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PubMed1989

A neuromodulator of synaptic transmission acts on the secretory apparatus as well as on ion channels.

The mechanisms that underlie synaptic plasticity have been largely inferred from electrophysiological studies performed at sites remote from synaptic terminals. Thus the mechanisms involved in plasticity at the secretory sites have remained ill-defined. We have now used somatic synapses of cultured Helisoma neurones to directly assess presynaptic ion conductances and study the secretory apparatus. At these synapses we determined the actions of a modulatory neuropeptide, Phe-Met-Arg-Phe-NH2 (FMRFa), on the release of the neurotransmitter acetylcholine (ACh). Using voltage- and calcium-clamp techniques, we have demonstrated that FMRFa causes a presynaptic inhibition of ACh release by (1) reducing the magnitude of the voltage-dependent calcium current, and (2) regulating the secretory apparatus. The photolabile calcium cage, nitr-5 (refs 3-8), was dialysed into the presynaptic cell. In response to ultraviolet light, calcium was released from nitr-5 and ACh secretion was stimulated. Under conditions of constant internal calcium, FMRFa reduced the rate of ACh release. Thus we conclude that FMRFa reduces the influx of calcium during the action potential and decreases the sensitivity of the secretory apparatus to elevated internal calcium, thereby contributing to a presynaptic inhibition of transmitter release.

Acetylcholine↗
PubMed2001

Neuromodulation of Na+ channels: an unexpected form of cellular plasticity.

Voltage-gated Na+ channels set the threshold for action potential generation and are therefore good candidates to mediate forms of plasticity that affect the entire neuronal output. Although early studies led to the idea that Na+ channels were not subject to modulation, we now know that Na+ channel function is affected by phosphorylation. Furthermore, Na+ channel modulation is implicated in the control of input-output relationships in several types of neuron and seems to be involved in phenomena as varied as cocaine withdrawal, hyperalgesia and light adaptation. Here we review the available evidence for the regulation of Na+ channels by phosphorylation, its molecular mechanism, and the possible ways in which it affects neuronal function.

Action Potentials↗
PubMed1998

Cloning of a rat brain succinic semialdehyde reductase involved in the synthesis of the neuromodulator gamma-hydroxybutyrate.

The gamma-hydroxybutyrate biosynthetic enzyme succinic semialdehyde reductase (SSR) was purified to homogeneity from rat brain. Peptides were generated by tryptic cleavage and sequenced. PCR primers were designed from the amino acid sequences of two of the peptides showing a similarity (75-85%) to a mitochondrial aldehyde dehydrogenase. A PCR-amplified DNA fragment was generated from recombinant plasmids prepared by a mass excision procedure from a rat hippocampal cDNA library and used as a probe to screen this cDNA library. One cDNA of 1341 bp had an open reading frame encoding a protein of 447 residues with a deduced molecular mass of 47967 Da. The enzyme was expressed in Escherichia coli. Immunoblotting analysis revealed the existence of a protein with the same electrophoretic mobility as the SSR purified from rat brain and with an estimated molecular mass of 45 kDa. Northern blot experiments showed that this enzyme was not expressed in the kidney or in the liver. In the brain tissue, a single but rather broad band was labelled under high stringency conditions, suggesting the presence of more than one messenger species coding for SSR. Hybridization in situ performed on brain tissue slices showed specific labelling of the hippocampus, the upper cortex layer, the thalamus, the substantia nigra, the cerebellum, the pons medulla and the olfactory tract. The recombinant enzyme showed catalytic properties similar to those of the SSR purified from rat brain, particularly in regard to its substrate affinities and Ki for inhibition by phthalaldehydic acid. Valproic acid did not inhibit the cloned SSR. This enzyme had 20-35% identity in highly conserved regions involved in NADPH binding with four other proteins belonging to the aldo-oxo reductase family.

Aldehyde Reductase↗
PubMed1998

Nitric oxide as neuromodulator of sympathetic transmission in rat vas deferens.

1. Electrical field stimulation (EFS) of muscle strips in vitro elicited a tetrodotoxin (TTX)-sensitive biphasic contractile response consisting of a phasic component followed by a tonic one. 2. The amplitude of both components of the response was impaired by N omega-nitro-L-arginine and potentiated by sodium nitroprusside. Cystamine caused a reduction in amplitude of both phasic and tonic components of the response to EFS. Neither N omega-nitro-L-arginine, sodium nitroprusside, nor cystamine induced changes in the resting muscle tone, or in the contractile response to exogenous agonists ATP and noradrenaline (NA). 3. The nitric oxide scavenger, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, induced a reduction in amplitude of both components of the response to EFS. 4. These results reveal a facilitatory prejunctional modulatory role for nitric oxide in sympathetic neurotransmission in rat vas deferens. Endogenous nitric oxide released in the extracellular space is presumed to potentiate neurotransmission by acting at prejunctional level via cGMP.

