Neuroscience
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The purpose of this study was to investigate sex-related differences in nociception elicited by s.c. injection of different concentrations (1-5%) of formalin. S.c. formalin-induced biphasic (early and late phases) persistent nociception was assessed by extracellularly recording the spontaneous activities of single spinal dorsal horn wide-dynamic range neurons in anesthetized male and female rats. The nociceptive responses of the dorsal horn wide-dynamic range neurons following s.c. injection of 5%, but not 1% and 2.5%, formalin in female rats were significantly stronger than the responses obtained in male rats. ⋯ Sex differences in formalin-induced tonic nociception are stimulus intensity dependent and related to the modulation from the supraspinal regions. S.c. formalin-induced late phase nociception in female rats is only sensitive to depression at a frequency of 50 Hz, but not 5 Hz, of conditioning electrical stimulation. This suggests that the involvement of the central mechanisms in the antinociceptive effects of conditioning electrical stimulation may be different at various frequencies of stimulation.
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Comparative Study
Absence of Reelin results in altered nociception and aberrant neuronal positioning in the dorsal spinal cord.
Mutations in reeler, the gene coding for the Reelin protein, result in pronounced motor deficits associated with positioning errors (i.e. ectopic locations) in the cerebral and cerebellar cortices. In this study we provide the first evidence that the reeler mutant also has profound sensory defects. We focused on the dorsal horn of the spinal cord, which receives inputs from small diameter primary afferents and processes information about noxious, painful stimulation. ⋯ Additionally, we detected neurokinin-1 receptors expressed by Dab1-labeled neurons in reeler laminae I-III and the lateral spinal nucleus. Consistent with these anatomical abnormalities having functional consequences, we found a significant reduction in mechanical sensitivity and a pronounced thermal hyperalgesia (increased pain sensitivity) in reeler compared with control mice. As the nociceptors in control and reeler dorsal root ganglia are similar, our results indicate that Reelin signaling is an essential contributor to the normal development of central circuits that underlie nociceptive processing and pain.
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A transcription factor known as cyclic AMP response element-binding protein has been shown to be involved in the central sensitization in neuropathic pain and inflammation pain. The present study examined the roles of cyclic AMP response element-binding protein and of the phosphorylated cyclic AMP response element-binding protein in the maintenance of mechanical and cold allodynia induced by a neuropathic pain model, "spared nerve injury," in rats. First, the results of immunohistochemical study showed that phosphorylated cyclic AMP response element-binding protein, but not cyclic AMP response element-binding protein, increased bilaterally in the spinal dorsal horn 14 days following spared nerve injury, indicating a possible contribution of phosphorylated cyclic AMP response element-binding protein in spared nerve injury. ⋯ Western blot results showed that the alleviation in intensity of behavioral performance was accompanied by a significant reduction of total cyclic AMP response element-binding protein and phosphorylated cyclic AMP response element-binding protein in the spinal dorsal horn. Moreover, there were no differences in cyclic AMP response element-binding protein and phosphorylated cyclic AMP response element-binding protein between ipsilateral and contralateral dorsal horns. Our data demonstrate a close association between the expression of behavioral hypersensitivity and cyclic AMP response element-binding protein activation in the spinal dorsal horn following spared nerve injury, supporting the notion that phosphorylated cyclic AMP response element-binding protein may play an important role in the maintenance of chronic neuropathic pain.
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Adeno-associated virus (AAV) vectors have gained a preeminent position in the field of gene delivery to the normal brain through their ability to achieve extensive transduction of neurons and to mediate long-term gene expression with no apparent toxicity. In adult animals direct infusion of AAV vectors into the brain parenchyma results in highly efficient transduction of target structures. However AAV-mediated global delivery to the adult brain has been an elusive goal. ⋯ AAV8 proved to be more efficient than AAV1 or AAV2 vectors for gene delivery to all of the structures analyzed, including the cerebral cortex, hippocampus, olfactory bulb, and cerebellum. Moreover the intensity of gene expression, assessed using a microarray reader, was considerably higher for AAV8 in all structures analyzed. In conclusion, the enhanced transduction achieved by AAV8 compared with AAV1 and AAV2 indicates that AAV8 is the superior serotype for gene delivery to the CNS.
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Fear-conditioned analgesia is an important survival response which is expressed upon re-exposure to a context previously paired with a noxious stimulus. The aim of the present study was to characterize further the behavioral, monoaminergic and hypothalamo-pituitary-adrenal axis alterations associated with expression of fear-conditioned analgesia. Rats which had received footshock conditioning 24 h earlier, exhibited reduced formalin-evoked nociceptive behavior upon re-exposure to the footshock chamber, compared with non-footshocked formalin-treated rats. ⋯ These data extend behavioral characterization of the phenomenon of fear-conditioned analgesia and suggest that measurement of ultrasound emission may be used as an ethologically relevant index of the defense response during fear-conditioned analgesia. Ultrasonic vocalization may also be a useful behavioral output to aid separation of nociception and aversion. The data provide evidence for discrete alterations in dopaminergic activity in the periaqueductal gray and thalamus and for altered hypothalamo-pituitary-adrenal axis activity following expression of defensive behavior.