Neuroscience
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Loss of GABA-mediated inhibition in the spinal cord is thought to mediate allodynia and spontaneous pain after nerve injury. Despite extensive investigation of GABA itself, relatively little is known about how nerve injury alters the receptors at which GABA acts. This study examined levels of GABA(B) receptor protein in the spinal cord dorsal horn, and in the L4 and L5 (lumbar designations) dorsal root ganglia one to 18 weeks after L5 spinal nerve ligation. ⋯ Levels of GABA(B(2)) remained undetectable. Finally, baclofen-stimulated binding of guanosine-5'-(gamma-O-thio)triphosphate in dorsal horn did not differ between sham and ligated rats. Collectively, these results argue that a loss of GABA(B) receptor-mediated inhibition, particularly of central terminals of primary afferents, is unlikely to mediate the development or maintenance of allodynia or spontaneous pain behaviors after spinal nerve injury.
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Pain from pancreatitis or pancreatic cancer can be both chronic and severe although little is known about the mechanisms that generate and maintain this pain. To define the peripheral sensory and sympathetic fibers involved in transmitting and modulating pancreatic pain, immunohistochemistry and confocal microscopy were used to examine the sensory and sympathetic innervation of the head, body and tail of the normal mouse pancreas. Myelinated sensory fibers were labeled with an antibody raised against 200 kD neurofilament H (clone RT97), thinly myelinated and unmyelinated peptidergic sensory fibers were labeled with antibodies raised against calcitonin gene-related peptide (CGRP) and post-ganglionic sympathetic fibers were labeled with an antibody raised against tyrosine hydroxylase (TH). ⋯ In addition to this extensive set of sensory and sympathetic nerve fibers that terminate in the pancreas, there were large bundles of en passant nerve fibers in the dorsal region of the pancreas that expressed RT97 or CGRP and were associated with the superior mesenteric plexus. These data suggest the pancreas receives a significant sensory and sympathetic innervation. Understanding the factors and disease states that sensitize and/or directly excite the nerve fibers that terminate in the pancreas as well as those that are en passant may aid in the development of therapies that more effectively modulate the pain that frequently accompanies diseases of the pancreas, such as pancreatitis and pancreatic cancer.
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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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Cannabinoids have profound effects on synaptic function and behavior. Of the two cloned cannabinoid receptors, cannabinoid receptor 1 (CB1) is widely distributed in the CNS and accounts for most of the neurological effects of cannabinoids, while cannabinoid receptor 2 (CB2) expression in the CNS is very limited. The presence of additional receptors [i.e. cannabinoid receptor 3 (CB3)] is suggested by growing evidence of cannabinoid effects that are not mediated by CB1 or CB2. ⋯ Eur J Neurosci 22:2387-2391]. Our results strongly suggest that cannabinoid-induced suppression of the Sch-CA1 synapse is mediated by CB1. Non-canonical cannabinoid receptors do not seem to play a major role in inhibiting transmitter release at this synapse.
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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.