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Review
. 2025 Apr 18;26(8):3835.
doi: 10.3390/ijms26083835.

Sex Differences in the Regulation of Interleukins in Chronic Pain: A Widely Recognized but Difficult-to-Tackle Factor

Jie Liu  1   2 , Zheng Li  1   2 , Jie Ju  1   2 , Tiantian Chu  1   2 , Feng Gao  1   2
Affiliations
Review

Sex Differences in the Regulation of Interleukins in Chronic Pain: A Widely Recognized but Difficult-to-Tackle Factor

Jie Liu et al. Int J Mol Sci. .

Abstract

Chronic pain is an extremely prevalent healthcare issue that has a profound impact on individuals and society. Sex and sex hormones regulate the pain threshold differently in males and females in pain processing. However, the regulatory mechanisms of sex differences in response to painful stimuli are still unclear, which contributes to the difficulty of analgesic drug development. Interleukins mediate neuroinflammation and are involved in the development of chronic pain. Recent studies have found that sex and sex hormones are involved in the regulation of pain thresholds by interleukins. Most previous studies used male animals to study the analgesic effects of treatments due to the complexity of estrogen. This review summarizes studies that used only female animals or both sexes to examine the impact of sex on interleukin-regulated chronic pain, to provide a theoretical basis for the development of more targeted precision medicines for pain.

Keywords: chronic pain; interleukins; neuroinflammation; sex differences.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The role of IL-1β in chronic pain from studies using females only or both sexes. Abbreviations: CCI, chronic constriction injury; CRPS, complex regional pain syndromes; DRG, dorsal root ganglion; MIA, monosodium iodoacetate; MOG35–55, myelin oligodendrocyte glycoprotein peptide 35–55; MS, multiple sclerosis; NLRP, nod-like receptor protein; OA, osteoarthritis; PMCA2, plasma membrane calcium ATPase 2; RA, rheumatoid arthritis; SC, spinal cord; TRPV1, transient receptor potential vanilloid 1.
Figure 2
Figure 2
The role of IL-6 in chronic pain from studies using females only or both sexes. Abbreviations: CCI, chronic constriction injury; CCI-ION, chronic constriction injury of the infraorbital nerve; CGRP, calcitonin gene-related peptide; CNTF, ciliary neurotrophic factor; DRG, dorsal root ganglion; JAK, janus kinase; MOG35–55, myelin oligodendrocyte glycoprotein peptide 35–55; MS, multiple sclerosis; OA, osteoarthritis; RvD5, D-series resolvins 5; SC, spinal cord; STAT3, signal transducer and activator of transcription 3; TRPV1, transient receptor potential vanilloid 1.
Figure 3
Figure 3
The role of IL-23/IL-17 in chronic pain from studies using females only or both sexes. Abbreviations: CCL17, C-C motif ligand 17; COX, cyclooxygenase; DRG, dorsal root ganglion; ERα, estrogen receptor α; GM-CSF, granulocyte macrophage-colony stimulating factor; ICS, intermittent cold stress; LTTL gel, gel Long-Teng-Tong-Luo; MOG35–55, myelin oligodendrocyte glycoprotein peptide 35–55; MS, multiple sclerosis; PI3K, phosphatidylinositol 3-kinase; SC, spinal cord; TNF, tumor necrosis factor; TRPV1, transient receptor potential vanilloid 1.
Figure 4
Figure 4
The role of IL-10 in chronic pain from studies using females only or both sexes. Abbreviations: CCI, chronic constriction injury; DRG, dorsal root ganglion; GRK, G-protein-coupled receptor kinase; ICOSaa, inducible co-stimulatory molecule agonist antibody; NP, neuropathic pain; SC, spinal cord; SNI, sciatic nerve injury; SNL, spinal nerve ligation.
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