Muneeb Hashmi

Background: Spinal cord injury (SCI) is a debilitating condition caused by trauma or disease that leads to partial or complete loss of motor, sensory, and autonomic function at and/or below the level of injury.¹ Neuropathic pain (NP) is a severe, complex complication of injury, affecting up to 70% of individuals with SCI.¹ After SCI, inflammation triggers neuronal hyperexcitability, increased glutamate levels, and sodium/calcium channel dysregulation, leading to clinical features such as allodynia, hyperalgesia, and paresthesia.² Current treatment strategies for SCI-induced NP include medications (anticonvulsants, antidepressants, and opioids), spinal cord stimulation, and cognitive behavioral therapy.³ However, NP is often refractory to these approaches, and patients frequently experience significant side effects.³ Consequently, attention has shifted toward alternative strategies that directly modulate the underlying pathophysiology – one such target is inflammation. Pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFα), along with chemokines CCL2, CCL7, and CCL8 and their receptors CCR1 and CCR3, have been increasingly implicated in pain signaling following SCI.^4,5 Pharmacological interventions targeting inflammatory pathways may also provide new avenues for NP treatment.³

Objective: In this narrative review, we explore the role of inflammatory mediators as therapeutic targets for neuropathic pain following spinal cord injury.

Search Methods: An online search in the PubMed database was conducted from 2017 to 2025 using the following keywords: “spinal cord injury”, “neuropathic pain”, “inflammation”, “cytokines”, “chemokines”, and “neuromodulation”.

Results: TNFα and its downstream targets (c-fos, c-jun, ERK1/2) were found to be upregulated in SCI models with peripheral inflammation, indicating a key role in neuronal hyperexcitability and pain sensitization.⁴ TNF receptors TNFR1 and TNFR2 are implicated in excitotoxicity and microglial activation, suggesting that targeting TNFα signaling may delay or prevent the onset of NP.⁴ Chemokines CCL2/7/8 and their receptors CCR1/3 were also significantly elevated in murine models of chronic constriction injury.⁵ Inhibitors targeting these signaling components had analgesic properties, reducing mechanical and thermal hypersensitivity in preclinical SCI models, highlighting chemokine blockade as a promising therapeutic approach.⁵ Further implicating inflammation, a phase IIA clinical trial demonstrated that the drug NFX88, when combined with pregabalin, significantly reduced NP symptoms by downregulating prostaglandin E2 (PGE2), phospholipases PLA1, PLA2, and PLD, and the synthesis of lysophosphatidic acid (LPA), key mediators involved in neuroinflammation and pain signaling.³

Conclusions: Studies suggest that inflammatory mediators such as TNFα, CCL2/7/8, and their receptors CCR1/2 represent promising therapeutic targets for the treatment of neuropathic pain following spinal cord injury. In addition, the novel pharmacologic agent NFX88 shows potential in alleviating refractory NP by targeting mediators of neuroinflammation and pain signaling. These findings underscore the need for continued research into inflammation-targeted therapies and neuromodulatory interventions for SCI-induced neuropathic pain.

Works Cited:

1. Hatch MN, Cushing TR, Carlson GD, Chang EY. Neuropathic pain and SCI: Identification and treatment strategies in the 21st century. J Neurol Sci. 2018;384:75-83. doi:10.1016/j.jns.2017.11.018
2. Forte G, Giuffrida V, Scuderi A, Pazzaglia M. Future Treatment of Neuropathic Pain in Spinal Cord Injury: The Challenges of Nanomedicine, Supplements or Opportunities?. Biomedicines. 2022;10(6):1373. Published 2022 Jun 10. doi:10.3390/biomedicines10061373
3. Escribá PV, Gil-Agudo ÁM, Vidal Samsó J, et al. Randomised, double-blind, placebo-controlled, parallel-group, multicentric, phase IIA clinical trial for evaluating the safety, tolerability, and therapeutic efficacy of daily oral administration of NFX88 to treat neuropathic pain in individuals with spinal cord injury. Spinal Cord. 2024;62(8):454-467. doi:10.1038/s41393-024-01006-4
4. Martin KK, Parvin S, Garraway SM. Peripheral Inflammation Accelerates the Onset of Mechanical Hypersensitivity after Spinal Cord Injury and Engages Tumor Necrosis Factor α Signaling Mechanisms. J Neurotrauma. 2019;36(12):2000-2010. doi:10.1089/neu.2018.5953
5. Pawlik K, Ciapała K, Ciechanowska A, Kwiatkowski K, Mika J. Pharmacological Evidence of the Important Roles of CCR1 and CCR3 and Their Endogenous Ligands CCL2/7/8 in Hypersensitivity Based on a Murine Model of Neuropathic Pain. Cells. 2022;12(1):98. Published 2022 Dec 26. doi:10.3390/cells12010098