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PubMed2002

BDNF: a neuromodulator in nociceptive pathways?

During development, brain-derived neurotrophic factor (BDNF) supports the survival of certain neuronal population in central and peripheral nervous system. In adulthood, BDNF has been suggested to act as an important modulator of synaptic plasticity. This article reviews and discusses its potential role as neuromodulator in the spinal dorsal horn. BDNF is synthesized in the cell body of primary sensory neurons (pre-synaptic neurons) and its expression is regulated in models of inflammatory and neuropathic pain. The high affinity receptor for BDNF, tropomyosine receptor kinase B (TrkB), is expressed by post-synaptic neurons of the dorsal horn. Stimulation of pre-synaptic nociceptive afferent fibres induces BDNF release and consequent activation of TrkB receptors leading to a post-synaptic excitability. Electrophysiological recordings showed that BDNF enhances the ventral root potential induced by C-fibre stimulation in an in vitro preparation. In addition, behavioural data indicate that antagonism of BDNF attenuates the second phase of hyperalgesia induced by formalin (in nerve growth factor-treated animals) and the thermal hyperalgesia induced by carageenan, suggesting that BDNF is involved in some aspects of central sensitisation in conditions of peripheral inflammation. In conclusion, BDNF meets many of the criteria necessary to define it as a neurotransmitter/neuromodulator in small diameter nociceptive neurons.

Animals↗

PubMed2000

Fine-tuning neuromodulation by adenosine.

In addition to its direct pre- and postsynaptic actions on neurones, adenosine is rich in nuances of priming, triggering and inhibiting the action of several neurotransmitters and neuromodulators. These actions are mediated by membrane adenosine receptors (A1, A2 and A3) and involve receptor-receptor interactions, which require, in most cases, the formation of an intermediate second messenger. The harmonic way adenosine builds its influence at synapses to control neuronal communication is operated through fine-tuning, 'synchronizing' or 'desynchronizing' receptor activation for neuropeptides such as calcitonin gene-related peptide and vasoactive intestinal peptide, nicotinic acetylcholine autofacilitatory receptors, NMDA receptors, metabotropic glutamate receptors, as well as its own adenosine receptors.

Adenosine↗

PubMed1998

Neuromodulation: urodynamic effects of sacral (S3) spinal nerve stimulation in patients with detrusor instability or detrusor hyperflexia.

The aim of this study was to determine the urodynamic effects of sacral (S3) nerve stimulation in patients with urge incontinence due to detrusor overactivity which has been refractory to conservative treatment. A total of 24 patients with idiopathic detrusor instability and five with neurogenic hyperreflexia were studied urodynamically before and 6 months after a permanent S3 foramen electrode implant. The urodynamic studies at follow-up were done with the stimulus on. Clinically, the average voiding frequency, the number of leakage episodes and pad use per 24 h decreased significantly. Improvement in several urodynamic parameters was noted. In the idiopathic as well as in the neurogenic group, the correlation between symptomatic and urodynamic improvement was incomplete. Neuromodulation leads to improvement of several urodynamic parameters in patients with urge incontinence due to detrusor overactivity which has been refractory to conservative treatment and appears to be a valuable treatment option in these patients.

Adult↗

PubMed2000

Orphanin FQ/nociceptin: a novel neuromodulator of gastrointestinal function?

Orphanin FQ/nociceptin (OFQ/N) has been immunohistochemically localized in the rat enteric nervous system, and mRNA signals for its precursor (i.e. prepro-OFQ/-N) and cognate receptor ORL-1 are expressed in the intestinal tract. OFQ/N inhibits neurogenic contractions in a variety of stomach and small intestine preparations in vitro, but contracts rodent colon. In vivo, it acts at peripheral and central nervous system sites to stimulate or inhibit mechanical activity in the stomach and colon, respectively. Thus, OFQ/N acts as a neuromodulator of gastrointestinal motility and may have additional roles in regulation of intestinal blood flow, active ion transport, and immunity.

Animals↗

PubMed2001

Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: different roles, different sources and different receptors.

Adenosine exerts two parallel modulatory roles in the CNS, acting as a homeostatic modulator and also as a neuromodulator at the synaptic level. We will present evidence to suggest that these two different modulatory roles are fulfilled by extracellular adenosine originated from different metabolic sources, and involve receptors with different sub-cellular localisation. It is widely accepted that adenosine is an inhibitory modulator in the CNS, a notion that stems from the preponderant role of inhibitory adenosine A(1) receptors in defining the homeostatic modulatory role of adenosine. However, we will review recent data that suggests that the synaptically localised neuromodulatory role of adenosine depend on a balanced activation of inhibitory A(1) receptors and mostly facilitatory A(2A) receptors. This balanced activation of A(1) and A(2A) adenosine receptors depends not only on the transient levels of extracellular adenosine, but also on the direct interaction between A(1) and A(2A) receptors, which control each other's action.

