecal (i.t.) injection of HIV-gp120 protein or spinal nerve ligation (SNL). Furthermore, Wnt5a, a prototypic Wnt ligand for non-canonical pathways, and its receptor Ror2 are also up-regulated in the SCDH of these models.ConclusionOur results suggest that Wnt signaling pathways are regulated by nociceptive input. The activation of Wnt signaling may regulate the expression of spinal central sensitization during the development of acute and chronic pain.

The Ryk Receptor Is Expressed in Glial and Fibronectin-Expressing Cells after Spinal Cord Injury

“…[3][4][5] A growing body of evidence suggests that Wnt signalling may be involved in homeostasis and disease progression in adult tissues, [6][7][8][9][10][11] including the spinal cord. 10,[12][13][14][15][16] Consistent with these findings, we have previously shown that most of Wnt ligands and inhibitors are expressed in the adult spinal cord of rats and, following SCI, are differentially induced with at least Wnt/b-catenin signalling activation in cells that appear to be involved in glial scarring. 13 Strategies seeking to modulate Wnt-dependent signaling pathways have been shown to be beneficial in different experimental models of CNS disorders 8,[17][18][19][20][21][22][23] including SCI.…”

Wnts Are Expressed in the Spinal Cord of Adult Mice and Are Differentially Induced after Injury

“…22,32 Interestingly, Wnt3a and Wnt5a have been recently described to be expressed by neurons of the ventral and dorsal horn of adult mice, and that the latter received Wnt3a and Wnt5a synapsis from dorsal root ganglia sensory neurons, with at least involvement of the b-catenin pathway, as evidenced by its enrichment in the pre-and postsynaptic contacts. 30,33 Moreover, the induction of central neuropathic pain by either peripheral nerve constriction, capsaicin administration, multiple sclerosis progression, or tumor cell implantation has been associated with dorsal horn up-regulation of the Wnt3a and Wnt5a ligands, the Fz1, Fz8, and Ror2 receptors, and the Wnt-canonical signaling pathway. 24,29,30 Significantly, specific Wnt inhibition, by either the Wnt5a antagonist, Box5, the b-catenin inhibitor, indomethacin, or the inhibitor of Wnt production (IWP-2) attenuated the induced mechanical allodynia and neuropathic pain, as well as the expression of proinflammatory factors associated with pain induction, such as tumor necrosis factor alpha and interleukins, providing a compelling functional evidence of a relevant Wnt role on spinal cord physiology.…”

“…30,33 Moreover, the induction of central neuropathic pain by either peripheral nerve constriction, capsaicin administration, multiple sclerosis progression, or tumor cell implantation has been associated with dorsal horn up-regulation of the Wnt3a and Wnt5a ligands, the Fz1, Fz8, and Ror2 receptors, and the Wnt-canonical signaling pathway. 24,29,30 Significantly, specific Wnt inhibition, by either the Wnt5a antagonist, Box5, the b-catenin inhibitor, indomethacin, or the inhibitor of Wnt production (IWP-2) attenuated the induced mechanical allodynia and neuropathic pain, as well as the expression of proinflammatory factors associated with pain induction, such as tumor necrosis factor alpha and interleukins, providing a compelling functional evidence of a relevant Wnt role on spinal cord physiology. 24,29 In this sense, it has been proved that the synthesis and secretion of neuronal Wnt proteins was controlled FIG.…”

“…24,25,[28][29][30][33][34][35]39 Therefore, by using a similar experimental design to our previous study in rats, but with spinal cord dorsal hemisection as an injury paradigm to reproduce the only report describing a role for Wnts in traumatic SCI, 28 we decided to assess, by qPCR, the temporal pattern of mRNA expression for all Wnt ligands in both uninjured and injured mice up to 14 days after spinal cord hemisection lesion. Consistent with our previous results in rats, most Wnt ligands were found to be expressed in the uninjured adult spinal cord.…”

“…25,33,34 In a different study, Tang and colleagues have reported that Wnt3a, Wnt5a, and the noncanonical receptor, receptor tyrosine kinase-like orphan receptor 2, were constitutively expressed by neurons and glial cells of the adult spinal cord of mice and that, in experimental models of multiple sclerosis and peripheral nerve injury, they might play a role on the process of remyelination and induction of neuropathic pain by, at least, activating the b-catenin canonical pathway. 24,29,30 Moreover, a previous thorough in situ hybridization mapping of key factors during development revealed that expression of most Wnt ligands and receptors was prolonged in the adult central nervous system (CNS) of mice, including the spinal cord. 35 Therefore, we decided to reassess, by means of quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC), a broad analysis of Wnt expression patterns in healthy and post-hemisection injury of the adult spinal cord of mice.…”