Abstract
Numerous studies have shown that pain sensation is affected by various immune molecules, such as cytokines, in tissues comprising the sensory pathway. Specifically, it has been shown that interleukin (IL)-17 promotes pain behaviour, but IL-10 suppresses it. IL-27 has been reported to have an anti-inflammatory effect through regulation of T cell differentiation, resulting in reduced IL-17 and induction of IL-10. Thus, we hypothesised that IL-27 would have some regulatory role in pain sensation. Here, we provide evidence that endogenous IL-27 constitutively controls thresholds for thermal and mechanical sensation in physiological and pathological conditions. Mice lacking IL-27 or its receptor WSX-1 spontaneously showed chronic pain-like hypersensitivity. Reconstitution of IL-27 in IL-27-deficient mice reversed thermal and mechanical hypersensitive behaviours. Thus, unlike many other cytokines induced by inflammatory events, IL-27 appears to be constitutively produced and to control pain sensation. Furthermore, mice lacking IL-27/WSX-1 signalling showed additional hypersensitivity when subjected to inflammatory or neuropathic pain models. Our results suggest that the mechanisms underlying hypersensitive behaviours caused by the ablation of IL-27/WSX-1 signalling are different from those underlying established chronic pain models. This novel pain control mechanism mediated by IL-27 might indicate a new mechanism for the chronic pain hypersensitivity.
Highlights
Chronic pain is defined as pain that lasts over three months
There were no significant differences among WT, WSX-1−/− (WSX-1-deficient), Epstein-Barr virus–induced gene 3 (EBI3)−/− [Epstein-Barr virus-induced gene 3 (EBI3)-deficient)], and p28−/− (p28-deficient) mice in any parameters obtained from the open field and rotarod tests, suggesting that IL-27/WSX-1 signalling-deficient mice did not have substantial dysfunctions in locomotor activity or anxiety-like behaviour
Reaction latencies measured with the hot-plate test (48 °C) in WSX-1−/−, EBI3−/−, and p28−/− mice were significantly reduced compared to the latency in WT mice (Fig. 1a)
Summary
Chronic pain is defined as pain that lasts over three months. Existing therapeutic strategies for this condition have limited effects[1,2]. To study the mechanisms that underlie chronic pain, two types of animal models have been widely used: inflammatory and neuropathic pain models[3]. In these models, animals display long-lasting hypersensitivity to thermal and/or mechanical stimuli. Animals display long-lasting hypersensitivity to thermal and/or mechanical stimuli Analyses of these models suggest that the immune system plays an important role in the induction of such hypersensitivities. Because we assumed that phenotypic differences would appear after induction of chronic pain due to the inducible nature of IL-27, we did not expect such a hypersensitive phenotype without any treatment. We focus on to investigate the roles of constitutive IL-27 on controlling the basal pain sensitivity
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