Spinal Mechanisms of Pain Modulation by Spinal Cord Stimulation: A Systematic Review

Abstract

Spinal cord stimulation (SCS) is a widely used neuromodulation therapy for chronic neuropathic pain, including failed back surgery syndrome and complex regional pain syndrome, but its mechanisms of action remain incompletely defined. This systematic review examined 40 unique preclinical animal studies to classify spinal mechanisms underlying SCS-induced analgesia. A comprehensive database search including PubMed, MEDLINE, and Cochrane was conducted through October 2024 following PRISMA guidelines. Studies were included if they investigated SCS effects on spinal cord cells such as dorsal horn neurons, dorsal column fibers, interneurons, or glia, and excluded if they involved brain structures. Mechanisms were categorized into three inhibition of ascending nociceptive transmission (n = 22), enhancement of descending inhibition (n = 5), and neuroimmune modulation via microglial and astrocytic pathways (n = 13). SCS was shown to enhance inhibitory signaling, reduce excitatory neurotransmitter release, and modulate dorsal horn activity at molecular and electroneurophysiological levels. It also promoted descending inhibition via serotonergic, opioid, and cholinergic mechanisms. Neuroimmune effects included suppression of proinflammatory cytokines and modulation of microglial and astrocyte activity, often through MAPK-related signaling. Risk of bias was assessed using the SYRCLE tool, revealing a variable methodological quality. The experimental frameworks utilized either neuropathic or inflammatory pain models, which exhibit substantial clinical relevance to chronic pain phenomena. Collectively, these findings suggest that SCS exerts analgesic effects through integrated spinal mechanisms involving neuronal inhibition, descending modulation, and glial suppression. However, the exclusive reliance on animal models limits direct clinical translatability, and future studies are needed to validate whether these mechanistic insights reliably extend to human physiology and therapeutic outcomes. This review provides a mechanistic framework to guide translational strategies for optimizing SCS therapy.

Introduction and background

Spinal cord stimulation (SCS) is an established neuromodulation therapy for managing pain conditions by delivering electrical impulses to the spinal cord [1]. The procedure involves the subcutaneous implantation of a pulse generator and the placement of electrodes in the epidural space adjacent to the spinal cord. Clinically, SCS is widely used for chronic neuropathic pain, including conditions such as failed back surgery syndrome (FBSS) and complex regional pain syndrome [2-3].

Currently, the advancements in neuromodulation practices, particularly SCS, have increased in therapeutic relevance and bolstered patient forecasts [4]. Conventional SCS typically employs tonic stimulation at frequencies of 40-60 Hz [5]. This modality is thought to target A-beta fibers in the dorsal column and work via the gate control theory of pain. Approximately a decade ago, high-frequency stimulation came to market with a proposed mechanism of action of modulation of dorsal horn neurons. Promising clinical results spurred a revolution in new waveform programming. Among these innovations, burst stimulation delivers packets of high-frequency pulses (500 Hz) at rate of 40 bursts per second, designed to emulate the physiological firing patterns of endogenous neurons and enhance analgesic efficacy [6]. Other recent SCS algorithms include closed-loop systems that use feedback control at the dorsal column and “differential target multiplexed” waveform that acts on glial cells [5]. These mechanisms remain poorly understood and unproven, and a stronger mechanistic understanding has the potential to refine device development and programming to improve clinical outcomes. Animal models of neuropathic pain allow for controlled investigations into how SCS affects nervous system structures and pathways implicated in pain processing [7]. Nevertheless, the underlying mechanisms associated with analgesic properties remain inadequately understood [8].

In light of the increasing dependence on SCS within clinical paradigms and the considerable volume of preclinical investigations conducted, it is both opportune and imperative to evaluate the extent to which experimental models have contributed to our comprehension of the biological mechanisms correlated with SCS-induced pain modulation and the processes through which pain manifests or recurs, particularly in individuals afflicted with FBSS, who are most frequently representative of candidates for SCS therapy [9].

The primary objective of this systematic review is to amalgamate and classify the relevant evidence sourced from studies that probe into mechanisms underlying SCS-induced analgesia in animal research. This assessment intends to deliver a broad perspective on the mechanisms that have been reviewed until now in the domain of preclinical research and to suggest possible channels for subsequent investigation. Such insights provide a framework to inform translational initiatives aimed at enhancing the efficacy and specificity of SCS in its prospective applications.

Review

Methods

To better understand the underlying mechanisms of SCS pain alleviation in animals, we systematically reviewed cohort studies from inception to October 18, 2024. This systematic review has been duly registered with the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY) (registration 202540047). The search flow diagram strictly follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Search Strategy

A comprehensive systematic search was conducted using the Cochrane Central Register of Control Trials. The search strategy is detailed in Appendix A.

