The Journal of neuroscience : the official journal of the Society for Neuroscience
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Understanding of the sequence and nature of the events that govern neuron-microglia communication is critical for the discovery of new mechanisms and targets for chronic pain treatment. The neuronal chemokine fractalkine (FKN) and its microglial receptor CX3CR1 may mediate such a function in the dorsal horn of the spinal cord after cleavage of the extracellular domain of this transmembrane chemokine by a protease. Here we report that in neuropathic rat dorsal horn, with dorsal root-attached preparations, soluble FKN (sFKN) contents are increased in the superfusates collected after noxious-like electrical stimulation of ipsilateral primary afferent fibers. ⋯ Indeed, the acute activation of dorsal horn microglia by lipopolysaccharide results in increased CatS activity in the superfusates, followed by increased sFKN contents. Consistent with these observations ex vivo, the levels of both sFKN and CatS activity in CSF samples increased significantly after peripheral nerve injury, associated with spinal microglial activation. Finally, because we found that both FKN immunoreactivity and mRNA are confined to dorsal horn neurons, we suggest that under neuropathic conditions, noxious stimulation of primary afferent fibers induces release of CatS from microglia, which liberates FKN from dorsal horn neurons, thereby contributing to the amplification and maintenance of chronic pain.
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Microinjection of pentobarbital into a restricted region of rat brainstem, the mesopontine tegmental anesthesia area (MPTA), induces a reversible anesthesia-like state characterized by loss of the righting reflex, atonia, antinociception, and loss of consciousness as assessed by electroencephalogram synchronization. We examined cerebral activity during this state using FOS expression as a marker. Animals were anesthetized for 50 min with a series of intracerebral microinjections of pentobarbital or with systemic pentobarbital and intracerebral microinjections of vehicle. ⋯ In the MPTA itself FOS expression was suppressed during systemic anesthesia. Differences in the pattern of brain activity in the two modes of anesthesia are consistent with the possibility that anesthetic endpoints might be achieved by alternative mechanisms: direct drug action for systemic anesthesia or via ascending pathways for MPTA-induced anesthesia. However, it is also possible that systemically administered agents induce anesthesia, at least in part, by a primary action in the MPTA with cortical inhibition occurring secondarily.
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The avian song control system undergoes pronounced seasonal plasticity in response to photoperiod and hormonal cues. The action of testosterone (T) and its metabolites in the song nucleus HVC is both necessary and sufficient to promote breeding season-like growth of its efferent nuclei RA (robust nucleus of the arcopallium) and Area X, suggesting that HVC may release a trophic factor such as brain-derived neurotrophic factor (BDNF) into RA and X. BDNF is involved in many forms of adult neural plasticity in other systems and is present in the avian song system. ⋯ Expression of the mRNA for the Trk B receptor of BDNF, however, did not vary with seasonal conditions in either HVC or RA. Local blockade of BDNF activity in RA via infusion of Trk-Fc fusion proteins inhibited the response to breeding conditions. Our results indicate that BDNF is sufficient to promote the seasonal plasticity in somatic area and cell density in RA, although NT-3 may also contribute to this process, and suggest that HVC may be a presynaptic source of increased levels of BDNF in RA of breeding-condition birds.
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Itch, an unpleasant sensation associated with the desire to scratch, is symptomatic of dermatologic and systemic disorders that often resist antihistamine treatment. Histamine-independent itch mediators include serotonin (5-HT) and agonists of the protease-activated receptor-2 (PAR-2). We used behavior, Fos immunohistochemistry, and electrophysiology to investigate if these mediators activate spinal dorsal horn neurons in a manner consistent with itch. ⋯ The prolonged responses of superficial dorsal horn neurons to SLIGRL-NH(2) and 5-HT suggest a role in signaling itch. However, their responsiveness to algogens is inconsistent with itch specificity. Alternatively, such neurons may signal itch, whereas noxious stimulus levels recruit these and a larger population of pruritogen-insensitive cells to signal pain which masks or occludes the itch signal.
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Randomized Controlled Trial
Medial prefrontal cortex activity is predictive for hyperalgesia and pharmacological antihyperalgesia.
Sodium channel blockers are known for reducing pain and hyperalgesia. In the present study we investigated changes in cerebral processing of secondary mechanical hyperalgesia induced by pharmacological modulation with systemic lidocaine. An experimental electrical pain model was used in combination with functional magnetic resonance imaging. ⋯ However, only activity in mPFC was inversely correlated to area of hyperalgesia during placebo and antihyperalgesic treatment effect. Furthermore, the difference of mPFC activity during hyperalgesia and placebo versus hyperalgesia and lidocaine correlated inversely with the change of the weighted hyperalgesic area (as a factor of area and rated pain intensity). We conclude that activity in mPFC correlates inversely with individual extent of central hyperalgesia and predicts individual pharmacological antihyperalgesic treatment response.