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Review
. 2024 Jun 9;14(6):589.
doi: 10.3390/brainsci14060589.

A Narrative Review of the Dorsal Root Ganglia and Spinal Cord Mechanisms of Action of Neuromodulation Therapies in Neuropathic Pain

Matheus Deroco Veloso da Silva  1 , Geovana Martelossi-Cebinelli  1 , Kelly Megumi Yaekashi  1 , Thacyana T Carvalho  2 , Sergio M Borghi  1   3 , Rubia Casagrande  4 , Waldiceu A Verri  1   5
Affiliations
Review

A Narrative Review of the Dorsal Root Ganglia and Spinal Cord Mechanisms of Action of Neuromodulation Therapies in Neuropathic Pain

Matheus Deroco Veloso da Silva et al. Brain Sci. .

Abstract

Neuropathic pain arises from injuries to the nervous system in diseases such as diabetes, infections, toxicity, and traumas. The underlying mechanism of neuropathic pain involves peripheral and central pathological modifications. Peripheral mechanisms entail nerve damage, leading to neuronal hypersensitivity and ectopic action potentials. Central sensitization involves a neuropathological process with increased responsiveness of the nociceptive neurons in the central nervous system (CNS) to their normal or subthreshold input due to persistent stimuli, leading to sustained electrical discharge, synaptic plasticity, and aberrant processing in the CNS. Current treatments, both pharmacological and non-pharmacological, aim to alleviate symptoms but often face challenges due to the complexity of neuropathic pain. Neuromodulation is emerging as an important therapeutic approach for the treatment of neuropathic pain in patients unresponsive to common therapies, by promoting the normalization of neuronal and/or glial activity and by targeting cerebral cortical regions, spinal cord, dorsal root ganglia, and nerve endings. Having a better understanding of the efficacy, adverse events and applicability of neuromodulation through pre-clinical studies is of great importance. Unveiling the mechanisms and characteristics of neuromodulation to manage neuropathic pain is essential to understand how to use it. In the present article, we review the current understanding supporting dorsal root ganglia and spinal cord neuromodulation as a therapeutic approach for neuropathic pain.

Keywords: central sensitization; current treatment; glial cells; neuromodulation; neuropathic pain.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 3
Figure 3
Central Sensitization and Glial Cells. (A) (A1) N-methyl-D-aspartate (NMDA) receptors contribute to central sensitization and their trafficking to the membrane is regulated by protein kinase C-dependent phosphorylation. (A2) The activation of NMDA receptors promotes the influx of calcium into neurons and the activation of intracellular signaling pathways, (A3) contributing to nociceptive neurotransmission [87,88]. (B) (B1) Glial cells, such as astrocytes, microglia, and oligodendrocytes [89], can be activated through Toll-like receptors (TLRs) and cytokines (IL-1β, TNF-α, and IL-6) produced during the development of the nociceptive response [90]. (B2) Furthermore, glial cells express several receptors for neurotransmitters, which can be activated through synaptic transmission [91]. (B3) When activated, these cells can further release cytokines (IL-1β, TNF-α, and IL-6) [92,93] and pro-inflammatory chemokines (CCL2 and CX3CL1) [94,95], or neuroexcitatory or neuromodulators signals (ATP, glutamate, and SP) [96], (B4) culminating in enhanced neuronal and glial activation [91]. Created using http://BioRender.com (accessed on 20 May 2024).
Figure 1
Figure 1
Pathophysiological Mechanisms of Neuropathic Pain. The initial damage to peripheral nerves occurs through varied noxious stimuli [39,40,41]. (A) Peripheral Mechanisms. (A1) In the PNS, this damage culminates in neurodegeneration due to the transection of neuronal axons [42], affecting the connection between the PNS and the CNS and (A2) the function of nociceptors, (A3) contributing to sensory loss [43]. (A1) Furthermore, primary sensory neurons can become sensitized, either to noxious stimuli or to the local inflammatory response [43,44]. (A4) In both cases, the persistence of the stimulus and the extent of PNS damage culminate in the generation of maladaptive repair, producing neuromas responsible for the ectopic action potential (summarized in Figure 2) [45,46]. (A5) Action potential propagation from peripheral nerves causes the (A6) release of several mediators in the DRG (e.g., ATP, CX3CL1, and CCL2), (A7) which activate satellite glial cells through specific receptors [47,48,49]. (A7) Taken together, the neuroinflammatory response initiated upon initial injury induces macrophage migration to the DRG [50]. (A8) The result is the release of pro-inflammatory mediators, such as TNF-α and IL-1β, which further amplify the sensitization and activation of nociceptor neurons causing pain [43]. (B) Central Mechanisms of neuropathic pain. (B1) With the persistence of the initial stimulus and the continuous input of afferent stimuli, the superficial neurons of the dorsal horn of the spinal cord also undergo degeneration due to glutamate-mediated excitotoxicity [51]. (B2) Furthermore, afferent fibers release excitatory amino acids and neuropeptides (e.g., calcitonin gene-related peptide, glutamate, and SP) into the dorsal horn of the spinal cord, (B3) promoting postsynaptic changes in second-order nociceptive neurons [50]. (B4) These changes result in neuronal plasticity, (B5) imbalance between the activation and inhibition of descending pathways, and (B6) central sensitization [52]. (B7,B8) As a result, there is abnormal entry of information into the cortex. Created using http://BioRender.com (accessed on 20 May 2024).
Figure 2
Figure 2
Ectopic Action Potentials and Neuropathic Pain. (A) (A1) Ectopic action potentials are generated through an increase in synaptic transmission between nociceptive neurons and spinal neurons [43]. (B) (B1) Taken together, the increased expression of voltage-gated sodium channels (VGSC; Nav.1.7, Nav 1.8, and NaV1.9) [53,54,55,56], calcium channels (Cav), potassium channels (TREK and TRAAK), cyclic nucleotide gated channels (HCN) [57,58,59,60], and transient receptor potential (TRP; TRPV1) [61,62] also contribute to the generation of ectopic action potentials. (B2) Plastic changes in nociceptor neurons, including the enhanced expression and activity of these channels, facilitate the generation of action potentials, resulting in neuronal sensitization [63,64]. Created using http://BioRender.com (accessed on 20 May 2024).
Figure 4
Figure 4
Neuropathic pain treatment approaches based on the targeted anatomical structure. Neuromodulation therapy approaches and site of approach are highlighted in bold. CBT (cognitive behavioral therapy). Created using http://BioRender.com (accessed on 30 April 2024).
Figure 5
Figure 5
Neuropathic pain mechanisms that are targeted by neuromodulation therapies. Created using http://BioRender.com (accessed on 29 May 2024).
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