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PubMed1997

Clinical evidence for a neuromodulator action of endothelin in the hypothalamic-pituitary-adrenal axis in man.

In order to investigate whether the ubiquitous signalling peptide endothelin might also act as a neuromodulator in the stimulation of the hypothalamic-pituitary-adrenal axis, 15 patients (4 female, 11 male, aged 35-67 years) with hypopituitarism were investigated and the results were compared to those of 8 healthy male volunteers (aged 24-31 years). Patients and controls received double-blind in random order either 0.1 IE per kg body weight regular insulin (insulin induced hypoglycemia) or 1 ml 0.9% sodium chloride (placebo) on 2 separate days. Control subjects only received on an additional day 0.1 IE per kg body weight regular insulin plus glucose 10% (euglycemic hyperinsulinemic glucose clamp). In control subjects hypoglycemia resulted in a significant increase in adrenocorticotropin (ACTH) and cortisol which was preceded by an increase in circulating endothelin levels (p < 0.01 vs placebo and euglycemic clamp) while endothelin, ACTH and cortisol remained unchanged both after placebo and in the euglycemic hyperinsulinemic clamp. In contrast, patients with hypopituitarism showed neither changes in circulating endothelin levels nor a stimulation of the hypothalamic-pituitary-adrenal axis during insulin-induced hypoglycemia. These data demonstrate that 1) endothelin levels are enhanced by metabolic stress 2) the responsiveness of endothelin levels to metabolic stress is linked to the presence of an intact pituitary gland and 3) endothelin might be involved in the stimulation of the hypothalamic-pituitary-adrenal axis.

Adrenocorticotropic Hormone↗

PubMed1999

The canine sympathetic neuropeptide galanin: a neurotransmitter in pancreas, a neuromodulator in liver.

Our laboratory has investigated the role of the neuropeptide galanin in the sympathetic neural control of both the canine endocrine pancreas and liver. Galanin mRNA and peptide were found in the neuronal cell bodies of the celiac ganglion, which projects fibers to both organs. Galanin fibers formed dense networks around the islets. Galanin was released from these nerves and the amount released appeared sufficient to markedly inhibit basal insulin secretion. We therefore propose that galanin is a sympathetic neurotransmitter in canine endocrine pancreas. Galanin was also found in hepatic nerves usually co-localized with tyrosine hydroxylase, a sympathetic marker. Further, intraportal administration of the sympathetic neurotoxin, 6-hydroxydopamine, abolished galanin staining in the hepatic parenchyma. We evaluated the role of galanin in mediating the actions of sympathetic nerves to increase hepatic glucose production and decrease hepatic arterial conductance. Local infusion of synthetic galanin had little effect by itself, but it did potentiate the action of norepinephrine to stimulate hepatic glucose production, demonstrating a neuromodulatory action. In contrast, galanin had no effect on hepatic arterial blood flow. We therefore propose that in the liver galanin functions as a neuromodulator of norepinephrine's metabolic action.

Animals↗

PubMed1979

Prostaglandin D2, a neuromodulator.

The distribution of prostaglandin D synthetase activity was determined in various tissues of rat by using the supernatant fraction (10,000 x g, 20 min) of the homogenates. The highest activity was found in brain, spinal cord, and alimentary tract. The activity was uniquitously distributed in all parts of brain, and the highest specific activity was found in hypothalamus and thalamus. Homogenates of two neuroblastoma cell lines were found to produce prostaglandin D2, whereas a glioma cell line was almost inactive. Prostaglandin D2 is a potent and specific activator of the adenylate cyclase system of cultured neuroblastoma cells, suggesting the possibility that it may act as a neuromodulator in the central nervous system.

Animals↗

PubMed1994

N- and P-type Ca2+ channels are involved in acetylcholine release at a neuroneuronal synapse: only the N-type channel is the target of neuromodulators.

Cholinergic transmission in an identified neuro-neuronal synapse of the Aplysia buccal ganglion was depressed by application of a partially purified extract of the funnel-web-spider venom (FTx) or of its synthetic analog (sFTx). This specific blocker of voltage-dependent P-type Ca2+ channels did not interfere with the effect of the N-type Ca2+ channel blocker omega-conotoxin, which could further decrease synaptic transmission after a previous application of FTx. Similar results were obtained when the reversal order of application of these two Ca2+ channel blockers was used. Both P- and N-type Ca2+ currents trigger acetylcholine release in the presynaptic neuron. The neuromodulatory effects of FMRF-amide, histamine, and buccalin on transmitter release disappeared after the blockade of the N-type Ca2+ channels but remained still effective in the presence of FTx. These results indicate that only N-type Ca2+ channels appear to be sensitive to the neuromodulators we have identified.

