Pain
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IL-17 is an important cytokine in the physiopathology of rheumatoid arthritis (RA). However, its participation in the genesis of nociception during RA remains undetermined. In this study, we evaluated the role of IL-17 in the genesis of articular nociception in a model of antigen (mBSA)-induced arthritis. ⋯ IL-17 injection also increased PGE(2) production, MMP-9 activity and COX-2, MMP-9 and PPET-1 mRNA expression in synovial membrane. These results suggest that IL-17 is a novel pro-nociceptive cytokine in mBSA-induced arthritis, whose effect depends on both neutrophil migration and various pro-inflammatory mediators, as TNF-alpha, IL-1beta, CXCR1/2 chemokines ligands, MMPs, endothelins, prostaglandins and sympathetic amines. Therefore, it is reasonable to propose IL-17 targeting therapies to control this important RA symptom.
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Peripheral inflammation induces persistent central sensitization characterized by mechanical allodynia and heat hyperalgesia that are mediated by distinct mechanisms. Compared to well-demonstrated mechanisms of heat hyperalgesia, mechanisms underlying the development of mechanical allodynia and contralateral pain are incompletely known. In this study, we investigated the distinct role of spinal JNK in heat hyperalgesia, mechanical allodynia, and contralateral pain in an inflammatory pain model. ⋯ Finally, CFA-induced bilateral mechanical allodynia was attenuated in mice lacking JNK1 but not JNK2. Taken together, our data suggest that spinal JNK, in particular JNK1 plays an important role in the maintenance of persistent inflammatory pain. Our findings also reveal a unique role of JNK1 and astrocyte network in regulating tactile allodynia and contralateral pain.
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Glial glutamate transporter-1 (GLT-1) plays an essential role in the maintenance of glutamate homeostasis and is involved in the development and maintenance of pathological pain. The present study was undertaken (1) to observe the anti-nociceptive effects of ceftriaxone (Cef) in a chronic neuropathic pain model induced by chronic constrictive nerve injury (CCI) of the sciatic nerve and (2) to identify the role of spinal GLT-1 in the process. CCI induced significant thermal hyperalgesia and mechanical allodynia, which began from postoperative day 3 and lasted to day 21. ⋯ It was found that intrathecal administration of Cef led to the specific up-regulation of GLT-1 expression and glutamate uptake ((3)H-glutamate) in the spinal dorsal horn, and similar anti-nociceptive effects to those of intraperitoneal administration of Cef. The above effects of intrathecal Cef administration were all significantly inhibited by intrathecal administration of GLT-1 antisense oligodeoxynucleotides (As-ODNs). These results indicate that Cef plays an anti-nociceptive role by up-regulating spinal GLT-1 expression and its function.
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Since many people with chronic fatigue present with pain and many people with chronic pain present with fatigue, we tested if fatigue would enhance the response to pain in male and female mice. We further tested for the activation of brainstem nuclei by the fatigue task using c-fos as a marker. Fatigue was induced by having mice spontaneously run in running wheel for 2h. ⋯ C-fos expression was observed in the nucleus raphe pallidus, obscurus, and magnus after the fatigue task suggesting an increased activity in the raphe nuclei in response to the fatigue task. Therefore, widespread hyperalgesia is enhanced by the fatigue response but not hyperalgesia at the site of insult. We suggest that this effect is sex-dependent and involves mechanisms in the brainstem to result in an enhanced hyperalgesia.
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Pro-inflammatory cytokine production after nociceptive stimuli is pivotal for hyperalgesia. As macrophage migration inhibitory factor (MIF), a pleiotropic cytokine produced mainly by nonneuronal tissue, has been involved in the regulation of neuronal functions, herein we examined the role for MIF in formalin-induced inflammatory pain model. MIF critically contributed to nociceptive behaviors following formalin injection. ⋯ Mechanistic studies revealed that MIF upregulated the expression of the spinal NMDA receptor subunit NR2B via the MAPK signaling pathway. Moreover, microglial cells were found to be the major source of spinal MIF after formalin administration by fluorescence colocalization. These data highlight spinal MIF plays a critical role in the pathogenesis of formalin-induced inflammatory pain and suggest MIF may be a potential target for therapy of such pathological condition.