Pain
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The proinflammatory cytokines tumor necrosis factor (TNF) α and interleukin (IL) 1β have been strongly implicated in the pathogenesis of neuropathic pain, but the intracellular signaling of these cytokines in glial cells is not fully understood. TNF receptor-associated factor 6 (TRAF6) plays a key role in signal transduction in the TNF receptor superfamily and the IL-1 receptor superfamily. In this study, we investigated the role of TRAF6 in neuropathic pain in mice after spinal nerve ligation (SNL). ⋯ Spinal TRAF6 inhibition via TRAF6 siRNA, shRNA lentivirus, or antisense oligodeoxynucleotides partially reversed SNL-induced neuropathic pain and spinal CCL2 expression. Finally, intrathecal injection of TNF-α-activated astrocytes induced mechanical allodynia, which was attenuated by pretreatment of astrocytes with TRAF6 siRNA. Taken together, the results suggest that TRAF6, upregulated in spinal cord astrocytes in the late phase after nerve injury, maintains neuropathic pain by integrating TNF-α and IL-1β signaling and activating the JNK/CCL2 pathway in astrocytes.
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Central poststroke pain (CPSP) is a central neuropathic pain condition caused by a cerebrovascular lesion affecting the central somatosensory nervous system. Once developed, CPSP is difficult to treat, so there is an interest in identifying stroke patients at risk for the development of CPSP. This study examined if sensory abnormalities, including evoked dysesthesia, allodynia, or hyperalgesia to static and dynamic touch, cold, and pinprick, at stroke onset are a predictor for the development of CPSP. ⋯ The presence of allodynia, hyperalgesia, or dysesthesia in response to the sensory examination at stroke onset increased the odds for CPSP at 6months by 4.6 (odds ratio; 95% confidence interval 1.5-13.9). The combination of reduced or absent sensation to pinprick or cold and early evoked pain or dysesthesia at onset increased odds by 8.0 (odds ratio; 95% confidence interval 2.6-24.8). In conclusion, early evoked pain or dysesthesia is a predictor for CPSP.
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Chemotherapy-induced peripheral neuropathy accompanied by chronic neuropathic pain is the major dose-limiting toxicity of several anticancer agents including the taxane paclitaxel (Taxol). A critical mechanism underlying paclitaxel-induced neuropathic pain is the increased production of peroxynitrite in spinal cord generated in response to activation of the superoxide-generating enzyme, NADPH oxidase. Peroxynitrite in turn contributes to the development of neuropathic pain by modulating several redox-dependent events in spinal cord. ⋯ The first relies on inhibition of the redox-sensitive transcription factor (NFκB) and mitogen activated protein kinases (ERK and p38) resulting in decreased production of neuroexcitatory/proinflammatory cytokines (TNF-α, IL-1β) and increased formation of the neuroprotective/anti-inflammatory IL-10. The second involves inhibition of redox-mediated posttranslational tyrosine nitration and modification (inactivation) of glia-restricted proteins known to play key roles in regulating synaptic glutamate homeostasis: the glutamate transporter GLT-1 and glutamine synthetase. Our results unravel a mechanistic link into biomolecular signaling pathways employed by A3AR activation in neuropathic pain while providing the foundation to consider use of A3AR agonists as therapeutic agents in patients with chemotherapy-induced peripheral neuropathy.
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Relationships between the paradoxical painful and non painful sensations induced by a thermal grill.
The simultaneous application of innocuous cutaneous warm and cold stimuli with a thermal grill can induce both paradoxical pain and paradoxical warmth (heat). The goal of this study was to investigate further the relationships between these paradoxical sensations. Stimuli were applied to the palms of the right hands of 21 volunteers with a thermode consisting of 6 bars, the temperature of which was controlled by Peltier elements. ⋯ The intensities of the warmth and unpleasantness evoked by the stimuli were directly related to the magnitude of the warm-cold differential. Our results suggest that there is a continuum between the painful and nonpainful paradoxical sensations evoked by the thermal grill that may share pathophysiological mechanisms. These data also confirm the existence of strong relationships between the thermoreceptive and nociceptive systems and the utility of the thermal grill for investigating these relationships.
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Two-pore domain background K(+) channels (K2p or KCNK) produce hyperpolarizing currents that control cell membrane polarity and neuronal excitability throughout the nervous system. The TREK2 channel as well as the related TREK1 and TRAAK channels are mechanical-, thermal- and lipid-gated channels that share many regulatory properties. TREK2 is one of the major background channels expressed in rodent nociceptive neurons of the dorsal root ganglia that innervate the skin and deep body tissues, but its role in somatosensory perception and nociception has remained poorly understood. ⋯ TREK2 is also involved in mechanical pain perception and in osmotic pain after sensitization by prostaglandin E2. TREK2 is involved in the cold allodynia that characterizes the neuropathy commonly associated with treatments with the anticancer drug oxaliplatin. These results suggest that positive modulation of the TREK2 channel may have beneficial analgesic effects in these neuropathic conditions.