Data Extraction

To guarantee the thoroughness of our search, the reference lists of sourced articles were meticulously scrutinized. Two authors (J.F. and H.Y.) independently undertook the data extraction process. Any discrepancies that arose were resolved through a consensus mechanism among the authors. Following the search, two independent reviewers evaluated the articles to ascertain their adherence to the inclusion criteria.

Study Selection

Pain is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” [10]. Our search was conducted in close consultation with a professional medical librarian to ensure a comprehensive and systematic retrieval of relevant studies that described potential mechanisms of pain within the context of SCS application in animals. Following an initial broad systematic search to identify relevant literature as described in Appendix A, only studies published from inception to date and in English were included. Included experimental and computational studies described quantifiable outcome measures and explicitly defined necessary interventions between a control group and an experimental group. Studies utilizing spinal cord cells, including dorsal column cells, dorsal horn cells, glial cells, and interneurons, were included. Studies utilizing brain or periaqueductal gray cells were excluded from our study. Systematic review studies or studies without the use of animals were excluded from our search. Research comparing different frequencies of SCS in its efficacy without describing pain and mechanisms was also excluded. Finally, studies involving brain cells were excluded to ensure that only those specifically related to spinal cord cells were included. A detailed description of the full search strategy is provided in the appendices.

Risk-of-Bias Assessment

To assess the risk of bias in this analysis of animal studies, the SYRCLE Risk of Bias (RoB) tool was utilized. This tool is an adaptation of the Cochrane Collaboration Risk of Bias tool, originally designed for human studies, and is tailored to address specific challenges in preclinical animal research. The SYRCLE RoB tool comprises 10 items aimed at evaluating potential biases, including selection, performance, detection, attrition, and reporting. A response of "yes" to an item indicates a low risk of bias, while a "no" corresponds to a high risk of bias. Responses that cannot be clearly categorized are deemed to indicate an unclear risk of bias. Of note, the SYRCLE RoB tool does not recommend the use of summary scores for reported items.

Data Collection

Our principal outcome is to identify, categorize, and summarize the pain mechanism of SCS in animals. Therefore, demographics, experimental characteristics, and study conclusions were collected from our study. Selected articles were collected by author(s), publication year, species, cell type, pain model used, and conclusion. This report was composed in accordance with the PRISMA checklist.

Results

Study Identification and Inclusion

In the examination of pain mechanisms modulated by SCS in spinal cord cells of animal models, an initial identification included 1,224 records. Of that, 57 duplicates were removed before screening. Of the remaining 1,167 records, 1,057 were excluded based on criteria from titles and abstracts. The residual 110 records were meticulously screened against the relevant exclusion criteria concerning systematic reviews, human subjects, brain cells, and periaqueductal gray cells. Finally, 40 full-text articles were selected for further analysis (Figure 1).

The studies included in this review are summarized in Table 1, which provides an overview of author(s), publication year, species, cell type, pain model used, and key conclusions. To enhance the clarity and depth of analysis, studies were further categorized based on their underlying mechanisms into three distinct inhibition of ascending nociceptive transmission at the dorsal horn (Table 1), enhancement of descending inhibition (Table 2), and neuroimmune microglial and astrocytic effects (Table 3). Among the 40 full-text articles reviewed, 22 were classified under inhibition of ascending nociceptive transmission, 5 under descending inhibition, and 13 under neuroimmune modulation.

To assess the risk of bias of the included studies, the SYRCLE RoB tool was utilized (Table 4). As recommended by the SYRCLE RoB tool, summary scores were not tabulated for the articles.

The studies were evaluated for bias based on key criteria including sequence generation, baseline characteristics, allocation concealment, random housing, blinding (performance and detection bias), random outcome assessment, incomplete outcome data, selective outcome reporting, and other sources of bias.

Discussion

Our systematic review consolidates preclinical evidence regarding the cellular and physiological mechanisms by which SCS alleviates pain in animal models. The experimental paradigms employed are classified as either neuropathic or inflammatory pain models, which exhibit clinical relevance to the phenomenon of chronic pain. The majority of investigations utilized rats in their animal study with the exception of one study that fails to specify the species employed.

While the SYRCLE tool does not generate a numerical summary score, the number of "Yes" responses per study ranged from one to nine, with an approximate average of 6.09. This indicates a moderate and inconsistent risk of bias across studies and underscores the importance of interpreting preclinical findings with caution. Studies are categorized into three mechanistic domains (inhibition of ascending nociceptive transmission at the dorsal horn, enhancement of descending inhibition and neuroimmune microglial and astrocytic effects) based on established literature precedence, detailed experimental methodologies, and the mechanistic conclusions drawn in each study. Inhibition of ascending nociceptive transmission at the dorsal horn was further subdivided into mechanisms at the molecular level and electroneurophysiological studies.

