Bipolar Directional Deep Brain Stimulation in Essential and Parkinsonian Tremor.

Objective: To compare directional monopolar, bipolar, and directional bipolar thalamic deep brain stimulation (DBS) in tremor patients.

Methods: Fourteen tremor patients (7 Essential Tremor and 7 Parkinson's Disease) implanted with directional DBS electrodes in the ventral intermediate nucleus (VIM) were enrolled. Side-effect thresholds of monopolar directional stimulation (DIRECT) were compared to circular DBS as well as, in a randomized design, to those of two different bipolar stimulation settings (BIPOLAR = circular anode; BI-DIRECT = directional anode).

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.

Correlation between the effects of local and intracerebroventricular infusions of galanin on 5-HT release studied by microdialysis, and distribution of galanin and galanin receptors in prefrontal cortex, ventral hippocampus, amygdala, hypothalamus, and striatum of awake rats.

The neuropeptide galanin is implicated in regulation of affective behavior, including modulation of 5-HT signaling. Here, we investigated, by use of microdialysis in freely moving rats, the effects of intracerebral (i.c.

Functional genomics of the rat neuromedin U receptor 1 reveals a naturally occurring deleterious allele.

Neuromedin U (NMU) plays an important role in a number of physiological processes, but the relative contribution of its two known receptors, NMUR1 and NMUR2, is still poorly understood. Here we report the existence of a SNP T(1022)→A (Val(341)→Glu) in the third exon of the rat Nmur1 gene that leads to an inactive receptor. This SNP is present within the coding region of the highly conserved NPXXY motif found within all class A type G protein-coupled receptors and translates to an NMUR1 receptor that is not expressed on the cell surface.

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

Delta 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.

Morphine priming in rats with chronic inflammation reveals a dichotomy between antihyperalgesic and antinociceptive properties of deltorphin.

We previously showed that prolonged morphine treatment and chronic inflammation both enhanced delta opioid receptor (deltaOR) cell surface density in lumbar spinal cord neurons. Here, we sought to determine whether administration of morphine to rats with chronic inflammation would further increase the bio-availability of deltaOR, and thereby the analgesic properties of the deltaOR agonist deltorphin, over that produced by inflammation alone. We found that chronic inflammation produced by injection of complete Freund's adjuvant (CFA) into the hind paw resulted in a bilateral increase in the binding and internalization of fluorescent deltorphin in neurons of the lumbar spinal cord as did prolonged morphine treatment [Morinville A, Cahill CM, Aibak H, Rymar VV, Pradhan A, Hoffert C, Mennicken F, Stroh T, Sadikot AF, O'Donnell D, Clarke PB, Collier B, Henry JL, Vincent JP, Beaudet A (2004a) Morphine-induced changes in delta opioid receptor trafficking are linked to somatosensory processing in the rat spinal cord.

Differential distribution and regulation of galanin receptors- 1 and -2 in the rat lumbar spinal cord.

The expression of the galanin receptor-1 and -2 (Gal(1) and Gal(2)) messenger ribonucleic acids (mRNAs) was studied in the lower spinal cord of rat by means of in situ hybridization, using ribonucleic acid probes (riboprobes). Naïve rats as well as rats with unilateral axotomy of the sciatic nerve or unilateral inflammation of the hindpaw were analyzed. In naïve rats, numerous Gal(1) mRNA-positive (+) neurons were detected in lamina (L) I-III.

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 D2 and/or D4 receptors (clozapine, haloperidol, (+/-)-sulpiride, domperidone, clozapine, risperidone, chlorpromazine, (+)-butaclamol and L-741,742).

Morphine and pain-related stimuli enhance cell surface availability of somatic delta-opioid receptors in rat dorsal root ganglia.

The present study demonstrates that perikaryaldelta-opioid receptors (deltaORs) in rat dorsal root ganglion (DRG) neurons bind and internalize opioid ligands circulating in the CSF. Using confocal and electron microscopy, we found that prolonged morphine treatment increased the cell surface density of these perikaryal deltaORs and, by way of consequence, receptor-mediated internalization of the fluorescent deltorphin (DLT) analog omega-Bodipy 576/589 deltorphin-I 5-aminopentylamide (Fluo-DLT) in all three types of DRG neurons (small, medium, and large). In contrast, chronic inflammatory pain induced by the injection of complete Freund's adjuvant (CFA) into one hindpaw selectively increased Fluo-DLT internalization in small and medium-sized DRG neurons ipsilateral to the inflammation.

