Neuroscience
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It is well known that neurons in the rostral ventromedial medulla (RVM) are involved in descending modulation of nociceptive transmission in the spinal cord. It has been shown that activation of neurokinin-1 receptors (NK-1Rs) in the RVM, which are presumably located on pain facilitating ON cells, produces hyperalgesia whereas blockade of NK-1Rs attenuates hyperalgesia. To obtain a better understanding of the functions of NK-1R expressing neurons in the RVM, we selectively ablated these neurons by injecting the stable analog of substance P (SP), Sar(9),Met(O2)(11)-Substance P, conjugated to the ribosomal toxin saporin (SSP-SAP) into the RVM. ⋯ SSP-SAP did not alter withdrawal responses to mechanical or heat stimuli under normal conditions, and did not alter analgesia produced by morphine administered into the RVM. In contrast, the duration of nocifensive behaviors produced by capsaicin and mechanical and heat hyperalgesia produced by capsaicin and CFA were decreased in rats pretreated with SSP-SAP as compared to those that received Blank-SAP. These data support our earlier studies using NK-1R antagonists in the RVM and demonstrate that RVM neurons that possess the NK-1R do not play a significant role in modulating acute pain or morphine analgesia, but rather are involved in pain facilitation and the development and maintenance of hyperalgesia.
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Certain patterns of neural activity can induce N-methyl-D-aspartic acid receptor (NMDAR)-dependent synaptic plasticity, one of the important foundations of memory. Here, we report that a patterned high-frequency stimulation (PHS) induces rat hippocampal long-term depression (LTD) in an NMDAR-independent manner that requires coactivation of GABA(A)Rs and muscarinic acetylcholine receptors (mAChRs), and endocytosis of AMPARs. Thus, we disclose that a patterned high-frequency stimulation triggers GABAAR and mAChR-dependent LTD in the hippocampus.
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β-Amyloid (Aβ) peptides are derived from the sequential cleavage of the amyloid precursor protein (APP). They are enriched in plaques present in Alzheimer's brains and thus play important roles in the pathogenesis of this disease. APP is also known to be expressed in the neurons of dorsal root ganglion (DRG) and contributes to neuronal survival and axonal growth during development. ⋯ In parallel with reduced pain sensitivity, the expression of pain mediators such as substance P, calcitonin gene-related peptide and transient receptor potential vanilloid-1 was significantly reduced in L4-6 DRG of CRND8 mice. Although i.pl. injection of CFA induced a rather similar pattern of inflammatory pain in 3-month-old CRND8 mice and their wild-type littermates, recovery from inflammatory pain seemed faster in 12-month-old CRND8 mice than wild-type mice. These findings suggest that APP and Aβ peptides suppress both nociception and inflammatory pain and are likely involved in blunt pain perception of Alzheimer's patients in clinical settings.
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Focal cortical injuries are well known to cause changes in function and excitability of the surviving cortical areas but the cellular correlates of these physiological alterations are not fully understood. In the present study we employed a well established ex vivo-in vitro model of focal laser lesions in the rat visual cortex and we studied membrane and firing properties of the surviving layer 2/3 pyramidal neurons. Patch-clamp recordings, performed in the first week post-injury, revealed an increased input resistance, a depolarized spike threshold as well as alterations in the firing pattern of neurons in the cortex ipsilateral to the lesion. ⋯ Conversely, application of glutamatergic or GABAA receptor blockers reduced the observed alterations and GABAB receptor blockers abolished the differences completely. All together the present findings suggest that changes in synaptic receptors function, following focal cortical injuries, can modulate membrane and firing properties of layer 2/3 pyramidal neurons. This previously unknown functional interplay between synaptic and membrane properties may constitute a novel cellular mechanism to explain alterations in neuronal network function and excitability following focal cortical injuries.
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Recombinant tissue-type plasminogen activator (rt-PA) is the mainstay of acute stroke treatment and the only approved medical therapy so far. Because of its fibrinolytic action, it is presumed to aggravate intracerebral hemorrhage (ICH). Since clinical features do not discriminate between ischemic stroke and ICH, brain imaging is strictly required before the initiation of thrombolysis. ⋯ In the 72 h observation, there was also no difference in functional outcome and hematoma volume. In our experimental study, we were not able to demonstrate that peracute rt-PA treatment in (primary) ICH has detrimental effects on hematoma expansion, hematoma volume or functional outcome. This finding needs careful consideration in future translational studies.