Neuroscience
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Spinal norepinephrine release and activation of spinal alpha(2)-adrenergic receptors represent important components of descending control of nociception. Recent studies have shown that nitric oxide is capable of stimulating neuronal norepinephrine release in the presence of thiol-containing compounds such as L-cysteine. In the present study, we tested a hypothesis in a rodent model of neuropathic pain that intrathecal injection of the nitric oxide donor S-nitroso-N-acetylpenicillamine and L-cysteine produces an antiallodynic action mediated by the spinal alpha(2)-adrenergic receptors. ⋯ Furthermore, the antiallodynic effect produced by intrathecal injection of a combination of S-nitroso-N-acetylpenicillamine and L-cysteine was abolished by pretreatment with intrathecal injection of a non-specific alpha-adrenergic receptor antagonist, phentolamine, or an alpha(2) receptor antagonist, idazoxan. This study provides the first functional evidence that spinal nitric oxide interacts with the thiol-containing compounds to produce an antiallodynic effect in neuropathic pain. We propose that such an action is mediated by endogenous norepinephrine and spinal alpha(2)-adrenergic receptors.
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For 11 AD cases and four normal elderly controls, post mortem volumes of the hippocampal subdivisions were calculated by using magnetic resonance imaging and histological sections. After at least six weeks of fixation in formalin, brains were examined on a 1.5-T Philips Gyroscan imager producing T1-weighted coronal images with a 3-mm slice thickness. Brains were then processed and embedded in paraffin. ⋯ Strong correlations between the magnetic resonance imaging subvolumes and neuronal counts were found for the hippocampus (r = 0.90, P < 0.001) and the hippocampus/subiculum subvolume (r = 0.84, P < 0.001). We conclude that very accurate volumetric measurements of the whole hippocampal formation can be obtained by using a magnetic resonance imaging protocol. Moreover, the strong correlations between magnetic resonance imaging-based hippocampal volumes and neuronal numbers suggest the anatomical validity of magnetic resonance imaging volume measurements.
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GABA(A) receptors are ligand-operated chloride channels assembled from five subunits in a heteropentameric manner. Using immunocytochemistry, we investigated the distribution of GABA(A) receptor subunits deriving from 13 different genes (alpha1-alpha6, beta1-beta3, gamma1-gamma3 and delta) in the adult rat brain. Subunit alpha1-, beta1-, beta2-, beta3- and gamma2-immunoreactivities were found throughout the brain, although differences in their distribution were observed. ⋯ In most pontine and cranial nerve nuclei and in the medulla, only subunit alpha1-, beta2- and gamma2-immunoreactivities were strong, whereas the inferior olive was significantly labeled only for subunits beta1, gamma1 and gamma2. In this study, a highly heterogeneous distribution of 13 different GABA(A) receptor subunit-immunoreactivities was observed. This distribution and the apparently typical patterns of co-distribution of these GABA(A) receptor subunits support the assumption of multiple, differently assembled GABA(A) receptor subtypes and their heterogeneous distribution within the adult rat brain.
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The effects of group II and group III metabotropic glutamate receptor agonists on synaptic responses evoked by primary afferent stimulation in the dorsal horn, but mostly substantia gelatinosa, neurons were studied in the spinal cord slice preparation using conventional intracellular recording technique. Bath application of a potent metabotropic glutamate receptor 2- and 3-selective agonist (2S,1'R,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl) glycine reversibly suppressed monosynaptic and polysynaptic excitatory postsynaptic potentials evoked by A primary afferent fibers stimulation, the effect likely mediated by mGlu3 receptor subtype. This suppressing effect of (2S,1'R,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl) glycine on primary afferent neurotransmission was dose dependent and reduced by (S)-alpha-ethylglutamate, a group II metabotropic glutamate receptor antagonist. (2S,1'R,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl) glycine suppressed excitatory postsynaptic potentials without inducing detectable changes of postsynaptic membrane potential and neuronal input resistance in dorsal horn neurons. ⋯ A clear facilitation of the (S)-2-amino-4-phosphonobutanoate-induced depression of monosynaptic and polysynaptic excitatory postsynaptic potentials in the absence of gamma-aminobutyric acid-subtype A receptor- and glycine-mediated synaptic inhibition was shown. Besides the depressant effect on excitatory synaptic transmission, inhibitory actions of group II and III metabotropic glutamate receptor agonists on the inhibitory postsynaptic potentials evoked by primary afferent stimulation in dorsal horn neurons were observed. These results suggest that group II and group III metabotropic glutamate receptors are expressed at primary afferent synapses in the dorsal horn region, and activation of the receptors suppresses synaptic transmission by an action on the presynaptic site.
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Following cholinergic denervation of the hippocampus by medial septal lesions, an unusual neuronal reorganization occurs in which peripheral adrenergic fibers arising from superior cervical ganglia grow into the hippocampus (hippocampal sympathetic ingrowth). Recent studies suggest that a similar process, in which sympathetic noradrenergic axons invade the hippocampus, can occur in Alzheimer's disease patients. In the last few years, the occurrence of apoptotic cell death has been studied in Alzheimer's disease patients and in animal models of this disorder. ⋯ The cytosolic expression of bcl-x was increased in hippocampal sympathetic ingrowth compared to control and cholinergic denervation. The cytosolic activity of caspase-3 appeared to be significantly decreased in hippocampal sympathetic ingrowth and increased in cholinergic denervation groups compared to control and cholinergic denervation/hippocampal sympathetic ingrowth, respectively. From the present results, we suggest that cholinergic denervation may be responsible for pro-apoptotic responses, while hippocampal sympathetic ingrowth may protect neurons from apoptosis in rat dorsal hippocampus.