Glial cells play an essential role in maintaining the proper functioning of the nervous system. They are more abundant than neurons in most neural tissues and provide metabolic and catabolic regulation, maintaining the homeostatic balance at the synapse. Chronic pain is generated and sustained by the disruption of glia-mediated processes in the central nervous system resulting in unbalanced neuron–glial interactions. Animal models of neuropathic pain have been used to demonstrate that changes in immune and neuroinflammatory processes occur in the course of pain chronification. Spinal cord stimulation (SCS) is an electrical neuromodulation therapy proven safe and effective for treating intractable chronic pain. Traditional SCS therapies were developed based on the gate control theory of pain and rely on stimulating large Aβ neurons to induce paresthesia in the painful dermatome intended to mask nociceptive input carried out by small sensory neurons. A paradigm shift was introduced with SCS treatments that do not require paresthesia to provide effective pain relief. Efforts to understand the mechanism of action of SCS have considered the role of glial cells and the effect of electrical parameters on neuron–glial interactions. Recent work has provided evidence that SCS affects expression levels of glia-related genes and proteins. This inspired the development of a differential target multiplexed programming (DTMP) approach using electrical signals that can rebalance neuroglial interactions by targeting neurons and glial cells differentially. Our group pioneered the utilization of transcriptomic and proteomic analyses to identify the mechanism of action by which SCS works, emphasizing the DTMP approach. This is an account of evidence demonstrating the effect of SCS on glia-mediated processes using neuropathic pain models, emphasizing studies that rely on the evaluation of large sets of genes and proteins. We show that SCS using a DTMP approach strongly affects the expression of neuron and glia-specific transcriptomes while modulating them toward expression levels of healthy animals. The ability of DTMP to modulate key genes and proteins involved in glia-mediated processes affected by pain toward levels found in uninjured animals demonstrates a shift in the neuron–glial environment promoting analgesia.
Hypothesis for the mechanism of action of ECAP‐controlled closed‐loop systems for spinal cord stimulation