Neuroscience
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Excess glutamate release and stimulation of post-synaptic glutamatergic receptors have been implicated in the pathophysiology of many neurological diseases. The hippocampus, and the pyramidal cell layer of the cornu ammonus 1 (CA1) region in particular, has been noted for its selective sensitivity to excitotoxic insults. The current studies examined the role of N-methyl-D-aspartate (NMDA) receptor subunit composition and sensitivity to stimulatory effects of the polyamine spermidine, an allosteric modulator of NMDA NR2 subunit activity, in hippocampal CA1 region sensitivity to excitotoxic insult. ⋯ The addition of spermidine significantly potentiated [(125)I]MK-801 binding and neurodegeneration induced by exposure to a non-toxic concentration of NMDA, exclusively in the CA1 region. This neurodegeneration was markedly reduced with co-exposure to ifenprodil. These data suggest that selective sensitivity of the CA1 region to excitotoxic stimuli may be attributable to the density of mature neurons expressing polyamine-sensitive NR2B polypeptide subunits.
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This study assessed the possible antinociceptive role of peripheral 5-HT(1) receptor subtypes in the rat formalin test. Rats were injected into the dorsum of the hind paw with 50 microl of diluted formalin (1%). Nociceptive behavior was quantified as the number of flinches of the injected paw. ⋯ The above antagonists did not produce any effect by themselves. These results suggest that peripheral activation of the 5-HT(1A,) 5-HT(1B), 5-HT(1D), 5-HT(1F) and, probably, 5-HT(1E) receptor subtypes leads to antinociception in the rat formalin test. Thus, the use of selective 5-HT(1) receptor agonists could be a therapeutic strategy to reduce inflammatory pain.
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Morphine-3-glucoronide (M3G) is a major morphine metabolite detected in cerebrospinal fluid of humans receiving systemic morphine. M3G has little-to-no affinity for opioid receptors and induces pain by unknown mechanisms. The pain-enhancing effects of M3G have been proposed to significantly and progressively oppose morphine analgesia as metabolism ensues. ⋯ Providing further evidence of proinflammatory activation, M3G upregulated TLR4 and CD11b (microglial/macrophage activation marker) mRNAs in dorsal spinal cord as well as IL-1 protein in the lumbosacral cerebrospinal fluid. Finally, in silico and in vivo data support that the glucuronic acid moiety is capable of inducing TLR4/MD-2 activation and enhanced pain. These data provide the first evidence for a TLR4 and IL-1 mediated component to M3G-induced effects, likely of at least microglial origin.
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Synphilin-1 is a cytoplasmic protein with unclear function. Synphilin-1 has been identified as an interaction partner of alpha-synuclein. The interaction between synphilin-1 and alpha-synuclein has implications in Parkinson's disease. ⋯ We found that Rotenone induced apoptotic cell death in N1E-115 cells via caspase-3 activation and poly (ADP-ribose) polymerase (PARP) cleavage. Overexpression of synphilin-1 significantly reduced Rotenone-induced cell death, caspase-3 activation and PARP cleavage. The results indicate that synphilin-1 displays trophic and protective effects in vitro, suggesting that synphilin-1 may play a protective role in Parkinson's disease (PD) pathogenesis and may lead to a potential therapeutic target for PD intervention.
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Subcutaneous injection of the peptide endothelin-1 (ET-1) into the rat's footpad is known to cause rapid, transient ipsilateral mechanical and thermal sensitization and nocifensive hind paw flinching. Here we report that local injection of ET-1 (2 nmoles) into one hind paw slowly sensitizes the contralateral paw to chemical and mechanical stimulation. There was a 1.5-2-fold increase in the hind paw flinching response, over that from the first injection, to a second injection of the same dose of ET-1 delivered 24 h later into the contralateral paw. ⋯ ET-1 injected s.c. at a segmentally unrelated location, the nuchal midline, caused no sensitization of the paws, obviating a systemic route of action. Local anesthetic block of the ipsilateral sciatic nerve during the period of initial response to ipsilateral ET-1 prevented contralateral sensitization, indicating the importance of local afferent transmission, although ipsilateral desensitization was not changed. These findings suggest that peripheral ET-1 actions lead to central sensitization that alters responses to selected stimuli.