Wnt/Ryk signaling contributes to neuropathic pain by regulating sensory neuron excitability and spinal synaptic plasticity in rats

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.

Dexmedetomidine Attenuates Neuropathic Pain by Inhibiting P2X7R Expression and ERK Phosphorylation in Rats

“…Electrophysiological studies have revealed that stimulation of P2X7R leads to reversible Ca 2+ and Na + influx and associated membrane voltage changes [42]. Ca 2+ influx has been widely viewed as the pivotal stimulus to elicit cell reactions and activate intracellular signaling pathways [4344], including ERK. As one of the classical mitogen-activated protein kinase (MAPK) signaling pathways, ERK may be activated by Ca 2+ , protein kinase C (PKC), and growth factors to regulate cell activities.…”

Ryk receptors on unmyelinated nerve fibers mediate excitatory synaptic transmission and CCL2 release during neuropathic pain induced by peripheral nerve injury

“…27 Wnt proteins are important for various developmental processes. Studies have demonstrated the dysregulation of Wnt signaling in certain diseases and disorders.…”

“…Anti-Ryk antibodies (Shanghai Institutes for Biological Sciences) were administrated at a concentration of 2 µg (dilution 1:10). 27 …”

Simultaneous inhibition of NMDA and mGlu1/5 receptors by levo‐corydalmine in rat spinal cord attenuates bone cancer pain

“…As it used to be thought that chronic pain is a reflection of the aberrant excitability of dorsal horn neurons evoked by peripheral sensory inputs . The increased neuronal excitability and spinal synaptic plasticity in rats promote the development of chronic pain . It has been reported that spontaneous Ca 2+ transients have been implicated in regulating plasticity in developing neurons .…”

“…23 The increased neuronal excitability and spinal synaptic plasticity in rats promote the development of chronic pain. 24 It has been reported that spontaneous Ca 21 transients have been implicated in regulating plasticity in developing neurons. 25 And primary cultures of spinal neurons display synchronized spontaneous Ca 21 oscillations.…”