Tuina Inhibits Synaptic Plasticity Through the Astrocytic NDRG2/GLT-1 Pathway to Alleviate Neuropathic Pain.

Abstract

While Tuina has demonstrated clinical efficacy in alleviating neuropathic pain (NP) induced by peripheral nerve injury, the underlying molecular mechanisms remain unclear. Synaptic plasticity in the spinal dorsal horn (SDH) is a key regulator of pain processing, wherein astrocytes play a central role. Regulation of N-myc downstream-regulated gene 2 (NDRG2) and glutamate transporter 1 (GLT-1) is particularly important in NP modulation. Accumulating evidence suggests that Tuina exerts analgesic effects by inhibiting aberrant synaptic plasticity. This study explored whether Tuina regulates synaptic plasticity through astrocytes to attenuate NP. Using an in vivo model, Tuina or the astrocytic inhibitor fluorocitrate was administered to a chronic constriction injury (CCI)-induced NP rat model for 14 days. Tuina significantly alleviated pain hypersensitivity in CCI rats, improved structural damage, suppressed astrocytic activation, reduced glutamate accumulation and restored the SDH's expression of proteins linked to synaptic plasticity. These effects were associated with inhibition of astrocytic NDRG2 and upregulation of GLT-1. Conversely, NDRG2 overexpression through AAV impaired Tuina's ability to promote glutamate transport, leading to glutamate accumulation, enhanced excitatory transmission and reduced analgesic efficacy. In conclusion, Tuina alleviates NP by modulating the astrocytic NDRG2/GLT-1 pathway, reducing synaptic glutamate levels and normalising synaptic plasticity. These findings provide new mechanistic insights into Tuina's analgesic action and have identified NDRG2/GLT-1 as a possible therapeutic target for NP treatment.