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.

Galanin increases membrane excitability and enhances Ca(2+) currents in adult, acutely dissociated dorsal root ganglion neurons.

We examined the effect of galanin (10(-15) - 10(-7) M) on dispersed, mainly small-sized dorsal root ganglion (DRG) neurons in adult rats using whole-cell patch-clamp. Galanin and AR-M1896, a selective galanin type 2 receptor (GalR2) agonist, both significantly increased the number of action potentials in response to current pulses in 77% of the neurons, indicating an increase in excitability. Galanin also caused a rise in input resistance, decreased the holding current for -60 mV and depolarized the resting potential.

Phylogenetic changes in the expression of delta opioid receptors in spinal cord and dorsal root ganglia.

To assess the validity of rodent models for investigating the role of delta opioid receptors (DOR) in analgesia, the distribution of DOR binding and mRNA were compared between rodent and primate spinal cord and dorsal root ganglia (DRG), using receptor autoradiography and in situ hybridization, respectively. In mouse and rat spinal cord, [(125)I]-deltorphin-labeled DOR binding sites were detected throughout the gray matter. In contrast, in primate and particularly in human spinal cord, DOR binding was mainly present in laminae I-II, with little to no binding in deeper layers.

Pro-nociceptive effects of neuromedin U in rat.

The neuropeptide neuromedin U (NMU) has been shown to have significant effects on cardiovascular, gastrointestinal and CNS functions. The peptide was first isolated from the porcine spinal cord and later shown to be present in spinal cords of other species. Little is known about the distribution of neuromedin U receptors (NMURs) in the spinal cord and the spinal action of the peptide.

Restricted distribution of galanin receptor 3 (GalR3) mRNA in the adult rat central nervous system.

Recent molecular cloning studies have established the existence of a third rat galanin receptor subtype, GalR3, however its precise distribution in the mammalian central nervous system (CNS) is not well established. In the present study, we examined the regional and cellular distribution of GalR3 mRNA in the CNS of the rat by in situ hybridization. Our findings indicate that GALR3 mRNA expression in the rat brain is discrete and highly restricted, concentrated mainly in the preoptic/hypothalamic area.

Amyloid beta peptide induces tau phosphorylation and loss of cholinergic neurons in rat primary septal cultures.

The neuropathological features associated with Alzheimer's disease (AD) brain include the presence of extracellular neuritic plaques composed of amyloid beta protein (Abeta), intracellular neurofibrillary tangles containing phosphorylated tau protein and the loss of basal forebrain cholinergic neurons which innervate regions such as the hippocampus and the cortex. Studies of the pathological changes that characterize AD and several other lines of evidence indicate that Abeta accumulation in vivo may initiate phosphorylation of tau protein, which by disrupting neuronal network may trigger the process of neurodegeneration observed in AD brains. However, the underlying cause of degeneration of the basal forebrain cholinergic neurons and their association, if any, to Abeta peptides or phosphorylated tau remains mostly unknown.

Systemic administration of kainic acid in adult rat stimulates expression of the chemokine receptor CCR5 in the forebrain.

As chemokines and their receptors are primarily expressed by glial cells in brain parenchyma, a model of glial cell proliferation may be useful to study the regulation of their expression in the brain. The well-established kainic acid seizure model was used in this study, focusing on the expression of the CCR5 chemokine receptor. Adult Sprague-Dawley rats were injected intraperitoneally with kainic acid (12 mg/kg), and in situ hybridization of CCR5 mRNA was performed at 12 h, 1, 3, or 7 days, posttreatment.

Nerve growth factor rapidly induces prolonged acetylcholine release from cultured basal forebrain neurons: differentiation between neuromodulatory and neurotrophic influences.