Acetylcholine↗

PubMed2004

Production of the neuromodulator H2S by cystathionine beta-synthase via the condensation of cysteine and homocysteine.

Hydrogen sulfide (H2S) has been observed in relatively high concentrations in the mammalian brain and has been shown to act as a neuromodulator. However, there is confusion in the literature regarding the actual source of H2S production. Reactions catalyzed by the cystathionine beta-synthase enzyme (CBS) are one possible source for the production of H2S. Here we show that the CBS enzyme can efficiently produce H2S via a beta-replacement reaction in which cysteine is condensed with homocysteine to form cystathionine and H2S. The production of H2S by this reaction is at least 50 times more efficient than that produced by hydrolysis of cysteine alone via beta-elimination. Kinetic studies demonstrate that the Km and Kcat for cysteine is 3-fold higher and 2-fold lower, respectively, than that for serine. Consistent with these data, in vitro reconstitution studies show that at physiologically relevant concentrations of serine, homocysteine, and cysteine, about 5% of the cystathionine formed is from cysteine. We also show that AdoMet stimulates this H2S producing reaction but that there is no evidence for stimulation by calcium and calmodulin as reported previously. In summary, these results confirm the ability of CBS to produce H2S, but show in contrast to prior reports that the major mechanism is via beta-replacement and not cysteine hydrolysis. In addition, these studies provide a biochemical explanation for the previously inexplicable homocysteine-lowering effects of N-acetylcysteine treatments in humans.

Calcium↗

PubMed1996

Angiotensin II regulation of neuromodulation: downstream signaling mechanism from activation of mitogen-activated protein kinase.

Angiotensin II (Ang II) stimulates expression of tyrosine hydroxylase and norepinephrine transporter genes in brain neurons; however, the signal-transduction mechanism is not clearly defined. This study was conducted to determine the involvement of the mitogen-activated protein (MAP) kinase signaling pathway in Ang II stimulation of these genes. MAP kinase was localized in the perinuclear region of the neuronal soma. Ang II caused activation of MAP kinase and its subsequent translocation from the cytoplasmic to nuclear compartment, both effects being mediated by AT1 receptor subtype. Ang II also stimulated SRE- and AP1-binding activities and fos gene expression and its translocation in a MAP kinase-dependent process. These observations are the first demonstration of a downstream signaling pathway involving MAP kinase in Ang II-mediated neuromodulation in noradrenergic neurons.

Angiotensin II↗

PubMed1989

Atrial natriuretic factor: neuromodulator of the central nervous system regulation of blood pressure.

Extensive examination in the mammalian brain for the presence of atrial natriuretic factors (ANF) has revealed both peptide and receptors specifically distributed throughout the central nervous system. High concentrations of ANF have been found in several hypothalamic nuclei, septal areas, the anteroventral third ventricular area (AV3V), and the median eminence, whereas moderate concentrations have been detected in the circumventricular organs and several brainstem nuclei. The receptors for ANF have been found in moderate to high concentrations in the olfactory lobe, AV3V region, and several circumventricular organs (subfornical organ, organum vasculosum of the lamina terminalis) as well as the nucleus tractus solitarius, median eminence, and choroid plexus. These findings suggest a role for ANF in modulating fluid and electrolyte balance, and blood pressure in this compartment, analogous to the proposed actions of this peptide hormone in the periphery. To determine whether ANF might function as a neuromodulator of blood pressure, we administered ANF via fourth ventricular injection into the brain of hypertensive (SHR) and normotensive rats (WKY). Atrial natriuretic factor caused a moderate and significant decrease in mean arterial blood pressure in both strains. The action of ANF appeared to be mediated by activating the central alpha 2-adrenergic nervous system, probably through the release of catecholamines. Further, a dependence on the secretion and action of an endogenous opioid was probably involved; heart rate was unaffected in these studies. Experiments from other laboratories indicate that central ANF may modulate the pressor effects of centrally acting angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2001

Neuromodulation for chronic refractory angina.