Animals↗
PubMed1998

An animal model for the neuromodulation of neurogenic bladder dysfunction.

OBJECTIVE: To develop an animal model to examine the pathophysiology by which S3 sacral root electrostimulation alters the micturition reflex in patients with bladder hyper-reflexia. MATERIALS AND METHODS: Chronic sacral nerve root electrostimulation was applied to spinally transected rats; 21 animals were divided into four groups. The spinal cord was completely transected at the T10-11 level and stainless-steel electrodes implanted into the sacral foramen in 17 animals; these animals were subsequently divided into two groups (1 and 2). Six rats in group 1 underwent sacral root elctrostimulation for 2 h/day and five in group 2 for 6 h/day, for 21 days. The sham group (group 3, six rats) received no stimulation and four rats were used as healthy controls (group 4). Voiding frequency was recorded and each animal was evaluated cystometrically at the end of the stimulation period. The results were compared with the sham and control groups. RESULTS: Spinal cord transection resulted in bladder areflexia and complete urinary retention; 7-9 days after the injury, the bladder recovered its activity. Twenty-one days after transection all animals had evidence of uninhibited bladder contractions. The mean (SD) hourly frequency of urination was 0.66 (0.18) in healthy controls, 0.83 (0.21) in group 1, 0.87 (0.34) in group 2 and 1.1 (0.31) in group 3. There was a significant decrease in eh cystometric signs of bladder hyper-reflexia in groups 1 and 2 when compared with group 3. CONCLUSIONS: This work reports and initial study showing that chronic electrostimulation of sacral nerve roots can reduce the signs of bladder hyper-reflexia in the spinally injured rat. To our knowledge, this is the first report describing the rat as an animal model to determine the effects of chronic electrostimulation on the micturition reflex.

Animals↗
PubMed2002

Sacral neuromodulation in functional urinary retention: an effective way to restore voiding.

OBJECTIVE: To determine the long-term efficacy and complications of sacral nerve stimulation as an alternative therapy for functional unobstructive urinary retention, often considered to be psychogenic and effectively treated by clean intermittent catheterization, but for which pelvic floor dysfunction has been recognized as a possible cause. PATIENTS AND METHODS: Twenty patients (17 women and three men, mean age 48 years) with idiopathic, unobstructive functional urinary retention and in whom other forms of therapy had failed, had a pulse generator implanted (Medtronic, Minneapolis, MN, USA) and a sacral nerve implant. Their mean duration of symptoms was 68 months; 13 patients had chronic pelvic and perineal pain associated with their obstructive voiding symptoms. All patients were managed with clean intermittent catheterization and pharmacological therapy (alpha-blockers) before the procedure. All patients had a percutaneous nerve evaluation before the permanent implant, which showed> 50% improvement in their symptoms. All patients were evaluated at 1, 6 12, 18 and 24 months, then yearly thereafter. The results were assessed both subjectively by patient's symptoms and objectively by checking the postvoid residual volume (PVR) and voided volume. RESULTS: Eighteen patients were able to void spontaneously with a mean increase in voided volume from 48 to 198 mL, and a significant decrease in PVR from 315 to 60 mL. Eighteen of the patients had a > or = 50% improvement in their symptoms and said they would recommend the therapy to a friend or relative. Complications occurred in six patients. CONCLUSION: Sacral nerve stimulation is an effective and durable new approach to functional urinary retention, with few associated complications. Test stimulation provides a valuable tool for selecting patients.

Adult↗
PubMed2006

Hydrogen sulfide is a novel prosecretory neuromodulator in the Guinea-pig and human colon.

