Prototypical antipsychotic drugs protect hippocampal neuronal cultures against cell death induced by growth medium deprivation

BACKGROUND: Several clinical studies suggested that antipsychotic-based medications could ameliorate cognitive functions impaired in certain schizophrenic patients. Accordingly, we investigated the effects of various dopaminergic receptor antagonists – including atypical antipsychotics that are prescribed for the treatment of schizophrenia – in a model of toxicity using cultured hippocampal neurons, the hippocampus being a region of particular relevance to cognition. RESULTS: Hippocampal cell death induced by deprivation of growth medium constituents was strongly blocked by drugs including antipsychotics (10(-10)-10(-6 )M) that display nM affinities for D(2 )and/or D(4 )receptors (clozapine, haloperidol, (±)-sulpiride, domperidone, clozapine, risperidone, chlorpromazine, (+)-butaclamol and L-741,742). These effects were shared by some caspases inhibitors and were not accompanied by inhibition of reactive oxygen species. In contrast, (-)-raclopride and remoxipride, two drugs that preferentially bind D(2 )over D(4 )receptors were ineffective, as well as the selective D(3 )receptor antagonist U 99194. Interestingly, (-)-raclopride (10(-6 )M) was able to block the neuroprotective effect of the atypical antipsychotic clozapine (10(-6 )M). CONCLUSION: Taken together, these data suggest that D2-like receptors, particularly the D(4 )subtype, mediate the neuroprotective effects of antipsychotic drugs possibly through a ROS-independent, caspase-dependent mechanism

Dissociation of the opioid receptor mechanisms that control mechanical and heat pain.

International audienceDelta and mu opioid receptors (DORs and MORs) are inhibitory G protein-coupled receptors that reportedly cooperatively regulate the transmission of pain messages by substance P and TRPV1-expressing pain fibers. Using a DOReGFP reporter mouse we now show that the DOR and MOR are, in fact, expressed by different subsets of primary afferents. The MOR is expressed in peptidergic pain fibers, the DOR in myelinated and nonpeptidergic afferents. Contrary to the prevailing view, we demonstrate that the DOR is trafficked to the cell surface under resting conditions, independently of substance P, and internalized following activation by DOR agonists. Finally, we show that the segregated DOR and MOR distribution is paralleled by a remarkably selective functional contribution of the two receptors to the control of mechanical and heat pain, respectively. These results demonstrate that behaviorally relevant pain modalities can be selectively regulated through the targeting of distinct subsets of primary afferent pain fibers

Prototypical antipsychotic drugs protect hippocampal neuronal cultures against cell death induced by growth medium deprivation-1

<p><b>Copyright information:</b></p><p>Taken from "Prototypical antipsychotic drugs protect hippocampal neuronal cultures against cell death induced by growth medium deprivation"</p><p>BMC Neuroscience 2006;7():28-28.</p><p>Published online 30 Mar 2006</p><p>PMCID:PMC1448194.</p><p>Copyright © 2006 Bastianetto et al; licensee BioMed Central Ltd.</p> three separate experiments, each performed in quadruplicate. *p < 0.05, **p < 0.01 compared to vehicle-treated groups

Prototypical antipsychotic drugs protect hippocampal neuronal cultures against cell death induced by growth medium deprivation-0

<p><b>Copyright information:</b></p><p>Taken from "Prototypical antipsychotic drugs protect hippocampal neuronal cultures against cell death induced by growth medium deprivation"</p><p>BMC Neuroscience 2006;7():28-28.</p><p>Published online 30 Mar 2006</p><p>PMCID:PMC1448194.</p><p>Copyright © 2006 Bastianetto et al; licensee BioMed Central Ltd.</p>esence or absence of reverse transcriptase, respectively. The two hippocampal cultures gave identical results. Expected size for PCR products: D1, 300 bp; D2, 538 bp and 451 bp; D3, 523 bp and 410 bp; D4, 324 bp; D5, 403 bp. Lane M, molecular size standard 100-bp ladder

Prototypical antipsychotic drugs protect hippocampal neuronal cultures against cell death induced by growth medium deprivation-2

<p><b>Copyright information:</b></p><p>Taken from "Prototypical antipsychotic drugs protect hippocampal neuronal cultures against cell death induced by growth medium deprivation"</p><p>BMC Neuroscience 2006;7():28-28.</p><p>Published online 30 Mar 2006</p><p>PMCID:PMC1448194.</p><p>Copyright © 2006 Bastianetto et al; licensee BioMed Central Ltd.</p> three separate experiments, each performed in quadruplicate

