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Wnt/Ryk signaling contributes to neuropathic pain by regulating sensory neuron excitability and spinal synaptic plasticity in rats.
- Source :
-
Pain [Pain] 2015 Dec; Vol. 156 (12), pp. 2572-2584. - Publication Year :
- 2015
-
Abstract
- Treating neuropathic pain continues to be a major clinical challenge and underlying mechanisms of neuropathic pain remain elusive. We have recently demonstrated that Wnt signaling, which is important in developmental processes of the nervous systems, plays critical roles in the development of neuropathic pain through the β-catenin-dependent pathway in the spinal cord and the β-catenin-independent pathway in primary sensory neurons after nerve injury. Here, we report that Wnt signaling may contribute to neuropathic pain through the atypical Wnt/Ryk signaling pathway in rats. Sciatic nerve injury causes a rapid-onset and long-lasting expression of Wnt3a, Wnt5b, and Ryk receptors in primary sensory neurons, and dorsal horn neurons and astrocytes. Spinal blocking of the Wnt/Ryk receptor signaling inhibits the induction and persistence of neuropathic pain without affecting normal pain sensitivity and locomotor activity. Blocking activation of the Ryk receptor with anti-Ryk antibody, in vivo or in vitro, greatly suppresses nerve injury-induced increased intracellular Ca and hyperexcitability of the sensory neurons, and also the enhanced plasticity of synapses between afferent C-fibers and the dorsal horn neurons, and activation of the NR2B receptor and the subsequent Ca-dependent signals CaMKII, Src, ERK, PKCγ, and CREB in sensory neurons and the spinal cord. These findings indicate a critical mechanism underlying the pathogenesis of neuropathic pain and suggest that targeting the Wnt/Ryk signaling may be an effective approach for treating neuropathic pain.
- Subjects :
- Animals
Behavior, Animal drug effects
Calcium Signaling
Calcium-Calmodulin-Dependent Protein Kinase Type 2 drug effects
Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism
Cyclic AMP Response Element-Binding Protein drug effects
Cyclic AMP Response Element-Binding Protein metabolism
Ganglia, Spinal metabolism
Hyperalgesia genetics
Hyperalgesia metabolism
Locomotion drug effects
MAP Kinase Signaling System drug effects
Male
Nerve Fibers, Unmyelinated drug effects
Neuralgia genetics
Neuronal Plasticity drug effects
Pain Threshold drug effects
Patch-Clamp Techniques
Protein Kinase C
Rats
Rats, Sprague-Dawley
Real-Time Polymerase Chain Reaction
Receptor Protein-Tyrosine Kinases antagonists & inhibitors
Receptor Protein-Tyrosine Kinases genetics
Receptors, N-Methyl-D-Aspartate drug effects
Receptors, N-Methyl-D-Aspartate metabolism
Sciatic Nerve injuries
Signal Transduction
Spinal Cord metabolism
Wnt Proteins antagonists & inhibitors
Wnt Proteins metabolism
Wnt Signaling Pathway drug effects
Wnt3A Protein antagonists & inhibitors
Wnt3A Protein metabolism
src-Family Kinases drug effects
src-Family Kinases metabolism
Astrocytes metabolism
Behavior, Animal physiology
Neuralgia metabolism
Neuronal Plasticity physiology
Posterior Horn Cells metabolism
Receptor Protein-Tyrosine Kinases metabolism
Sensory Receptor Cells metabolism
Wnt Signaling Pathway physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1872-6623
- Volume :
- 156
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Pain
- Publication Type :
- Academic Journal
- Accession number :
- 26407042
- Full Text :
- https://doi.org/10.1097/j.pain.0000000000000366