European journal of pain : EJP
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Peripheral nerve injury resulting in neuropathic pain induces the upregulation of interleukin (IL)-6 and tumor necrosis factor-alpha, which binds to tumor necrosis factor receptor 1 (TNFR1) and induces NF-kappaB and p38 MAPK activation in the spinal cord and dorsal root ganglia (DRG). We here investigated whether TNFR1 regulates IL-6 expression through NF-kappaB or p38 MAPK activations in the spinal cord and DRG in rats with chronic constriction injury (CCI) of the sciatic nerve. ⋯ In addition, NF-kappaB decoy, but not p38 MAPK inhibitor, SB203580 reduced CCI-elevated IL-6 expression in the spinal cord and DRG. Therefore, these data suggest that TNFR1 induces IL-6 upregulation and neuropathic pain through NF-kappaB, but not p38 MAPK activation in the spinal cord and DRG and that the NF-kappaB/IL-6 pathways in the DRG may be less dependent on TNFR1 than the spinal cord pathway.
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Diabetes mellitus is the leading cause of peripheral neuropathy worldwide. Despite this high level of incidence, underlying mechanisms of the development and maintenance of neuropathic pain are still poorly understood. Evidence supports a prominent role of glial cells in neuropathic pain states. ⋯ Astrocytic activation in this model appears to be limited and is unaffected by Gabapentin treatment. Consequently, spinal microglial activation is a key mechanism underlying diabetic neuropathy. Furthermore, we suggest that Gabapentin may exert its anti-allodynic actions partially through alterations of microglial cell function.
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High pain threshold is a supportive diagnosis criterion for Prader-Willi syndrome (PWS), but its pathogenesis is poorly understood. In this study we investigate sensory pathways in PWS, in order to evaluate peripheral or central involvement in altered sensory perception. ⋯ Our data suggest that altered perception in PWS does not seem attributable to a peripheral nerve derangement due to metabolic factors or obesity. Impairment of the small nociceptive neurons of dorsal root ganglia or involvement of hypothalamic region may not be excluded.
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Dorsal horn neuron (DHN) sensitization can be induced and maintained by nociceptor activation. In previous studies, only a small increase in ongoing DHN activity was present immediately after plantar incision; yet, powerful activation of nociceptors was prominent 1 day after incision. In the present study, rats underwent plantar incision or sham surgery as control. ⋯ This study demonstrates that 1 day after incision, DHN sensitization manifests in markedly increased spontaneous activities, enhanced responses to mechanical stimuli and expanded receptive fields (RFs). Separate groups of neurons appear to transmit spontaneous activity and enhanced responses to mechanical stimuli. Inhibition of spontaneous activity by blockade of afferent input indicates that the prolonged spinal hyperactivity remains largely dependent on the ongoing primary afferent activity.
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Osteoarthritis (OA) is associated with chronic debilitating joint pain. Pain is the result of an emotional and sensory experience and preclinical models of OA can thus be useful to better understand the underlying mechanisms of the disease and test new therapeutic options. We induced unilateral knee OA in Sprague-Dawley rats using monosodium iodoacetate (MIA), a glycolysis inhibitor and assessed the effects of acute and chronic morphine and gabapentin using a battery of quantitative behavioural outcome measures of pain and disability. ⋯ These measures were significantly reduced after both acute (13.3% of sham response, p<0.01, von Frey 6g) and chronic (38.3%, p<0.05) morphine whilst only chronic gabapentin (37.0%, p<0.05) had an effect. We show the reliability of the model in terms of mechanical hypersensitivity and demonstrate cooling hypersensitivity and ambulatory-evoked pain. In terms of translational research, the effects of morphine and gabapentin validate the model and suggest trials of these therapeutic approaches in OA patients.