A novel role of microtubule affinity-regulating kinases in neuropathic pain.

BACKGROUND AND PURPOSE

Neuropathic pain affects millions of patients but there are currently few viable therapeutic options available. Microtubule affinity-regulating kinases (MARKs) regulate the dynamics of microtubules and participate in synaptic remodeling. It is unclear whether these changes are involved in the central sensitization of neuropathic pain. This study examined the role of MARK1 or MARK2 in regulating neurosynaptic plasticity induced by neuropathic pain.

EXPERIMENTAL APPROACH

A rat spinal nerve ligation (SNL) model was established to induce neuropathic pain. The role of MARKs in nociceptive regulation was assessed by genetically knocking down MARK1 or MARK2 in amygdala and systemic administration of PCC0105003, a novel small molecule MARKs inhibitor. The cognitive function, anxiety-like behaviors and motor coordination capability were also examined in SNL rats. Synaptic remodeling-associated signaling changes were detected with electrophysiological recording, Golgi-Cox staining, western blotting and qRT-PCR.

KEY RESULTS

MARK1 and MARK2 expression levels in amygdala and spinal dorsal horn were elevated in SNL rats. MARK1 or MARK2 knockdown in amygdala and PCC0105003 treatment partially attenuated pain-like behaviors along with improved cognitive deficit, anxiogenic-like behaviors and motor coordination in SNL rats. Inhibition of MARKs signaling reversed synaptic plasticity at the functional and structural levels by suppressing NR2B/GluR1 and EB3/Drebrin signaling pathways both in amygdala and spinal dorsal horn.

CONCLUSION AND IMPLICATIONS

These results suggest that MARKs-mediated synaptic remodeling plays a key role in the pathogenesis of neuropathic pain and that pharmacological inhibitors of MARKs such as PCC0105003 could represent a novel therapeutic strategy for the management of neuropathic pain.

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