Spinal neuron-glial crosstalk and ion channel dysregulation in diabetic neuropathic pain

Abstract

Diabetic neuropathic pain (DNP) is one of the most prevalent complications of diabetes, characterized by a high global prevalence and a substantial affected population with limited effective therapeutic options. Although DNP is closely associated with hyperglycemia, an increasing body of research suggests that elevated blood glucose levels are not the sole inducers of DNP. The pathogenesis of DNP is intricate, involving the release of inflammatory mediators, alterations in synaptic plasticity, demyelination of nerve fibers, and ectopic impulse generation, yet the precise mechanisms remain to be elucidated. The spinal dorsal horn coordinates dynamic interactions between peripheral and central pain pathways, wherein dorsal horn neurons, microglia, and astrocytes synergize with Schwann cell-derived signals to process nociceptive information flow. Abnormally activated neurons can alter signal transduction by modifying the local microenvironment, compromising myelin integrity, and diminishing trophic support, leading to neuronal sensitization and an amplifying effect on peripheral pain signals, which in turn triggers neuropathic pain. Ion channels play a pivotal role in signal conduction, with the modulation of sodium, potassium, and calcium channels being particularly crucial for the regulation of pain signals. In light of the rising incidence of diabetes and the current scarcity of effective DNP treatments, a thorough investigation into the interactions between neurons and glial cells, especially the mechanisms of ion channel function in DNP, is imperative for identifying potential drug targets, developing novel therapeutic strategies, and thereby enhancing the prospects for DNP management.

Keywords: Schwann cells; astrocytes; diabetic neuropathic pain; ion channels; microglia; spinal dorsal horn.

Figure 1

Pathogenic mechanisms of diabetic neuropathic pain. Diabetic neuropathic pain involves complex and multifactorial pathogenic mechanisms, including hyperglycemia, neuroglial activation, synaptic plasticity abnormalities, microvascular dysfunction, neurotrophic deficiency, oxidative stress, ion channel dysregulation, and inflammatory pathways, among others.

Figure 2

Spinal dorsal horn and spinal nerve neuronal cells in mediating diabetic neuropathic pain. Microglia, astrocytes, and Schwann cells synergistically mediate neuroinflammatory signaling and neuronal hyperexcitability in diabetic neuropathy. Activated microglia release pro-inflammatory cytokines (e.g., TNF-α, IL-1β), amplifying nociceptive transmission. Astrocytes sustain neuroinflammation by propagating cytokine cascades and disrupting glutamate homeostasis, leading to central sensitization. Schwann cells, through peripheral nerve damage, secrete nerve growth factor (NGF), which sensitizes nociceptive neurons and enhances pain signaling to the spinal cord. Neuronal circuits in the spinal dorsal horn integrate these inputs, with neurotrophic factors further promoting synaptic plasticity and chronic pain.

Figure 3

Ion channels’ role in the pathogenesis of diabetic neuropathic pain. Extracellular calcium ions (Ca²⁺) activate TRPM7 and TRPV4 channels, leading to an increase in intracellular calcium levels, which in turn activates caspase 8 and caspase 9, promoting cell apoptosis. Intracellular reactive oxygen species (ROS) regulate the opening of ion channels, exacerbating oxidative stress and promoting the transcription and release of cytokines, thereby intensifying pain. Following Yoda1 activation of the mechanosensitive Piezo1 channel, ATP release exacerbates K⁺ efflux and P2X receptor-mediated Na⁺/Ca²⁺ influx, leading to inhibition of glutamate transporter function and amplification of nociceptive signaling. Concurrently, the PLC-IP3 pathway triggers endoplasmic reticulum Ca²⁺ release via hydrolysis of PIP₂, enhancing spontaneous slow inward currents (SICs) and inducing central sensitization and mechanical allodynia. BDNF alleviates hyperalgesia by activating the TrkB receptor and inhibiting potassium ion efflux.