The European journal of neuroscience
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A great deal of experimental evidence has already been accumulated that hyperpolarization-activated and cyclic nucleotide-gated cation channels (HCN) expressed by peripheral nerve fibers contribute to the initiation of nerve activities leading to pain. Complementing these findings, we have recently demonstrated that HCN subunit 2 (HCN2) channel protein is also widely expressed by axon terminals of substance P (SP)-containing peptidergic nociceptive primary afferents in laminae I-IIo of the spinal dorsal horn, and postulated that they may play a role in spinal pain processing. In the present study, we investigated how the expression of HCN2 ion channels in the spinal dorsal horn may change in inflammatory pain evoked by unilateral injection of complete Freund's adjuvant (CFA) into the hind paw of rats. ⋯ The elevation of HCN2 immunoreactivity was paralleled by an increase in SP immunoreactivity. In addition, similarly to control animals, the co-localization between HCN2 and SP immunoreactivity was remarkably high, suggesting that central axon terminals of nociceptive primary afferents that increased their SP expression in response to CFA injection into the hind paw also increased their HCN2 expression. The results indicate that HCN2 ion channel mechanisms may play a role in SP-mediated spinal pain processing not only in naive animals but also in chronic inflammatory pain.
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Gilles de la Tourette Syndrome (GTS) is characterized by multiple motor and one or more vocal/phonic tics. Psychopathology and co-morbidity occur in approximately 80-90% of clinical cohorts. The most common psychopathologies are attention deficit hyperactivity disorder, obsessive-compulsive behaviours, obsessive-compulsive disorder, depression, anxiety and certain behavioural disorders. ⋯ This paper reviews critically and in detail all studies published to date. Only two studies on just a few patients fulfil some of the evidence-based criteria. DBS for GTS is therefore still highly experimental.
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Eccentric muscle exercise is a common cause of acute and chronic (lasting days to weeks) musculoskeletal pain. To evaluate the mechanisms involved, we have employed a model in the rat, in which eccentric hind limb exercise produces both acute mechanical hyperalgesia as well as long-term changes characterized by enhanced hyperalgesia to subsequent exposure to an inflammatory mediator. Eccentric exercise of the hind limb produced mechanical hyperalgesia, measured in the gastrocnemius muscle, which returned to baseline at 120 h post-exercise. ⋯ This marked prolongation of PGE(2) hyperalgesia induced by eccentric exercise was prevented by the spinal intrathecal injection of oligodeoxynucleotide antisense to protein kinase Cε, a second messenger in nociceptors implicated in the induction of chronic pain. Exercise-induced hyperalgesia and prolongation of PGE(2) hyperalgesia were inhibited by the spinal intrathecal administration of antisense for the interleukin-6 but not the tumor necrosis factor α type 1 receptor. These findings provide further insight into the mechanism underlying exercise-induced chronic muscle pain, and suggest novel approaches for the prevention and treatment of exercise- or work-related chronic musculoskeletal pain syndromes.
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Ca(2+) /calmodulin-dependent protein kinase II (CaMKII) is a key mediator of long-term potentiation (LTP), which can be triggered by N-methyl-d-aspartate (NMDA) receptor-mediated Ca(2+) influx. We previously demonstrated that Fyn kinase-mediated phosphorylation of NR2B subunits of NMDA receptors at Tyr1472 in the dorsal horn was involved in a neuropathic pain state even 1 week after nerve injury. Here we show that Y1472F-KI mice with a knock-in mutation of the Tyr1472 site to phenylalanine did not exhibit neuropathic pain induced by L5 spinal nerve transection, whereas they did retain normal nociceptive responses and induction of inflammatory pain. ⋯ There was no difference in the Ca(2+) response to glutamate and sensitivity to NMDA receptor antagonists between naive wild-type and Y1472F-KI mice, and the Ca(2+) response to glutamate was attenuated in the Y1472F-KI mice after nerve injury. Autophosphorylation of CaMKII at Thr286 was markedly impaired in Y1472F-KI mice after nerve injury, but there was no difference in phosphorylation of CaMKII at Thr305 or protein kinase Cγ at Thr674, and activation of neuronal nitric oxide synthase and microglia in the superficial layer of spinal cord between wild-type and Y1472F-KI mice after the operation. These results demonstrate that the attenuation of neuropathic pain is caused by the impaired NMDA receptor-mediated CaMKII signaling in Y1472F-KI mice, and suggest that autophosphorylation of CaMKII at Thr286 plays a central part not only in LTP, but also in persistent neuropathic pain.