eNeuro
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Volatile anesthetics affect neuronal signaling by poorly understood mechanisms. Activation of central dopaminergic pathways has been implicated in emergence from general anesthesia. The volatile anesthetic isoflurane differentially inhibits glutamatergic and GABAergic synaptic vesicle (SV) exocytosis by reducing presynaptic Ca2+ influx without affecting the Ca2+-exocytosis relationship, but its effects on dopaminergic exocytosis are unclear. ⋯ Additionally, isoflurane inhibited single AP-evoked Ca2+ influx by 41 ± 3% and single AP-evoked exocytosis by 34 ± 6%. Comparable reductions in exocytosis and Ca2+ influx were produced by lowering extracellular [Ca2+]. Thus, isoflurane inhibits exocytosis from dopaminergic neurons by a mechanism distinct from that in non-dopaminergic neurons involving reduced Ca2+ entry through CaV2.1 and/or CaV2.2.
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BDNF is a critical contributor to neuronal growth, development, learning, and memory. Although extensively studied in the brain, BDNF is also expressed by primary afferent sensory neurons in the peripheral nervous system. Unfortunately, anatomical and functional studies of primary afferent-derived BDNF have been limited by the availability of appropriate molecular tools. ⋯ In addition, because BDNF null mice are not viable and even Cre-mediated deletion of BDNF from sensory neurons could have developmental consequences, here we deleted BDNF selectively from sensory neurons, in the adult, using an advillin-Cre-ER line crossed to floxed BDNF mice. We found that BDNF deletion in the adult altered few itch or acute and chronic pain behaviors, beyond sexually dimorphic phenotypes in the tail immersion, histamine, and formalin tests. Based on the anatomical distribution of sensory neuron-derived BDNF and its limited contribution to pain and itch processing, we suggest that future studies of primary afferent-derived BDNF should examine behaviors evoked by activation of myelinated primary afferents.
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Nogo receptor-1 (NgR1) signaling is involved in the limitation of axonal regeneration following spinal cord injury (SCI) through collapsing the growth cone and inhibiting neurite outgrowth. Lateral olfactory tract usher substance (LOTUS), a NgR antagonist, suppresses these pathological conditions. A previous report demonstrated the positive effects of LOTUS expression on motor function through raphespinal tract regeneration using pan-neuronally LOTUS-overexpressing transgenic mice. ⋯ Furthermore, histological analyses revealed that LOTUS had a neuroprotective effect on the injured spinal cord through suppressing cellular apoptosis during the acute phase. These neuroprotective and regenerative effects contributed to significant motor functional recovery and restoration of the motor evoked potential (MEP). Therefore, LOTUS application could prove beneficial in the treatment of SCI by promoting axonal regeneration of some descending fibers, reducing axonal dieback of CST fibers and encouraging motor function recovery.
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CD137L (4-1BBL) is a costimulatory molecule whose signaling can promote monocyte/macrophage functions; however, CD137L-mediated microglial response and its role in neuropathic pain remain unknown. We investigated CD137L following peripheral nerve injury-induced neuropathic pain using a spinal nerve L5 transection (L5Tx) murine model in both sexes. First, C57BL/6_CD137L knock-out (KO) mice displayed decreased mechanical and diminished heat hypersensitivity compared to wild-type (WT) controls, beginning on day 3 to up to day 35 post-L5Tx. ⋯ Following L5Tx, female CD137L KO mice did not show increased iNOS mRNA and had reduced numbers of IL-1β+ cells compared to WT. At 21 d post-surgery, CD137L KO mice had higher total numbers of arginase (Arg)-1+ cells and Arg-1+ microglia. Altogether, results indicate that spinal cord CD137L contributes to the development of peripheral nerve injury-induced neuropathic pain, which may be in part mediated through CD137L's modulation of the pro- and anti-inflammatory balance within the spinal cord.