WNT signaling underlies the pathogenesis of neuropathic pain in rodents
Yan-Kai Zhang, Zhi-Jiang Huang, Su Liu, Yue-Peng Liu, Angela A. Song, Xue-Jun Song
Yan-Kai Zhang, Zhi-Jiang Huang, Su Liu, Yue-Peng Liu, Angela A. Song, Xue-Jun Song
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Research Article Neuroscience

WNT signaling underlies the pathogenesis of neuropathic pain in rodents

Abstract

Treating neuropathic pain is a major clinical challenge, and the underlying mechanisms of neuropathic pain remain elusive. We hypothesized that neuropathic pain–inducing nerve injury may elicit neuronal alterations that recapitulate events that occur during development. Here, we report that WNT signaling, which is important in developmental processes of the nervous system, plays a critical role in neuropathic pain after sciatic nerve injury and bone cancer in rodents. Nerve injury and bone cancer caused a rapid-onset and long-lasting expression of WNTs, as well as activation of WNT/frizzled/β-catenin signaling in the primary sensory neurons, the spinal dorsal horn neurons, and astrocytes. Spinal blockade of WNT signaling pathways inhibited the production and persistence of neuropathic pain and the accompanying neurochemical alterations without affecting normal pain sensitivity and locomotor activity. WNT signaling activation stimulated production of the proinflammatory cytokines IL-18 and TNF-α and regulated the NR2B glutamate receptor and Ca2+-dependent signals through the β-catenin pathway in the spinal cord. These findings indicate a critical mechanism underlying the pathogenesis of neuropathic pain and suggest that targeting the WNT signaling pathway may be an effective approach for treating neuropathic pain, including bone cancer pain.

Authors

Yan-Kai Zhang, Zhi-Jiang Huang, Su Liu, Yue-Peng Liu, Angela A. Song, Xue-Jun Song

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Figure 9

Spinal blockade of WNT signaling inhibits bone cancer pain in TCI mice.

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Spinal blockade of WNT signaling inhibits bone cancer pain in TCI mice. ...
(A–D) Blocking WNT signaling in the early phase delayed the onset of mechanical allodynia (A) and thermal hyperalgesia (B), while in the later phase, it suppressed the ongoing mechanical allodynia (C) and thermal hyperalgesia (D). Each administration is indicated by an arrow on the corresponding time point. (E–H) Blocking WNT signaling reduced TCI-induced spontaneous pain manifested as guarding (E) and flinching (F), as well as movement-evoked pain manifested as guarding (G) and reduced limb use (H). Three doses of each drug were given daily for 3 consecutive days on days 7, 8, and 9 after TCI. Drug doses (A–H) (i.t., 10 μl): IWP-2 (10 μM); Fz-8/Fc (2 μg); human Fc (2 μg); and DMSO (1%). The human Fc and DMSO were used as controls. Measurements were made 4 hours after the last injection. Eight rats were included in each group. Two-way ANOVA (A–D), 1-way ANOVA (E–H). An individual Student’s t test was used to test the specific difference between the drug-treated group and its control groups (A and B), and between the data point before drug administration and each of the data points after drug administration (C and D). *P < 0.05, **P < 0.01 versus sham + DMSO. #P < 0.05, ##P < 0.01 versus TCI + DMSO and/or TCI + human Fc.