Annals of the New York Academy of Sciences
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Ann. N. Y. Acad. Sci. · Jun 2010
Presynaptic inhibition of primary afferents by depolarization: observations supporting nontraditional mechanisms.
Primary afferent neurotransmission is the fundamental first step in the central processing of sensory stimuli and is controlled by pre- and postsynaptic inhibitory mechanisms. Presynaptic inhibition (PSI) is probably the more powerful form of inhibitory control in all primary afferent fibers. A major mechanism producing afferent PSI is via a channel-mediated depolarization of their intraspinal terminals, which can be recorded extracellularly as a dorsal root potential (DRP). ⋯ There is still no "squeaky clean" evidence of this organization. This paper describes recent and historical work that supports the existence of PAD occurring by more direct pathways and with a complex pharmacology that questions the proprietary role of GABA and GABA(A) receptors in this process. Cholinergic transmission in particular may contribute significantly to PAD, including via direct release from primary afferents.
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Ann. N. Y. Acad. Sci. · Jun 2010
Isoflurane modulates neuronal excitability of the nucleus reticularis thalami in vitro.
The thalamus has a key function in processing sensory information, sleep, and cognition. We examined the effects of a common volatile anesthetic, isoflurane, on modulation of neuronal excitability in reticular thalamic nucleus (nRT) in intact brain slices from immature rats. In current-clamp recordings, isoflurane (300-600 micromol/L) consistently depolarized membrane potential, decreased input resistance, and inhibited both rebound burst firing and tonic spike firing modes of nRT neurons. ⋯ Thus, at clinically relevant concentrations, isoflurane inhibits neuronal excitability of nRT neurons in developing brain via multiple ion channels. Inhibition of the neuronal excitability of thalamic cells may contribute to impairment of sensory information transfer in the thalamocortical network by general anesthetics. The findings may be important for understanding cellular mechanisms of anesthesia, such as loss of consciousness and potentially damaging consequences of general anesthetics on developing mammalian brains.
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Ann. N. Y. Acad. Sci. · Jun 2010
Role of NKCC1 and KCC2 in the development of chronic neuropathic pain following spinal cord injury.
Neuropathic pain is a common problem following spinal cord injury (SCI). Effective analgesic therapy has been hampered by the lack of knowledge about the mechanisms underlying post-SCI neuropathic pain. Current evidence suggests GABAergic spinal nociceptive processing is a critical functional node in this complex phenotype, representing a potential target for therapeutic intervention. ⋯ Inhibition of NKCC1 with its potent antagonist bumetanide reduces pain behavior in rats following SCI. Moreover, the injured spinal cord tissues exhibit a significant transient upregulation of NKCC1 protein and a concurrent downregulation of KCC2 protein. Thus, imbalanced function of NKCC1 and KCC2 may contribute to the induction and maintenance of the chronic neuropathic pain following SCI.
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Ann. N. Y. Acad. Sci. · Apr 2010
ReviewProthymosin alpha as robustness molecule against ischemic stress to brain and retina.
Following stroke or traumatic damage, neuronal death via both necrosis and apoptosis causes loss of functions, including memory, sensory perception, and motor skills. As necrosis has the nature to expand, while apoptosis stops the cell death cascade in the brain, necrosis is considered to be a promising target for rapid treatment for stroke. We identified the nuclear protein, prothymosin alpha (ProTalpha) from the conditioned medium of serum-free culture of cortical neurons as a key protein-inhibiting necrosis. ⋯ In the ischemic brain or retina, ProTalpha showed a potent inhibition of both necrosis and apoptosis. By use of anti-brain-derived neurotrophic factor or anti-erythropoietin IgG, we found that ProTalpha inhibits necrosis, but causes apoptosis, which is in turn inhibited by ProTalpha-induced neurotrophins under the condition of ischemia. From the experiment using anti-ProTalpha IgG or antisense oligonucleotide for ProTalpha, it was revealed that ProTalpha has a pathophysiological role in protecting neurons in stroke.
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Fibromyalgia (FM) is a chronic pain syndrome characterized by widespread pain, fatigue, sleep alterations, and distress. Emerging evidence points toward augmented pain processing within the central nervous system as having a primary role in the pathophysiology of this disorder. Recent studies have identified distinct FM subgroups on the basis of clinical, neurochemical, and neuroendocrinological abnormalities, including increased cerebrospinal fluid levels of substance P and excitatory amino acids and functional abnormalities in the hypothalamic-pituitary-adrenal axis, and sympathoadrenal (autonomic nervous) system. ⋯ Antidepressants, nonsteroidal anti-inflammatory drugs, opioids, sedatives, muscle relaxants, and alpha2-delta agonists have all been used to treat FM with varying results. Physical exercise and multimodal cognitive-behavioral therapy seem to be the most widely accepted and beneficial forms of nonpharmacological therapy. Studies predicting treatment response indicate that it is useful if not essential to tailor the choice of treatment components to the needs of individual patients.