Adenosine↗

PubMed2002

Neuropeptides in the nervous system of Drosophila and other insects: multiple roles as neuromodulators and neurohormones.

Neuropeptides in insects act as neuromodulators in the central and peripheral nervous system and as regulatory hormones released into the circulation. The functional roles of insect neuropeptides encompass regulation of homeostasis, organization of behaviors, initiation and coordination of developmental processes and modulation of neuronal and muscular activity. With the completion of the sequencing of the Drosophila genome we have obtained a fairly good estimate of the total number of genes encoding neuropeptide precursors and thus the total number of neuropeptides in an insect. At present there are 23 identified genes that encode predicted neuropeptides and an additional seven encoding insulin-like peptides in Drosophila. Since the number of G-protein-coupled neuropeptide receptors in Drosophila is estimated to be around 40, the total number of neuropeptide genes in this insect will probably not exceed three dozen. The neuropeptides can be grouped into families, and it is suggested here that related peptides encoded on a Drosophila gene constitute a family and that peptides from related genes (orthologs) in other species belong to the same family. Some peptides are encoded as multiple related isoforms on a precursor and it is possible that many of these isoforms are functionally redundant. The distribution and possible functions of members of the 23 neuropeptide families and the insulin-like peptides are discussed. It is clear that each of the distinct neuropeptides are present in specific small sets of neurons and/or neurosecretory cells and in some cases in cells of the intestine or certain peripheral sites. The distribution patterns vary extensively between types of neuropeptides. Another feature emerging for many insect neuropeptides is that they appear to be multifunctional. One and the same peptide may act both in the CNS and as a circulating hormone and play different functional roles at different central and peripheral targets. A neuropeptide can, for instance, act as a coreleased signal that modulates the action of a classical transmitter and the peptide action depends on the cotransmitter and the specific circuit where it is released. Some peptides, however, may work as molecular switches and trigger specific global responses at a given time. Drosophila, in spite of its small size, is now emerging as a very favorable organism for the studies of neuropeptide function due to the arsenal of molecular genetics methods available.

Amino Acid Sequence↗

PubMed2003

Percutaneous tibial nerve stimulation as neuromodulative treatment of chronic pelvic pain.

PURPOSE: Neuromodulative therapies have been used with moderate success in patients with chronic pelvic pain. Intermittent Percutaneous Tibial Nerve Stimulation (PTNS) is a new, minimally invasive treatment option, which has shown to significantly decrease accompanying pain complaints in patients with lower urinary tract dysfunction, such as urge incontinence or urgency/frequency. In our study, we evaluate the objective results of PTNS in patients with chronic pelvic pain as their main complaint. MATERIALS AND METHODS: In a prospective multicentre trial PTNS was evaluated in 33 patients with chronic pelvic pain. Effects were recorded by Visual Analogue Scale (VAS) for pain diaries, the McGill pain questionnaire and the SF-36 general quality of life questionnaire at baseline and after 12 weeks of treatment. Subjective (patients' request to continue chronic treatment to keep the obtained success) and objective responses (decrease in mean VAS >50% and VAS <3 after treatment) were evaluated. RESULTS: A subjective response was seen in 42% of all patients. In seven patients (21%) mean VAS decreased >50%, in six cases (18%) the decrease was >25%. After 12 weeks of treatment, seven patients (21%) ended up with a mean VAS <3. In all patients quality of life (SF-36) significantly improved, as did the total pain rate intensity (McGill). CONCLUSIONS: Despite very modest overall success rates and the need for placebo-controlled studies, PTNS may have a place in the treatment of patients with chronic pelvic pain who have already tried many other therapies and are left with no further option.

Adult↗

PubMed2003

Urodynamic results of sacral neuromodulation correlate with subjective improvement in patients with an overactive bladder.

