Pain
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Adenosine triphosphate-sensitive potassium (K(ATP)) channels are suggested to be involved in pathogenesis of neuropathic pain, but remain underinvestigated in primary afferents and in the spinal cord. We examined alterations of K(ATP) channels in rat spinal cord and tested whether and how they could contribute to neuropathic pain. The results showed that protein expression for K(ATP) channel subunits SUR1, SUR2, and Kir6.1, but not Kir6.2, were significantly downregulated and associated with thermal hyperalgesia and mechanical allodynia after sciatic nerve injury. ⋯ Furthermore, preadministration of an astroglial gap junction decoupler carbenoxolone (10 μg) completely reversed the inhibitory effects of CRO treatment on the hyperalgesia and allodynia and phosphorylation of NR1 and NR2B receptors and the subsequent activation of Ca(2+)-dependent signals Ca(2+)/calmodulin-dependent kinase II and cyclic adenosine monophosphate (cAMP) response element binding protein. These findings suggest that nerve injury-induced downregulation of the K(ATP) channels in the spinal cord may interrupt the astroglial gap junctional function and contribute to neuropathic pain, thus the K(ATP) channels opener can reduce neuropathic pain probably partly via regulating the astroglial gap junctions. This study may provide a new strategy for treating neuropathic pain using K(ATP) channel openers in the clinic.
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Lumbar disc hernia (LDH) is a leading cause of chronic pain in adults. The underlying pathology of chronic pain after discectomy remains unclear. Chronic local inflammation is considered to underlie painful symptomatology. ⋯ However, TNFR2 protein levels in AF negatively correlated with VAS scores (r=-0.60 at 6 weeks and r=-0.60 at 12 months follow-up). These data indicate that TNF-α levels could determine the clinical outcome in LDH patients after discectomy. Moreover, the opposite correlation of TNF receptors with pain sensation suggests that an unbalanced expression plays a role in the generation of pain.
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Early, preemptive blockade of nerve growth factor (NGF)/tropomyosin receptor kinase A (TrkA) attenuates tumor-induced nerve sprouting and bone cancer pain. A critical unanswered question is whether late blockade of NGF/TrkA can attenuate cancer pain once NGF-induced nerve sprouting and neuroma formation has occurred. By means of a mouse model of prostate cancer-induced bone pain, anti-NGF was either administered preemptively at day 14 after tumor injection when nerve sprouting had yet to occur, or late at day 35, when extensive nerve sprouting had occurred. ⋯ In this model, as in most cancers, the individual cancer cell colonies have a limited half-life because they are constantly proliferating, metastasizing, and undergoing necrosis as the parent cancer cell colony outgrows its blood supply. Similarly, the sensory and sympathetic nerve fibers that innervate the tumor undergo sprouting at the viable/leading edge of the parent tumor, degenerate as the parent cancer cell colony becomes necrotic, and resprout in the viable, newly formed daughter cell colonies. These results suggest that preemptive or late-stage blockade of NGF/TrkA can attenuate nerve sprouting and cancer pain.
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Chronic neuropathic pain is associated with long-term changes at multiple levels of the neuroaxis, including in the brain, where electrical stimulation has been used to manage severe pain conditions. However, the clinical outcome of deep brain stimulation is often mixed, and the mechanisms are poorly understood. By means of electrophysiologic methods, we sought to characterize the changes in neuronal activity in the ventral posterolateral nucleus of the thalamus (VPL) in a rat model of peripheral neuropathic pain, and to reverse these changes with low-voltage, high-frequency stimulation (HFS) in the VPL. ⋯ Compared to naive rats, burst firing properties (burst events, percentage of spikes in burst, and mean interburst time) were altered in rats with CCI, whereas these changes were reversed to near normal after HFS. Thermal hyperalgesia in rats with CCI was significantly attenuated by HFS. Therefore, this study demonstrates that electrical stimulation within the VPL can effectively modulate some nociceptive phenomena associated with peripheral neuropathic pain.
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An important issue in physical rehabilitation is how to protect from or to reduce the effects of peripheral nerve injury. In the present study, we examined whether ankle joint mobilization (AJM) would reduce neuropathic pain and enhance motor functional recovery after nerve injury. In the axonotmesis model, AJM during 15 sessions every other day was conducted in rats. ⋯ Peripheral nerve injury increased the immunoreactivity for CD11b/c and GFAP in the spinal cord (P<0.05), and AJM markedly reduced CD11b/c and GFAP immunoreactivity (P<0.01). These results show that AJM in rats produces an antihyperalgesic effect and peripheral nerve regeneration through the inhibition of glial activation in the dorsal horn of the spinal cord. These findings suggest new approaches for physical rehabilitation to protect from or reduce the effects of nerve injury.