Neuromodulation is the use of therapies which alter the relationship between the heart, its autonomic innervation and the central nervous system with the objective of reducing the ischaemic burden and diminishing the perception of angina.

Angina Pectoris↗

PubMed2003

Central neuromodulation in chronic migraine patients with suboccipital stimulators: a PET study.

Electrical stimulation of primary sensory afferents is known to have an antinociceptive effect. Animal and functional imaging studies suggest a role for supraspinal structures in this response. Eight patients with chronic migraine (> or =15 days per month of attacks of migraine without aura), who had shown a marked beneficial response to implanted bilateral suboccipital stimulators, were studied. Stimulation evoked local paraesthesia, the presence of which was a criterion of pain relief. On stimulation, the headache began to improve instantaneously and was completely suppressed within 30 min. On switching off the stimulation, the headache recurred instantly and peaked within 20 min. PET scans were performed using regional cerebral blood flow (rCBF) as a marker of neuronal activity. Each patient was scanned in the following three states: (1) stimulator at optimum settings: patient pain-free but with paraesthesia; (2) stimulator off: patient in pain and no paraesthesia; (3) stimulator partially activated: patient with intermediate levels of pain and paraesthesia. All scans were processed and analysed using Statistical Parametric Mapping (SPM) 99. There were significant changes in rCBF in the dorsal rostral pons, anterior cingulate cortex (ACC) and cuneus, correlated to pain scores, and in the ACC and left pulvinar, correlated to stimulation-induced paraesthesia scores. The activation pattern in the dorsal rostral pons is highly suggestive of a role for this structure in the pathophysiology of chronic migraine. The localization and persistence of activity during stimulation is exactly consistent with a region activated in episodic migraine, and with the persistence of activation of that area after successful treatment. The dorsal rostral pons may be a locus of neuromodulation by suboccipital stimulation. In addition, suboccipital stimulation modulated activity in the left pulvinar.

Adult↗

PubMed2003

Carnitine: a neuromodulator in aged rats.

A wide range of morphological and biochemical changes occur in the central nervous system with increasing age. L-carnitine, a naturally occurring compound, plays a vital role in fatty acid transport across the mitochondrial membrane. L-carnitine (300 mg/kg body wt/day) was administered intraperitoneally to young and old male Wistar rats for 7, 14, and 21 days. Carnitine, dopamine, epinephrine, and serotonin levels were assayed in discrete regions of the brain. Carnitine supplementation increased the levels of dopamine, epinephrine, and serotonin in the experimental animals in our study. Response to carnitine supplementation varied among the brain regions that have been studied. The regions rich in cholinergic neurons such as the cortex, hippocampus, and striatum showed more response after 21 days of carnitine treatment. The results of the present study suggest the role of L-carnitine as a neuromodulator and antiaging medication.

Aging↗

PubMed2003

Identification of SLURP-1 as an epidermal neuromodulator explains the clinical phenotype of Mal de Meleda.

Mal de Meleda is an autosomal recessive inflammatory and keratotic palmoplantar skin disorder due to mutations in the ARS B gene, encoding for SLURP-1 (secreted mammalian Ly-6/uPAR-related protein 1). SLURP-1 belongs to the Ly-6/uPAR superfamily of receptor and secreted proteins, which participate in signal transduction, immune cell activation or cellular adhesion. The high degree of structural similarity between SLURP-1 and the three fingers motif of snake neurotoxins and Lynx1 suggests that this protein interacts with the neuronal acetylcholine receptors. We found that SLURP-1 potentiates the human alpha 7 nicotinic acetylcholine receptors that are present in keratinocytes. These results identify SLURP-1 as a secreted epidermal neuromodulator which is likely to be essential for both epidermal homeostasis and inhibition of TNF-alpha release by macrophages during wound healing. This explains both the hyperproliferative as well as the inflammatory clinical phenotype of Mal de Meleda.

Acetylcholine↗

PubMed1995

Neuromodulation of transplanted gonadotropin-releasing hormone neurons in male and female hypogonadal mice with preoptic area brain grafts.