The Nonlinear Eigenvalue Problem

Nonlinear eigenvalue problems arise in a variety of science and engineering applications and in the past ten years there have been numerous breakthroughs in the development of numerical methods. This article surveys nonlinear eigenvalue problems associated with matrix-valued functions which depend nonlinearly on a single scalar parameter, with a particular emphasis on their mathematical properties and available numerical solution techniques. Solvers based on Newton's method, contour integration, and sampling via rational interpolation are reviewed. Problems of selecting the appropriate parameters for each of the solver classes are discussed and illustrated with numerical examples. This survey also contains numerous MATLAB code snippets that can be used for interactive exploration of the discussed methods

Morphine-induced changes in delta opioid receptor trafficking are linked to somatosensory processing in the rat spinal cord.

An in vivo fluorescent deltorphin (Fluo-DLT) internalization assay was used to assess the distribution and regulation of pharmacologically available delta opioid receptors (deltaORs) in the rat lumbar (L4-5) spinal cord. Under basal conditions, intrathecal injection of Fluo-DLT resulted in the labeling of numerous deltaOR-internalizing neurons throughout dorsal and ventral horns. The distribution and number of Fluo-DLT-labeled perikaryal profiles were consistent with that of deltaOR-expressing neurons, as revealed by in situ hybridization and immunohistochemistry, suggesting that a large proportion of these cells was responsive to intrathecally administered deltaOR agonists. Pretreatment of rats with morphine for 48 hr resulted in a selective increase in Fluo-DLT-labeled perikaryal profiles within the dorsal horn. These changes were not accompanied by corresponding augmentations in either deltaOR mRNA or (125)I-deltorphin-II binding levels, suggesting that they were attributable to higher densities of cell surface deltaOR available for internalization rather than to enhanced production of the receptor. Unilateral dorsal rhizotomy also resulted in increased Fluo-DLT internalization in the ipsilateral dorsal horn when compared with the side contralateral to the deafferentation or to non-deafferented controls, suggesting that deltaOR trafficking in dorsal horn neurons may be regulated by afferent inputs. Furthermore, morphine treatment no longer increased Fluo-DLT internalization on either side of the spinal cord after unilateral dorsal rhizotomy, indicating that microOR-induced changes in the cell surface availability of deltaOR depend on the integrity of primary afferent inputs. Together, these results suggest that regulation of deltaOR responsiveness through microOR activation in this region is linked to somatosensory information processing

Article Delta Opioid Receptors Presynaptically Regulate Cutaneous Mechanosensory Neuron Input to the Spinal Cord Dorsal Horn

International audienceCutaneous mechanosensory neurons detect mechanical stimuli that generate touch and pain sensation. Although opioids are generally associated only with the control of pain, here we report that the opioid system in fact broadly regulates cutaneous mecha-nosensation, including touch. This function is predominantly subserved by the delta opioid receptor (DOR), which is expressed by myelinated mecha-noreceptors that form Meissner corpuscles, Merkel cell-neurite complexes, and circumferential hair follicle endings. These afferents also include a small population of CGRP-expressing myelinated noci-ceptors that we now identify as the somatosensory neurons that coexpress mu and delta opioid receptors. We further demonstrate that DOR activation at the central terminals of myelinated mechanorecep-tors depresses synaptic input to the spinal dorsal horn, via the inhibition of voltage-gated calcium channels. Collectively our results uncover a molecular mechanism by which opioids modulate cuta-neous mechanosensation and provide a rationale for targeting DOR to alleviate injury-induced mechanical hypersensitivity

Delta opioid receptors presynaptically regulate cutaneous mechanosensory neuron input to the spinal cord dorsal horn.

Cutaneous mechanosensory neurons detect mechanical stimuli that generate touch and pain sensation. Although opioids are generally associated only with the control of pain, here we report that the opioid system in fact broadly regulates cutaneous mechanosensation, including touch. This function is predominantly subserved by the delta opioid receptor (DOR), which is expressed by myelinated mechanoreceptors that form Meissner corpuscles, Merkel cell-neurite complexes, and circumferential hair follicle endings. These afferents also include a small population of CGRP-expressing myelinated nociceptors that we now identify as the somatosensory neurons that coexpress mu and delta opioid receptors. We further demonstrate that DOR activation at the central terminals of myelinated mechanoreceptors depresses synaptic input to the spinal dorsal horn, via the inhibition of voltage-gated calcium channels. Collectively our results uncover a molecular mechanism by which opioids modulate cutaneous mechanosensation and provide a rationale for targeting DOR to alleviate injury-induced mechanical hypersensitivity