Pain
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Damage on one side of the body can also result in pain on the contralateral unaffected side, called mirror-image pain (MIP). Currently, the mechanisms responsible for the development of MIP are unknown. In this study, we investigated the involvement of spinal microglia and interleukin-1β (IL-1β) in the development of MIP using a peripheral inflammatory pain model. ⋯ However, i.t. pretreatment with fluorocitrate, an astrocyte inhibitor, restored minocycline- or IL-1ra-induced contralateral MA. These results suggest that spinal IL-1β derived from activated microglia temporarily suppresses astrocyte activation, which can ultimately prevent the development of contralateral MA under inflammatory conditions. These findings imply that microglial IL-1β plays an important role in regulating the induction of inflammatory MIP.
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Decreased spinal cord GABAergic inhibition is a major contributor to the persistent neuropathic pain that can follow peripheral nerve injury. Recently, we reported that restoring spinal cord GABAergic signaling by intraspinal transplantation of cortical precursors of GABAergic interneurons from the embryonic medial ganglionic eminence (MGE) can reverse the mechanical hypersensitivity (allodynia) that characterizes a neuropathic pain model in the mouse. ⋯ Transplants from these mice, in which GABA is synthesized but cannot be stored or released, had no effect on mechanical hypersensitivity or heat hyperalgesia in the paclitaxel model. Taken together, these results demonstrate the therapeutic potential of GABAergic precursor cell transplantation in diverse neuropathic pain models and support our contention that restoration of inhibitory controls through release of GABA from the transplants is their mode of action.
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Primary and metastatic cancers that affect bone are frequently associated with severe and intractable pain. The mechanisms underlying the pathogenesis of bone cancer pain still remain largely unknown. Previously, we have reported that sensitization of primary sensory dorsal root ganglion (DRG) neurons contributes to the pathogenesis of bone cancer pain in rats. ⋯ Moreover, we revealed that functional upregulation of transient receptor potential vanilloid channel type 1 (TRPV1) in DRG neurons through the activation of Janus kinase (JAK)/phosphatidylinositol 3-kinase (PI3K) signaling pathway contributes to the effects of IL-6 on the pathogenesis of bone cancer pain. Therefore, suppression of functional upregulation of TRPV1 in DRG neurons by the inhibition of JAK/PI3K pathway, either before surgery or after surgery, reduces the hyperexcitability of DRG neurons and pain hyperalgesia in bone cancer rats. We here disclose a novel intracellular pathway, the IL-6/JAK/PI3K/TRPV1 signaling cascade, which may underlie the development of peripheral sensitization and bone cancer-induced pain.
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Intense inflammatory pain caused by urate crystals in joints and other tissues is a major symptom of gout. Among therapy drugs that lower urate, benzbromarone (BBR), an inhibitor of urate transporters, is widely used because it is well tolerated and highly effective. We demonstrate that BBR is also an activator of voltage-gated KCNQ potassium channels. ⋯ Notably, the analgesic effects of BBR are largely mediated through peripheral and not through central KCNQ channels, an observation supported both by pharmacokinetic studies and in vivo experiments. Moreover, multiple residues in the superficial part of the voltage sensing domain of KCNQ channels were identified critical for the potentiation activity of BBR by a molecular determinant investigation. Our data indicate that activation of peripheral KCNQ channels mediates the pain relief effects of BBR, potentially providing a new strategy for the development of more effective therapies for gout.