Inhibition of Ascending Nociceptive Transmission at the Dorsal Horn

Molecular biology SCS inhibits ascending nociceptive signaling at the dorsal horn through both molecular and electroneurophysiological mechanisms. On the molecular level, SCS enhances inhibitory neurotransmission, particularly via GABAergic and endocannabinoid pathways, while also reducing excitatory drive in dorsal horn neurons. Multiple studies report increased GAD65 expression and enhanced GABA release following stimulation [16,22]. GABA(B) receptor activation plays a central role in suppressing excitatory amino acid release, an effect reversed by GABA(B) antagonists [20-21]. Moreover, SCS engages adenosine receptor pathways to normalize tactile thresholds [19], and chronic pain conditions such as diabetic neuropathy may limit SCS efficacy due to reduced KCC2 expression and impaired GABA(A)-mediated inhibition [17]. Additionally, CB1 receptor-mediated endocannabinoid activation contributes to long-lasting analgesic effects following repetitive SCS [12]. The impact of SCS on wide-dynamic range neurons appears to be frequency-sensitive, with modeling studies showing GABAergic tone shaping optimal parameters [15], and projection neuron modulation extending beyond classical gate control mechanisms [14]. Notably, dorsal root ganglion stimulation appears to provide analgesia through non-GABAergic pathways, emphasizing mechanistic diversity [11].

Electroneurophysiological Electroneurophysiological studies further support these findings by demonstrating circuit-level modulation of spinal neurons. SCS alters firing patterns in the dorsal horn in a frequency and duration-dependent manner, favoring the activation of inhibitory interneurons [25]. Markers of neuronal activation, such as c-Fos expression, are elevated after stimulation confirming both early and late-phase neural engagement [18]. Evoked compound action potential (ECAP) and electromyography (EMG) recordings during lateralized stimulation demonstrate preferential ipsilateral recruitment of spinal neurons [24]. Moreover, SCS reduces the long-term potentiation of C-fiber inputs [31], thereby modulating central sensitization. Intensity-dependent inhibition of wide-dynamic range neurons further supports the idea that optimal stimulation parameters are critical for efficacy [28].

Additionally, low-frequency sub-perception SCS activates only a limited set of dorsal column axons that engage dorsal horn inhibitory circuits without recruiting ascending pathways [26]. It was also demonstrated that low-threshold A-fiber activation at sub-motor intensities contributes significantly to analgesia by selectively engaging local spinal circuits [30]. Finally, suppression of dorsal horn hyperexcitability and principal after discharges by SCS underscores its potent local inhibitory action [32].

Enhancement of Descending Inhibition

SCS enhances descending inhibitory control by promoting the spinal release of key neuromodulators, including serotonin, endogenous opioids, and acetylcholine. Activation of spinal 5-HTt and 5-HT receptors facilitates GABAergic inhibition [36], while frequency-dependent release of opioid peptides such as methionine enkephalin contributes to analgesia blocked by antagonists [33-34]. Cholinergic signaling via muscarinic M4 receptors further supports nociceptive modulation [37], illustrating the multifaceted chemical basis of SCS-induced descending inhibition.

Neuroimmune Modulation: Microglial and Astrocytic Effects

Chronic pain is increasingly understood as a neuroimmune condition involving sustained activation of microglia and astrocytes within the spinal cord. SCS counters this by downregulating pro-inflammatory mediators such as IL-1β, TNF-α, NF-κB, and TLR4 [40,50], reducing CSF1 signaling [41], and inhibiting the p38 MAPK and MAPK/ERK pathways [44-45]. It also suppresses superficial microglial activation in key dorsal horn segments [46] and shifts glial states toward a neuroprotective phenotype using advanced waveform-specific paradigms such as DTMP (differential target multiplexed programming) [42] and HF10 SCS (10-kilohertz high-frequency spinal cord stimulation) [38]. Proteomic and transcriptomic studies demonstrate that these effects extend to gene expression regulation and oxidative stress pathways [39,43], while acute imaging studies confirm rapid reductions in spinal metabolic activity following stimulation [48]. These findings support the rationale for waveform-specific programming in clinical practice, particularly for patients with neuroinflammatory phenotypes, and may inform future device designs that target glial modulation more precisely.

Conclusions

While extensive research has been conducted on SCS in animal models, a systematic review specifically focusing on the pain mechanisms modulated by SCS in spinal cord cells has been lacking. The mechanisms underpinning SCS analgesia, as delineated in the comprehensive analysis of selected studies, are categorized into three primary the inhibition of ascending nociceptive transmission at the dorsal horn, the enhancement of descending inhibition, and neuroimmune modulation, specifically focusing on the effects of microglia and astrocytes. The experimental paradigms employed consist of either neuropathic or inflammatory pain models in rats, which bear significant clinical correlations to chronic pain phenomena. This review addresses that gap by providing a comprehensive analysis of the available literature, categorizing cellular pain modulation mechanisms, assessing study quality, and outlining key trends to guide translational and therapeutic advancements. Nevertheless, the therapeutic implications drawn from this review should be interpreted with caution given the exclusive use of animal data and the variability in methodological quality across studies.