Neuroscience
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Rostral agranular insular cortex (RAIC) projects to periaqueductal gray (PAG) and inhibits spinal nociceptive transmission by activating PAG-rostral ventromedial medulla (RVM) descending antinociceptive circuitry. Despite being generated from the same precursor prepronociceptin, nocistatin (NST) and nociceptin/orphanin FQ (N/OFQ) produce supraspinal analgesic and hyperalgesic effects, respectively. Prepronociceptin is highly expressed in the RAIC. ⋯ There were two separate populations of RAIC-PAG pyramidal neurons, one responding to NST and the other one to N/OFQ. Our results suggest that G(alphaq/11)-coupled NST receptor mediates NST excitation of RAIC-PAG glutamatergic neurons, which is expected to cause the supraspinal analgesia by enhancing the activity of RAIC-PAG-RVM antinociceptive pathway. Opposite effects of NST and N/OFQ on supraspinal pain regulation are likely to result from their opposing effects on RAIC-PAG pyramidal neurons.
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Our previous study showed that perinatal exposure to interleukin-1beta (IL-1beta), an inflammatory cytokine, induces acute injury to developing white matter in the neonatal rat brain, and alpha-phenyl-n-tert-butyl-nitrone (PBN), a free radical scavenger and antioxidant, protects against IL-1beta-induced acute brain injury. The objective of the present study was to further examine whether perinatal exposure to IL-1beta resulted in persistent brain damage and neurological disabilities, and whether PBN offers lasting protection. Intracerebral injection of IL-1beta (1 microg/kg) was performed in postnatal day 5 (P5) Sprague-Dawley rat pups and PBN (100 mg/kg) or saline was administered intraperitoneally 5 min after IL-1beta injection. ⋯ Although some neurobehavioral deficits such as performance in negative geotaxis, cliff avoidance, beam walking, and locomotion were spontaneously reversible, sustained deficits such as poor performance in the vibrissa-elicited forelimb-placing test, the pole test, the passive avoidance task, and the elevated plus-maze task were still observable at P21. Perinatal IL-1beta exposure resulted in persistent brain damage including enlargement of ventricles, loss of mature oligodendrocytes, impaired myelination as indicated by the decrease in myelin basic protein immunostaining, axonal and dendritic injury, and loss of hippocampal CA1 neurons and tyrosine hydroxylase positive neurons in the substantia nigra and ventral tegmental areas of the rat brain. Treatments with PBN provided lasting protection against the IL-1beta-induced brain injury and improved the associated neurological dysfunctions in juvenile rats, suggesting that prompt treatments for brain injury induced by perinatal infection/inflammation might have important long-term consequences.
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Large conductance calcium-activated potassium (BK(Ca)) channels are membrane proteins contributing to electrical propagation through neurons. Calcitonin gene-related peptide (CGRP) is a neuropeptide found in the trigeminovascular system (TGVS). Both BK(Ca) channels and CGRP are involved in migraine pathophysiology. ⋯ The BK(Ca) channel protein and the modulatory beta2- and beta4-subunt proteins were more expressed in the TNC than in the TG. Iberiotoxin induced an increase in CGRP release from the TNC that was attenuated by NS11021. Thus, BK(Ca) channels might have a role in trigeminovascular pain transmission.
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Nociceptive pathways with first-order neurons located in the trigeminal ganglion (TG) provide sensory innervation to the head, and are responsible for a number of common chronic pain conditions, including migraines, temporomandibular disorders and trigeminal neuralgias. Many of those conditions are associated with inflammation. Yet, the mechanisms of chronic inflammatory pain remain poorly understood. ⋯ Double-immunohistochemistry with antibodies against BDNF combined with one of nociceptor markers, CGRP or transient receptor potential vanilloid type 1 (TRPV1), revealed that BDNF is significantly upregulated in TRPV1-immunoreactive (IR) neurons in both rats and mice, and CGRP-IR neurons in mice, but not rats. Overall, the inflammation-induced upregulation of BDNF is stronger in mice compared to rats. Thus, mouse TG provides a suitable model to study molecular mechanisms of inflammation-dependent regulation of BDNF expression in vivo.
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Lamina I of the spinal cord contains many projection neurons that express the neurokinin 1 receptor (NK1r). It has been reported that these cells can undergo long-term potentiation (LTP), which may result from insertion of AMPA-type glutamate receptors (AMPArs) containing GluA1 or GluA4 subunits. We therefore investigated synaptic AMPAr expression on these cells with immunocytochemistry following antigen-retrieval. ⋯ Both types of cell received contacts from peptidergic primary afferents, however, on the large cells these appeared to constitute over half of the glutamatergic synapses, and were often associated with elongated AMPAr puncta. This suggests that these afferents, which probably contain substance P, provide a powerful, secure synaptic input to large NK1r-expressing projection neurons. These results demonstrate the importance of GluA4-containing AMPArs in nociceptive transmission and raise the possibility that different forms of LTP in lamina I projection neurons may be related to differential expression of GluA1/GluA4.