Implantation of normal preoptic area (POA) tissue into the third ventricle of adult hypogonadal (HPG) mice provides a source of GnRH neurons that innervate the host median eminence and stimulate reproductive development in the sterile mutants. To further evaluate graft-host integration, the effects of N-methyl-D,L-aspartic acid (NMA) and opiate antagonists on LH secretion in HPG mice with POA transplants (HPG/POA) were tested. NMA challenges significantly stimulated LH secretion in 10 of 11 HPG/POA females. Only 5 of 12 HPG/POA males responded to the same treatment. Administration of the opiate antagonists naloxone or naloxone methiodide was ineffective in stimulating LH release in any mice, but opiate antagonist pretreatment significantly potentiated the LH secretory response to NMA in female, but not male, HPG/POA mice. A potential anatomical substrate for this facilitation may be the beta-endorphin-immunoreactive innervation of the POA grafts in all HPG/POA brains examined. beta-Endorphin fibers were also present in the median eminence in the vicinity of GnRH outgrowth from the grafts. However, similar innervation patterns in HPG/POA males that did not respond to opioid antagonism suggests that this is not sufficient. We tested whether the sex difference in HPG/POA responsivity to neuromodulation is related to the steroid milieu in the hosts. 17 beta-Estradiol (E2) treatment facilitated the LH secretory response of male HPG/POA to NMA challenges whether animals were castrated and given an E2 capsule prior to graft implantation or one week before testing two months after graft surgery. Intact or vehicle (sesame oil)-treated, castrated HPG/POA males rarely responded to NMA challenges, yet graft-derived GnRH innervation of the hosts' median eminence was comparable in all treatment groups. GnRH challenge testing indicated that pituitary sensitivity of the HPG/POA males was not significantly altered by E2 treatment, suggesting that estrogen acted centrally. These results indicate that the activity of grafted GnRH neurons may be modulated by endogenous opioids of host origin as well as by the hormonal milieu.

Animals↗

PubMed2003

Cloning and characterization of a rat brain receptor that binds the endogenous neuromodulator gamma-hydroxybutyrate (GHB).

Gamma-hydroxybutyrate (GHB) is an endogenous neuromodulator with therapeutical applications in anesthesia, sleep disorders, and drug addiction. We report the cloning of a GHB receptor from a rat hippocampal cDNA library. This receptor has a molecular mass of 56 kDa and belongs to the seven-transmembrane receptor family. The peptidic sequence has no significant homology with any known receptor, including GABA(B) receptors. Its mRNA is restricted to the brain and is particularly abundant in the hippocampus, cortex, striatum, thalamus, olfactory bulbs, and cerebellum, matching the distribution of GHB binding sites in rat brain. Southern blot revealed the presence of homologous sequences in several species including the human. Binding assays on transfected CHO cells showed a dissociation constant (Kd) of 426 nM for GHB and no affinity for GABA, baclofen, or glutamate. In patch-clamp experiments, transfected CHO cells revealed a functional G-protein-coupled receptor as demonstrated by GTP-gamma-S-induced irreversible activation. Application of 0.1-15 microM GHB specifically induced an inward current at negative membrane potentials that was not reproduced by application of baclofen (10 microM). CGP-55845, a GABA(B) receptor antagonist, did not inhibit the GHB-induced response nor did the GHB receptor antagonist NCS-382, suggesting that the GHB receptor system includes several subtypes.

Animals↗

PubMed2000

Percutaneous neuromodulation therapy: does the location of electrical stimulation effect the acute analgesic response?

We studied the effect of the location of electrical stimulation on the acute analgesic response to percutaneous neuromodulation therapy in patients with nonradiating neck pain. Sixty-eight patients received three different nonpharmacologic modalities, namely "needles only" (neck), local (neck) dermatomal stimulation, and remote (lower back) dermatomal stimulation in a random sequence over the course of an 11-wk study period. All treatments were given for 30 min, 3 times per week for 3 wk, with 1 wk "off" between each modality. The assessment tools included the health status survey short form (SF-36) questionnaire, as well as 10-cm visual analog scales for assessing pain, physical activity, and quality of sleep. The pain visual analog scale was repeated 5-10 min after each treatment session. The daily oral nonopioid analgesic requirements were recorded in the patient diary during the entire study period. At the end of each 3-wk treatment block, the SF-36 questionnaire was repeated. Compared with needles only and remote dermatomal stimulation, local dermatomal stimulation produced a significantly greater decrease in pain (38%+/-17% vs 9%+/- 16% and 13%+/-18%), increase in physical activity (41%+/-21% vs 11% +/-17% and 16%+/-15%), and improvement in the quality of sleep (34% +/-18% vs 7%+/-17% and 10%+/-18%) compared with baseline values (P<0.05). The need for oral analgesic medications was decreased by an average of 6%+/-15%, 37%+/-18%, and 9%+/-13% during the 3-wk treatment period with the needle only, local dermatomal, and remote dermatomal stimulation, respectively. The posttreatment SF-36 test results revealed that all three modalities produced improvements compared with the prestudy scores for both the physical component summary and mental component summary. However, the magnitude of the changes in the physical component summary and mental component summary with local dermatomal stimulation was significantly greater (+7.9 and +3.6, respectively) than needle only (+3.4 and +1.7, respectively) or remote dermatomal stimulation (+3.7 and +1.9, respectively). No side effects were reported at the needle insertion sites. We conclude that electrical stimulation at the specific dermatomal levels corresponding to the local pathology produces greater short-term improvements in pain control, physical activity, and quality of sleep in patients with chronic neck pain.