Long-term exposure to nerve growth factor (NGF) is well established to have neurotrophic effects on basal forebrain cholinergic neurons, but its potential actions as a fast-acting neuromodulator are not as well understood. We report that NGF (0.1-100 ng/ml) rapidly (<60 min) and robustly enhanced constitutive acetylcholine (ACh) release (148-384% of control) from basal forebrain cultures without immediate persistent increases in choline acetyltransferase activity.

Neurotrophins differentially enhance acetylcholine release, acetylcholine content and choline acetyltransferase activity in basal forebrain neurons.

Several lines of evidence indicate that nerve growth factor is important for the development and maintenance of the basal forebrain cholinergic phenotype. In the present study, using rat primary embryonic basal forebrain cultures, we demonstrate the differential regulation of functional cholinergic markers by nerve growth factor treatment (24--96 h). Following a 96-h treatment, nerve growth factor (1--100 ng/mL) increased choline acetyltransferase activity (168--339% of control), acetylcholine content (141--185%), as well as constitutive (148--283%) and K(+)-stimulated (162--399%) acetylcholine release, but increased release was not accompanied by increased high-affinity choline uptake.

Pharmacological characterization of endogenous acetylcholine release from primary septal cultures.

A detailed investigation of endogenous acetylcholine (ACh) release from primary embryonic septal cultures is described in this study. Applications of veratridine (25 microM) or increasing extracellular concentrations of K(+) (6-100 mM) induced robust increases of endogenous ACh release ( approximately 500-15,000 fmol/well/10 min). Release stimulated with K(+) (25 mM) was sustainable and did not differ significantly over 180 min.

Chemokines and chemokine receptors in the CNS: a possible role in neuroinflammation and patterning.

Chemokines constitute a growing family of structurally and functionally related small (8-10 kDa) proteins associated with inflammatory-cell recruitment in host defence. In addition to their well-established role in the immune system, recent data suggest their involvement in the maintenance of CNS homeostasis, in neuronal patterning during ontogeny and as potential mediators of neuroinflammation, playing an essential role in leukocyte infiltration into the brain. Chemokines and their G protein-coupled receptors are constitutively expressed at low-to-negligible levels in various cell types in the brain.

Interleukin-2 increases choline acetyltransferase activity in septal-cell cultures.

Interleukin-2 (IL-2) is a potent modulator of in vitro acetylcholine release in hippocampal slices [Hanisch et al. (1993) J. Neurosci.

The neonatal lesion of the meso-telencephalic dopaminergic pathway increases intrastriatal D2 receptor levels and synthesis and this effect is reversed by neonatal dopaminergic rich-graft.

The ascending dopaminergic pathway of 3-day-old rats has been unilaterally destroyed by the injection of 6-hydroxydopamine into the lateral hypothalamus. Five days later, a suspension containing embryonic dopaminergic neurones was injected in the lesioned neostriatum. Rotational responses to dopaminergic agonists were tested eight months after grafting and animals were killed one month later.

Transplantation of fetal nigral cells reverses the increase of preproenkephalin mRNA levels in the rat striatum caused by 6-OHDA lesion of the dopaminergic nigrostriatal pathway: a quantitative in situ hybridization study.

Unilateral 6-hydroxydopamine (6-OHDA)-induced lesion of the nigrostriatal dopamine (DA) pathway causes a significant increase of preproenkephalin (PPE) messenger RNA (mRNA) levels in the DA-depleted striatum in rat brain. Using an in situ hybridization (ISH) technique and computer-assisted microdensitometry, we quantified the changes in PPE mRNA levels in the striatum. Seven months after lesion, levels of PPE mRNA were 75% higher in the DA-depleted striatum than in the contralateral control striatum of the same animal or in the striatum of sham control animals.

Intrastriatal transplants of embryonic dopaminergic neurons counteract the increase of striatal enkephalin immunostaining but not serotoninergic sprouting elicited by a neonatal lesion of the nigrostriatal dopaminergic pathway.

The aim of the our experiment was to compare the ability of intrastriatal implants of embryonic dopaminergic neurons to reverse two kinds of postlesion modification in the host brain: the change in the activity level of neurons in the denervated area and morphological modifications, e.g. collateral sprouting.