Interleukin-6: evolving role in the management of neuropathic pain in neuroimmunological disorders

Abstract

Background Neuropathic pain in neuroimmunological disorders refers to pain caused by a lesion or disease of the somatosensory system such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). MS and NMOSD are autoimmune disorders of the central nervous system, and ≥ 50% of patients with these disorders experience chronic neuropathic pain. The currently available medications for the management of neuropathic pain have limited effectiveness in patients with MS and NMOSD, and there is an unmet medical need to identify novel therapies for the management of chronic neuropathic pain in these patients. In this review article, we summarize the role of interleukin-6 (IL-6) in the pathogenesis of MS and NMOSD and the ameliorative effects of anti–IL-6 therapies in mouse models of experimental autoimmune encephalomyelitis (EAE). Main body Intraperitoneal injection of MR16-1, an anti–IL-6 receptor (IL-6R) antibody, reduced mechanical allodynia and spontaneous pain in EAE mice, which was attributed to a reduction in microglial activation and inhibition of the descending pain inhibitory system. The effect of anti–IL-6 therapies in ameliorating neuropathic pain in the clinical setting is controversial; a reduction in pain intensity has been reported with an anti–IL-6 antibody in four studies, namely a case report, a pilot study, a retrospective observational study, and a case series. Pain intensity was evaluated using a numerical rating scale (NRS), with a lower score indicating lesser pain. A reduction in the NRS score was reported in all four studies. However, in two randomized controlled trials of another anti–IL-6R antibody, the change in the visual analog scale pain score was not statistically significantly different when compared with placebo. This was attributed to the low mean pain score at baseline in both the trials and the concomitant use of medications for pain in one of the trials, which may have masked the effects of the anti–IL-6R antibody on neuropathic pain. Conclusion Thus, anti–IL-6 therapies might have a potential to reduce neuropathic pain, but further investigations are warranted to clarify the effect of inhibition of IL-6 signaling on neuropathic pain associated with MS and NMOSD.

Chronic alcohol induced mechanical allodynia by promoting neuroinflammation: A mouse model of alcohol‐evoked neuropathic pain

“…Notably, we observed a selective increase of IL‐6 in the dependent mice, which was not found in the non‐dependent mice. IL‐6 is implicated in pain (Serizawa et al, 2021) and is also involved in processes related to the development of addiction (Dennis et al, 2014; Doremus‐Fitzwater et al, 2014; Roberts et al, 2019). Further functional and morphological experiments will establish specific markers for alcohol‐induced neuropathy including IL‐6 pathway that may represent a specific linkage of the allodynia associated to alcohol dependence.…”

A common mechanism links Epstein‐Barr virus infections and autoimmune diseases

“…Latent membrane protein 1 (LMP1) is one of the latent genes predominantly expressed in the type III latency cells, and LMP1 is expressed in healthy carriers transiently as well as in autoimmune disease patients, especially in lupus 17–20 . LMP1 functions as an inflammation‐promoting factor, at least by inducing a panel of proinflammatory cytokines, some of which are clearly associated with autoimmunity 19,21–23 . Second, acute EBV infections in mononucleosis generate a wave of cytokines and chemokines including interleukin 1 beta (IL‐1β), IL‐1 receptor antagonist (IL‐1Ra), IL‐6, IL‐8, IL‐18, tumor necrosis factor‐α, interferon alpha/beta (IFN‐α/β), IFN‐γ, monokine induced by IFN‐γ (Mig), IFN‐γ‐inducible protein 10 (IP‐10) and granulocyte macrophage colony‐stimulating factor (GM‐CSF) (reviewed in 24 .…”

“…[17][18][19][20] LMP1 functions as an inflammation-promoting factor, at least by inducing a panel of proinflammatory cytokines, some of which are clearly associated with autoimmunity. 19,[21][22][23] Second, acute EBV infections in mononucleosis generate a wave of cytokines and chemokines including interleukin 1 beta (IL-1β), IL-1 receptor antagonist (IL-1Ra), IL-6, IL-8, IL-18, tumor necrosis factor-α, interferon alpha/beta (IFN-α/β), IFN-γ, monokine induced by IFN-γ (Mig), IFN-γ-inducible protein 10 (IP-10) and granulocyte macrophage colony-stimulating factor (GM-CSF) (reviewed in. 24 During persistent phase, EBV infections of human naïve B-lymphocytes are predicted to produce the similar but less amounts of cytokines in vivo because EBV-specific CTLs will be present and functional (Figure 1A).…”

Lysophosphatidylcholine: Potential Target for the Treatment of Chronic Pain

“…Macrophages or microglia are activated in response to noxious stimuli such as nerve injury. Activated macrophages or microglia result in the production and release of pro-inflammatory mediators, which lead to the development of chronic pain [ 98 , 99 ]. LPC induced macrophage and microglia recruitment and activation in the mouse spinal cord [ 100 , 101 , 102 ].…”