Activities of Daily Living↗

PubMed2001

The effect of montage on the analgesic response to percutaneous neuromodulation therapy.

The analgesic response to percutaneous neuromodulation therapy (PNT) is influenced by the location, frequency, and duration of electrical stimulation. We evaluated the effect of different patterns of stimulation (montages) on the acute analgesic response to PNT when applied at the same dermatomal levels in 72 consenting patients with low back pain. All of the patients received a standardized montage (I) and three alternative montage (II-IV) patterns according to a randomized, single-blinded, crossover study design. All of the PNT treatments were administered at identical alternating stimulation frequencies of 15 and 30 Hz for a period of 30 min, three times per week for two consecutive weeks, with 1 wk "off" between each modality. Pretreatment assessments included the health status survey short form (SF-36) questionnaire, as well as visual analog scale scores for pain, physical activity, and quality of sleep (with 0 = the best to 10 = the worst). The pain visual analog scale was repeated 5--10 min after each treatment session. The daily oral analgesic usage was recorded in a patient diary. All four montages produced significant improvements in pain (42%--64%), physical activity (35%--51%), and quality of sleep (28%--46%), as well as 23% to 47% reductions in the daily oral analgesic usage. However, Montage II was significantly more effective than the standard (Montage I) and the other two montages studied. These data suggest that the pattern of stimulation (i.e., montage) can influence the acute analgesic response to PNT.

Adult↗

PubMed1998

Neuromodulation in bladder dysfunction.

Neuromodulation is one option for the management of a wide variety of lower urinary tract disorders, including non-neuropathic and neuropathic bladder dysfunctions. The mechanisms of action of the reported techniques remain unclear; urodynamic changes are minimal, but symptomatic improvements are common. Although the treatment is relatively free from side-effects compared with more aggressive surgical options, the placebo effect is likely to be significant. Its exact cost effectiveness is unclear, but the technology is a welcome addition to the range of treatment options for lower urinary tract dysfunctions, such as urgency and urge incontinence.

Electric Stimulation Therapy↗

PubMed1994

Modeling the control of reticular thalamic oscillations by neuromodulators.

Compartmental models of thalamic reticular (RE) neurons were investigated based on current-clamp and voltage-clamp data. Spontaneous oscillations in the model arise from the interaction between inhibitory synaptic currents and the rebound burst of RE cells. These oscillations critically depend on the level of the resting membrane potential. A network of RE neurons can be switched between silent and sustained oscillatory behavior by modulating a leak potassium current through neuromodulatory synapses. These results suggest that neuromodulators, such as noradrenaline, serotonin and glutamate, can exert a decisive control over the oscillatory activity of systems of RE cells. The model may explain why the isolated RE nucleus oscillates spontaneously in vivo but not in vitro.

Electrophysiology↗

PubMed2001

Functional recovery after brain lesion--contralateral neuromodulation: an fMRI study.

Behavioral recovery takes place even after permanent damage to the entire brain region normally controlling sensorimotor hind limb function in the rat. In our study, 2 weeks after full behavioral recovery from an experimental unilateral permanent brain damage, the topographic representation of the previous paretic hindlimb was investigated by fMRI. The analysis showed that during electrical stimulation of the previously paretic hindlimb, two normally inactive brain regions were now being activated. One region was the non-damaged contralateral sensori-motor cortex and the other region was located lateral to the lesion. These results suggest that behavioral recovery can be explained by functional reorganization and neuromodulation of the brain.

Afferent Pathways↗