Shehza Ghaffar

Background: Spinal cord injury (SCI) is a devastating neurological condition that leads to dysfunctions with widespread impacts on functioning.¹ SCI is most commonly caused by trauma but can also result from various disease processes.^1,2 An estimated 250,000–500,000 new SCI cases occur annually worldwide, yet treatment options remain limited.³ Furthermore, almost 2 of 3 people living with SCI will develop neuropathic pain within 6 months, a chronic noxious condition that can be debilitating, with females having higher pain morbidity.^4,5 The aggregate of pain onset following SCI is influenced by various factors, including the extent of injury, inflammation, and acute treatment efforts.² More recent studies also highlight a role for biological sex in the manifestation and progression of neuropathy.⁶ This sex-based disparity is driven by multifactorial biological mechanisms, including hormonal differences and the varying expression of pain-related receptors and inflammatory markers across the sexes.⁶

Objective: This narrative literature review explored the mechanisms by which estrogen contributes to sex differences in neuropathic pain after spinal cord injury, particularly through interactions with receptors.

Search Methods: An online search in the PubMed database was conducted from 2017 to 2025 using the following keywords: “estrogen”, “biological sex”, “spinal cord injury”, “neuropathic pain”.

Results: Estrogen has neuroprotective and analgesic effects after SCI.⁶ In animal models, E2 significantly reduced nociceptive symptoms, and was linked to lower inflammation and microglial activity.⁶ When estrogen-receptor antagonists were co-administered, the pain relief was reversed, confirming that the effect of E2 is receptor dependent.⁶ Additionally, the estrous cycle plays a role in this neuropathic sexual dimorphism.⁷ When sex hormones are rapidly changing or are low, the female model is more susceptible to symptoms of pain.⁷ Nociception can also disrupt the estrous cycle and impair recovery, showing a two-way relationship: hormonal fluctuations can manifest higher levels of pain, and this pain can reciprocally delay a normal estrous cycle that could benefit recovery.⁷ While the mechanism mediating the effect of estrogen on pain is still largely unknown, data suggests that sex differences are linked to estrogen modulation of GABA receptors and GPER signaling.^8,9 There is evidence that activation of E2 modulated α6 subunit-containing GABAA receptors inhibits nociceptive transmission in models of neuropathic pain.⁸ However, the expression of these receptors varies in males and females after injury.⁸ Females showed a greater reduction in α6-GABAA expression—especially at the spinal dorsal horn—leading to heightened pain responses.⁸ In contrast, this reduction of antinociceptive receptors is less severe in males with no change in the spinal cord tissue.⁸ G protein-coupled estrogen receptor, alternatively, has been shown to interact with β-alanine to increase neuron excitability and drive neuroinflammation, both of which amplify pain responses.⁹ When GPER was blocked, pain-related neuron activity and inflammation markers were reduced, suggesting that GPER could be a valuable target for pain therapy.⁹

Conclusions: Ultimately, the studies confirm the ambivalent yet interrelated nature of  estrogens after SCI. In pathological states, sex-specific receptor changes affect pain, especially α6-GABAA or GPER. Further research into estrogen’s downstream mechanisms could be key to promising avenues for novel hormonal therapies and to help mitigate disparities female patients encounter.

Works Cited:

1. Shoup JA, Welter J, Binswanger IA, et al. Spinal cord injury and prescribed opioids for pain: a scoping review. Pain Med. 2023;24(10):1138-1152. doi:10.1093/pm/pnad073
2. Anjum A, Yazid MD, Fauzi Daud M, et al. Spinal Cord Injury: Pathophysiology, Multimolecular Interactions, and Underlying Recovery Mechanisms. Int J Mol Sci. 2020;21(20):7533. Published 2020 Oct 13. doi:10.3390/ijms21207533
3. Kim T, Chelluboina B, Chokkalla AK, Vemuganti R. Age and sex differences in the pathophysiology of acute CNS injury. Neurochem Int. 2019;127:22-28. doi:10.1016/j.neuint.2019.01.012
4. Stewart AN, MacLean SM, Stromberg AJ, et al. Considerations for Studying Sex as a Biological Variable in Spinal Cord Injury. Front Neurol. 2020;11:802. Published 2020 Aug 5. doi:10.3389/fneur.2020.00802
5. Stampacchia G, Gerini A, Morganti R, et al. Pain characteristics in Italian people with spinal cord injury: a multicentre study. Spinal Cord. 2022;60(7):604-611. doi:10.1038/s41393-021-00656-y
6. Lee JY, Choi HY, Ju BG, Yune TY. Estrogen alleviates neuropathic pain induced after spinal cord injury by inhibiting microglia and astrocyte activation. Biochim Biophys Acta Mol Basis Dis. 2018;1864(7):2472-2480. doi:10.1016/j.bbadis.2018.04.006
7. Baine RE, Johnston DT, Strain MM, et al. Noxious Stimulation Induces Acute Hemorrhage and Impairs Long-Term Recovery after Spinal Cord Injury (SCI) in Female Rats: Evidence Estrous Cycle May Have a Modulatory Effect. Neurotrauma Rep. 2022;3(1):70-86. Published 2022 Jan 31. doi:10.1089/neur.2021.0055
8. Rodríguez-Palma EJ, Islas-Espinoza AM, Ramos-Rodríguez II, et al. Estradiol modulates the role of the spinal α6-subunit containing GABAA receptors in female rats with neuropathic pain. Eur J Pharmacol. 2024;974:176616. doi:10.1016/j.ejphar.2024.176616
9. Xu Z, Xie W, Feng Y, et al. Positive interaction between GPER and β-alanine in the dorsal root ganglion uncovers potential mechanisms: mediating continuous neuronal sensitization and neuroinflammation responses in neuropathic pain. J Neuroinflammation. 2022;19(1):164. Published 2022 Jun 21. doi:10.1186/s12974-022-02524-9