OBJECTIVES: Standard urodynamic investigations showed no correlation between the efficacy of sacral neuromodulation (SNS) and urodynamic data. Ambulant urodynamic investigations (ACM) are presented as more sensitive and reliable in detecting and quantifying bladder overactivity. In this study we looked at the correlation and results of ambulant urodynamic data and the clinical effects of SNS. METHODS: Data of patients with bladder overactivity, who underwent an ACM before and during SNS were investigated. Blind analyses of the ACM were performed and the detrusor activity index (DAI) was calculated as the degree of bladder overactivity of the detrusor. The ACM parameters, before and during SNS, were analyzed and correlated to the clinical effect of SNS. RESULTS: In 22 of the 34 patients a DAI before and during stimulation could be calculated because of quality aspects. In all other patients, the other ambulatory urodynamic parameters could be analyzed and a significant reduction was found in bladder overactivity. A significant correlation (p = 0.03) was found in DAI reduction of the ACM before and during SNS as compared to the clinical improvement in overactive bladder symptoms. CONCLUSIONS: The objective and subjective results show a decrease in bladder overactivity during SNS. During SNS bladder instabilities are still present, which is in accordance with the published literature. The reduction of the DAI during SNS as compared to before SNS correlates significantly to the clinical effect of SNS.

Adult↗

PubMed1996

Functional heterogeneity of pituitary gonadotropes in response to a variety of neuromodulators.

Agents previously implicated in control of the hypothalamo-pituitary-gonadal axis were screened for their ability to regulate male rat gonadotropes directly. GnRH-evoked gonadotropin release is accompanied by oscillations of intracellular Ca2+ concentration ([Ca2+]i) and of an outward K+ current that is activated by Ca2+. Substances that caused current responses similar to those with GnRH were hypothesized to evoke secretion. Endothelin-1, oxytocin, neurotensin, pituitary adenylate cyclase-activating polypeptide, and serotonin raised [Ca2+]i and evoked LH release as assayed by the reverse hemolytic plaque assay. These agents affected only subpopulations of gonadotropes establishing functional heterogeneity of pituitary gonadotropes. One neuromodulator (ATP) evoked ionic current in all gonadotropes but the current was different than that evoked by GnRH. Many other substances, including galanin and neuropeptide Y, caused no changes in currents and were considered not to affect [Ca2+]i and not to be secretagogues for gonadotropes.

Animals↗

PubMed2002

A trace amine, tyramine, functions as a neuromodulator in Drosophila melanogaster.

The tyramine receptor (TyrR) is a G protein-coupled receptor for trace amines, cloned in Drosophila melanogaster, and claimed to be either an octopamine receptor or a tyramine receptor. We previously reported that in the larval neuromuscular junctions, the modulatory effect on the excitatory junction potentials of tyramine is distinctly different from that of octopamine. The effect of tyramine but not of octopamine was selectively abolished in the TyrR mutant hono, suggesting that this gene encodes a receptor for tyramine, and not for octopamine. We examined whether there was a gene-dosage effect of this tyramine modulation using combinations of hono, deficiency (Df) and wild-type alleles. The tyramine effect was observed in hono heterozygotes (+/hono), which showed intermediate levels of response, but was not seen in +/Df or hono/Df hemizygotes. While these further suggest that tyramine is the true ligand, it is possible that the gene-dosage effect is only evident above some threshold of gene expression levels. Immunohistochemical staining using an anti-tyramine antibody identified tyramine-containing neurons in the larval central nervous system, some of which were distinct from the octopamine-containing neurons. Taken together, these results strongly suggest that tyramine functions as a neuromodulator.

Animals↗

PubMed2003

Hippocampal cytochrome P450s synthesize brain neurosteroids which are paracrine neuromodulators of synaptic signal transduction.

Hippocampal pyramidal neurons and granule neurons of adult male rats are equipped with a complete machinery for the synthesis of pregnenolone, dehydroepiandrosterone, 17beta-estradiol and testosterone as well as their sulfate esters. These brain neurosteroids are synthesized by cytochrome P450s (P450scc, P45017alpha and P450arom) from endogenous cholesterol. Synthesis is acutely dependent on the Ca(2+) influx attendant upon neuron-neuron communication via N-methyl-D-aspartate (NMDA) receptors. Pregnenolone sulfate, estradiol and corticosterone rapidly modulate neuronal signal transduction and the induction of long-term potentiation via NMDA receptors and putative membrane steroid receptors. Brain neurosteroids are therefore promising neuromodulators that may either activate or inactivate neuron-neuron communication, thereby mediating learning and memory in the hippocampus.

Animals↗

PubMed2000

Effect of partial sensory deprivation on monoaminergic neuromodulators in striate cortex of adult cat.

