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Regulation of Wnt signaling by nociceptive input in animal models.

Shi Y, Yuan S, Li B, Wang J, Carlton SM, Chung K, Chung JM, Tang SJ - Mol Pain (2012)

Bottom Line: In addition, Wnt3a, a prototypic Wnt ligand that activates the canonical pathway, is also enriched in the superficial layers.Furthermore, Wnt5a, a prototypic Wnt ligand for non-canonical pathways, and its receptor Ror2 are also up-regulated in the SCDH of these models.Our results suggest that Wnt signaling pathways are regulated by nociceptive input.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.

ABSTRACT

Background: Central 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.

Results: Fluorescent 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.

Conclusion: Our 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.

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Up-regulation of Wnt signaling proteins in the neuropathic pain model.A. Neuropathic pain was induced 1 week post L5 spinal nerve ligation (SNL, n = 6). Mice with sham operation (without SNL, n = 6) were used as controls. B-F. Wnt3a (A), ABC (B), TBC (C), Wnt5a (D), and Ror2 C (E) proteins in the ipsilateral (ipsi) and contralateral (contra) sides of the SCDH at 7 days after unilateral L5 spinal nerve ligation (SNL). Compared with the contra side, significant increases in the levels of Wnt signaling proteins were detected in the ipsi side of SNL but not control mice (n = 3). Data are summarized in graphs at right (**, p < 0.01; *, p < 0.05; #, p > 0.05; student’s t-test).
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Figure 8: Up-regulation of Wnt signaling proteins in the neuropathic pain model.A. Neuropathic pain was induced 1 week post L5 spinal nerve ligation (SNL, n = 6). Mice with sham operation (without SNL, n = 6) were used as controls. B-F. Wnt3a (A), ABC (B), TBC (C), Wnt5a (D), and Ror2 C (E) proteins in the ipsilateral (ipsi) and contralateral (contra) sides of the SCDH at 7 days after unilateral L5 spinal nerve ligation (SNL). Compared with the contra side, significant increases in the levels of Wnt signaling proteins were detected in the ipsi side of SNL but not control mice (n = 3). Data are summarized in graphs at right (**, p < 0.01; *, p < 0.05; #, p > 0.05; student’s t-test).

Mentions: Next, we were interested in examining the regulatory effect induced by peripheral nerve injury on Wnt signaling proteins. In this experiment, we used the neuropathic pain model produced by unilateral L5 spinal nerve ligation (SNL) [60], which is a well-established model that develops various hallmarks of chronic pain and central sensitization including neuroinflammation, hyperexcitation of spinal dorsal neurons and disinhibition of inhibitory interneurons [61-63]. As shown in Figure 8A, one week after SNL, the mice demonstrated increased paw withdrawal frequencies in response to mechanical stimulation with von Frey filaments: 0.10 g force, 92.86 ± 3.59% compared to 7.15 ± 1.84% (p < 0.05, n = 6) and 0.40 g force, 98.57 ± 1.43% compared to 18.57 ± 2.6% (p < 0.05, n = 6), for the sham-operated mice. Immunoblotting analysis of the SCDH from SNL mice at one week post-ligation showed that Wnt3a was significantly up-regulated in the ipsilateral (ipsi) compared to the contralateral (contra) side (5.9 fold, p < 0.01) (Figure 8 B). Similarly, both ABC (Figure 8 C) and TBC (Figure 8 D) were increased in the ipsi side of the SCDH with similar magnitudes of increase (2.0 fold, p < 0.05 for ABC and 1.6 fold, p < 0.05 for TBC). In addition, we also observed that non-canonical pathway signaling proteins, Wnt5a (Figure 8 E) and its co-receptor Ror2 (Figure 8 F), increased in the SNL model. Thus, Wnt signaling proteins are up-regulated following peripheral nerve injury.


Regulation of Wnt signaling by nociceptive input in animal models.

Shi Y, Yuan S, Li B, Wang J, Carlton SM, Chung K, Chung JM, Tang SJ - Mol Pain (2012)

Up-regulation of Wnt signaling proteins in the neuropathic pain model.A. Neuropathic pain was induced 1 week post L5 spinal nerve ligation (SNL, n = 6). Mice with sham operation (without SNL, n = 6) were used as controls. B-F. Wnt3a (A), ABC (B), TBC (C), Wnt5a (D), and Ror2 C (E) proteins in the ipsilateral (ipsi) and contralateral (contra) sides of the SCDH at 7 days after unilateral L5 spinal nerve ligation (SNL). Compared with the contra side, significant increases in the levels of Wnt signaling proteins were detected in the ipsi side of SNL but not control mice (n = 3). Data are summarized in graphs at right (**, p < 0.01; *, p < 0.05; #, p > 0.05; student’s t-test).
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Figure 8: Up-regulation of Wnt signaling proteins in the neuropathic pain model.A. Neuropathic pain was induced 1 week post L5 spinal nerve ligation (SNL, n = 6). Mice with sham operation (without SNL, n = 6) were used as controls. B-F. Wnt3a (A), ABC (B), TBC (C), Wnt5a (D), and Ror2 C (E) proteins in the ipsilateral (ipsi) and contralateral (contra) sides of the SCDH at 7 days after unilateral L5 spinal nerve ligation (SNL). Compared with the contra side, significant increases in the levels of Wnt signaling proteins were detected in the ipsi side of SNL but not control mice (n = 3). Data are summarized in graphs at right (**, p < 0.01; *, p < 0.05; #, p > 0.05; student’s t-test).
Mentions: Next, we were interested in examining the regulatory effect induced by peripheral nerve injury on Wnt signaling proteins. In this experiment, we used the neuropathic pain model produced by unilateral L5 spinal nerve ligation (SNL) [60], which is a well-established model that develops various hallmarks of chronic pain and central sensitization including neuroinflammation, hyperexcitation of spinal dorsal neurons and disinhibition of inhibitory interneurons [61-63]. As shown in Figure 8A, one week after SNL, the mice demonstrated increased paw withdrawal frequencies in response to mechanical stimulation with von Frey filaments: 0.10 g force, 92.86 ± 3.59% compared to 7.15 ± 1.84% (p < 0.05, n = 6) and 0.40 g force, 98.57 ± 1.43% compared to 18.57 ± 2.6% (p < 0.05, n = 6), for the sham-operated mice. Immunoblotting analysis of the SCDH from SNL mice at one week post-ligation showed that Wnt3a was significantly up-regulated in the ipsilateral (ipsi) compared to the contralateral (contra) side (5.9 fold, p < 0.01) (Figure 8 B). Similarly, both ABC (Figure 8 C) and TBC (Figure 8 D) were increased in the ipsi side of the SCDH with similar magnitudes of increase (2.0 fold, p < 0.05 for ABC and 1.6 fold, p < 0.05 for TBC). In addition, we also observed that non-canonical pathway signaling proteins, Wnt5a (Figure 8 E) and its co-receptor Ror2 (Figure 8 F), increased in the SNL model. Thus, Wnt signaling proteins are up-regulated following peripheral nerve injury.

Bottom Line: In addition, Wnt3a, a prototypic Wnt ligand that activates the canonical pathway, is also enriched in the superficial layers.Furthermore, Wnt5a, a prototypic Wnt ligand for non-canonical pathways, and its receptor Ror2 are also up-regulated in the SCDH of these models.Our results suggest that Wnt signaling pathways are regulated by nociceptive input.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.

ABSTRACT

Background: Central 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.

Results: Fluorescent 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.

Conclusion: Our 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.

Show MeSH
Related in: MedlinePlus