The role of monoaminergic neuromodulators in the reorganization of cortical topography following limited sensory deprivation in the adult cat was investigated. The total concentrations of dopamine, noradrenaline, serotonin and their major metabolites were measured in the visual cortex of both normal control and experimental animals using microbore high-performance liquid chromatography coupled with electrochemical detection. The experimental animals were subjected to a binocular retinal lesion corresponding to the central 10 degrees of vision and killed two weeks post-lesion. The sensory deprivation was confirmed in area 17 by measuring immediate-early gene zif-268 messenger RNA expression. Following the retinal lesion, the total concentrations of noradrenaline and dopamine were significantly higher in the non-deprived cortex of retinal lesion cats than in the deprived cortex of retinal lesion cats and the cortex of normal animals. This pattern follows the release of the excitatory neurotransmitter glutamate under the same conditions. Serotonin levels were significantly lower in the deprived cortex, and its metabolite 5-hydroxyindole-3-acetic acid was significantly higher in the non-deprived cortex than in deprived cortex and normal cortex. From these results, we suggest that the modulation of noradrenaline, dopamine and serotonin is regulated by visual afferent activity.

Animals↗

PubMed1998

Alterations in K+ evoked profiles of neurotransmitter and neuromodulator amino acids after focal ischemia-reperfusion.

Secondary elevations in extracellular amino acids occur during reperfusion after transient cerebral ischemia. The delayed accumulation of excitatory amino acids may contribute to the progressive development of neuronal injury. In this study, we explored the mechanisms that may be involved in this phenomenon. Microdialysis samples from probes located in rabbit cortex were analysed with a chiral amino acid procedure. Concentrations of neurotransmitters (L-Glu, GABA), N-methyl-D-aspartate receptor modulators (D-Ser, Gly), an inhibitory neuromodulator (Tau), the lipid component phosphoethanolamine, and L-Gln, L-Ser and L-Ala were measured. Depolarization via perfusion with potassium was used to assess the status of release/reuptake systems at 2 and 4 h reperfusion after 2 h transient focal ischemia. Background experiments classified potassium evoked responses as calcium dependent or calcium-independent by inclusion of 30 microM omega-conopeptide MVIIC or by inclusion of 20 mM magnesium and ommision of calcium. During ischemia, large elevations of almost all amino acids occurred. During reperfusion, secondary elevations in transmitter amino acids (L-Glu, GABA) and N-methyl-D-aspartate receptor modulators (D-Ser, Gly) occurred. Tau remained slightly elevated whereas the lipid component phosphoethanolamine remained high and stable during reperfusion. Reperfusion significantly potentiated the potassium response for amino acids with calcium-dependent responses (L-Glu and GABA). In contrast, calcium-independent responses (Tau, phosphoethanolamine, L-Gln) were significantly attenuated. Intermediate behavior was observed with Gly, while no potassium responses were observed for D-Ser, L-Ser or L-Ala. These data demonstrate that perturbations in evoked amino acid profiles after ischemia-reperfusion are selective. Reduction of calcium-independent responses implicate a general decline in efficacy of transporter mechanisms that restore transmembrane gradients of ions and transmitters. Decreased efficacy of transporter systems may reduce transmitter reuptake and account for the amplified release of L-Glu and GABA, thus contributing to progressive neural dysfunction after cerebral ischemia.

Animals↗

PubMed1999

Opioid peptides as possible neuromodulators of the afferent synaptic transmission in the frog semicircular canal.

Vestibular receptors of the frog, Rana temporaria, were examined for the effect of bath-applied opioid peptide leu-enkephalin, its synthetic analogue dalargin and the specific opiate antagonist naloxone. Multiunit afferent activity of the whole vestibular nerve was recorded in an in vitro preparation. Leu-enkephalin (0.005-100 nM) and dalargin (0.1-100 nM) depress the resting discharge frequency. Naloxone (10 nM-1 microM) antagonizes responses induced by leu-enkephalin and dalargin that suggests a specific action of opioid peptides. Leu-enkephalin and delargin inhibit the excitatory action of L-glutamate. The effects of opioid peptides on L-glutamate-induced responses are unaffected by Co2+ block of transmitter release from hair cells that could speak in favour of the postsynaptic nature of these responses. At the same time, the other possible site of action of opioid peptides, such as efferent system, can not be excluded. The results indicate that opiate receptors are present in hair cells and that the neurotransmitter L-glutamate is involved in opiate action at the peripheral vestibular system of the frog. We suggest that opioid peptides may act as a neuromodulator in this system.

Animals↗

PubMed1999

Nitric oxide transforms serotonin into an inactive form and this affects neuromodulation.

Nitric oxide is a highly reactive molecule, diffusible and therefore ubiquitous in the central nervous system. Consequently, nitric oxide or nitric oxide-derived nitrogen oxides must enter into contact with neuromodulators and they can modify these molecules, especially monoamines, and thus change their regulatory action on synaptic transmission. We tested this possibility on a well-known, identified cholinergic synapse of Aplysia buccal ganglion, in which we have found that evoked acetylcholine release was decreased by extracellularly applied serotonin. We show that this modulatory effect of serotonin was largely reduced not only in the presence of 3-morpholinosydnonimine, a nitric oxide donor, but also when endogenous nitric oxide synthase was activated. We have shown that this decrease in the serotonin effect is due to the formation of chemical derivatives of serotonin, mainly a symmetric serotonin dimer, 4-nitroso-serotonin and 4-nitro-serotonin, which are ineffective in reproducing the modulatory effect of serotonin. Serotonin is involved in the regulation of several central functions, such as sleep-wake activity or mood. The consequences of chemical modifications of serotonin by nitric oxide must be taken into account in physiological as well as pathological situations. In addition, our results highlight the importance of the physiological implications of interactions between free radicals and neuromediators in the nervous system.

Acetylcholine↗

PubMed2000

4-Hydroxybenzaldehyde from Gastrodia elata B1. is active in the antioxidation and GABAergic neuromodulation of the rat brain.

Ether fraction of G. elata methanol extract significantly inhibited the recovery time and severity induced by pentylenetetrazole (PTZ) treatment. Pretreatment of ether fraction of G. elata methanol extract successfully prevented diminution of brain GABA level in subconvulsive dose of PTZ-treated rats. 4-Hydroxybenzaldehyde, an analogue of p-hydroxybenzyl alcohol, showed an inhibitory effect on the GABA transaminase, and its inhibitory activity was higher than that of valproic acid, a known anticonvulsant. In the brain of PTZ-treated rats, brain lipid peroxidation was significantly increased, while it recovered to the control level after treatment with 4-hydroxybenzaldehyde. It may be concluded that antioxidation and positive modulation of GABAergic neuromodulation of 4-hydroxybenzaldehyde partially contribute to an antiepileptic and anticonvulsive activity of G. elata B1.

4-Aminobutyrate Transaminase↗

PubMed1997

Age-dependent changes of presynaptic neuromodulation via A1-adenosine receptors in rat hippocampal slices.

The presynaptic neuromodulation of stimulation-evoked release of [3H]-acetylcholine by endogenous adenosine, via A1-adenosine receptors, was studied in superfused hippocampal slices taken from 4-, 12- and 24-month-old rats. 8-Cyclopentyl-1,3-dimethylxanthine (0.25 microM), a selective A1-receptor antagonist, increased significantly the electrical field stimulation-induced release of [3H]-acetylcholine in slices prepared from 4- and 12-month-old rats, showing a tonic inhibitory action of endogenous adenosine via stimulation of presynaptic A1-adenosine receptors. In contrast, 8-cyclopentyl-1,3-dimethylxanthine had no effect in 24-month-old rats. 2-Chloroadenosine (10 microM), an adenosine receptor agonist decreased the release of [3H]-acetylcholine in slices taken from 4- and 12-month-old rats, and no significant change was observed in slices taken from 24-month-old rats. In order to show whether the number/or affinity of the A1-receptors was affected in aged rats, [3H]-8-cyclopentyl-1,3-dimethylxanthine binding was studied in hippocampal membranes prepared from rats of different ages. Whereas the Bmax value was significantly lower in 2-year-old rats than in younger counterparts, the dissociation constant (Kd) was not affected by aging, indicating that the density rather than the affinity of adenosine receptors was altered. Endogenous adenosine levels present in the extracellular space were also measured in the superfusate by high performance liquid chromatography (HPLC) coupled with ultraviolet detection, and an age-related increase in the adenosine level was found. In summary, our results indicate that during aging the level of adenosine in the extracellular fluid is increased in the hippocampus. There is a downregulation and reduced responsiveness of presynaptic adenosine A1-receptors, and it seems likely that these changes are due to the enhanced adenosine level in the extracellular space.

Acetylcholine↗

PubMed2003

Sacral neuromodulation for chronic pain conditions.

Some of the pelvic pain syndromes seem to have features of neurogenic inflammation and neuropathic pain in common. As opposed to being separate disease entities, they may represent a spectrum of clinical presentations of CRPS I of the pelvis. Sacral nerve root stimulation provides good symptomatic relief of pain and voiding dysfunction. The techniques of retrograde root stimulation may offer superior results with fewer complications and lead migrations when compared with other methods. Perhaps neuromodulation should be used earlier in the treatment paradigm for these disorders, before the potentially injurious procedures of hydrodistention, bladder installations, and cystectomies.

Adult↗