BACKGROUND & AIMS: Hydrogen sulfide (H(2)S) has been suggested as a novel gasomediator. We explored its unknown neuromodulatory role in human and guinea-pig colon. METHODS: We used immunohistochemistry to detect H(2)S-producing enzymes cystathionine gamma-lyase (CSE) and cystathionine beta-synthase (CBS) in enteric neurons, Ussing chambers to measure mucosal ion secretion, and neuroimaging with voltage- and Ca(++)-sensitive dyes to record H(2)S effects on guinea-pig and human enteric neurons. RESULTS: More than 90% of guinea-pig and human submucous and myenteric neurons were colabeled for CSE and CBS. Myenteric interstitial cells of Cajal were CSE-immunoreactive. The exogenous H(2)S donor NaHS (0.2-2.5 mmol/L) concentration-dependently increased chloride secretion in human and guinea-pig submucosa/mucosa preparations, but not in the colonic epithelial cell line T84. The secretory response was reduced significantly by tetrodotoxin (0.5 micromol/L), capsaicin desensitization (10 micromol/L), and the transient receptor potentials vanilloid receptor 1 antagonist capsazepine (10 micromol/L). The endogenous H(2)S donor L-cysteine also induced secretion that was diminished significantly by capsaicin desensitization, the CBS inhibitor amino-oxyacetic acid, and the CSE inhibitor propargylglycine. NaHS increased spike discharge in 23% of guinea-pig and 36% of human submucous neurons, but had no effect on Ca(++) mobilization in cultured guinea-pig enteric neurons. This excitatory response was reduced significantly by capsaicin desensitization and capsazepine, but not by glibenclamide (10 micromol/L). CONCLUSIONS: The presence of H(2)S-producing enzymes in human and guinea-pig enteric neurons, the excitatory action on enteric neurons, and the prosecretory effects of NaHS suggest H(2)S as a novel gut-signaling molecule. Its action mainly involves transient receptor potentials vanilloid receptor 1 receptors on extrinsic afferent terminals, which in turn activate enteric neurons.

Adult↗
PubMed1990

[Purinergic neuromodulation].

Adenosine and its nucleotides participate in the regulation of various functions in the nerve system and in some internal organs. These purines are released from a variety of nervous and non-nervous cellular sources. Adenosine receptors are situated extracellular; they mediate some effects of the adenosine and are coupled negatively (A1 adenosine receptors) and positively (A2 adenosine receptors) to adenylate cyclase. The physiological effects of adenosine are inhibitory; they are exerted synaptically and extrasynaptically. The main synaptic modulatory effect is the presynaptic inhibition of the excitatory and inhibitory neurotransmitters release. Postsynaptically adenosine modulate the answer to neurotransmitter effects. ATP functions probably as co-transmitter or transmitter in the non-adrenergic non-cholinergic autonomic neurons. Neuromodulatory and the majority of metabolic adenosine effects are antagonized by methylxanthines. Exogenous substances can influence the molecular mechanisms of adenosine systems; some of the induced pharmacodynamical effects could be of therapeutic interest. Drug-interactions with adenosine systems can cause side effects.

Adenine Nucleotides↗
PubMed1988

[Significance of neurotransmitters and neuromodulators in regulating respiration. A. Central aminergic neurons].

Experimental and clinical findings on the role of the central aminergic mechanisms in the control of respiration are reviewed. Dopamine, histamine, norepinephrine and serotonin inhibit spinal cord and cortical neurons; acetylcholine stimulates these neurons. The importance of these pharmacological effects for the control of respiration is not yet clear. Brain stem dopaminergic and serotonergic mechanisms stimulate respiratory neurons; a brain stem noradrenergic mechanism inhibits these neurons. A cholinergic mechanism is involved in the control of central chemosensitivity, and probably of the respiratory periodicity. Histamine stimulates the brain stem neurons, its effects on respiratory neurons have not yet been investigated.

Brain↗
PubMed1992

Exercise and neuromodulators: choline and acetylcholine in marathon runners.

Certain neurotransmitters (i.e., acetylcholine, catecholamines, and serotonin) are formed from dietary constituents (i.e., choline, tyrosine and tryptophan). Changing the consumption of these precursors alters release of their respective neurotransmitter products. The neurotransmitter acetylcholine is released from the neuromuscular junction and from brain. It is formed from choline, a common constituent in fish, liver, and eggs. Choline is also incorporated into cell membranes; membranes may likewise serve as an alternative choline source for acetylcholine synthesis. In trained athletes, running a 26 km marathon reduced plasma choline by approximately 40%, from 14.1 to 8.4 uM. Changes of similar magnitude have been shown to reduce acetylcholine release from the neuromuscular junction in vivo. Thus, the reductions in plasma choline associated with strenuous exercise may reduce acetylcholine release, and could thereby affect endurance or performance.

Acetylcholine↗
PubMed1999

Purification of serine racemase: biosynthesis of the neuromodulator D-serine.

High levels of D-serine occur in mammalian brain, where it appears to be an endogenous ligand of the glycine site of N-methyl-D-aspartate receptors. In glial cultures of rat cerebral cortex, D-serine is enriched in type II astrocytes and is released upon stimulation with agonists of non-N-methyl-D-aspartate glutamate receptors. The high levels of D-serine in discrete areas of rat brain imply the existence of a biosynthetic pathway. We have purified from rat brain a soluble enzyme that catalyzes the direct racemization of L-serine to D-serine. Purified serine racemase has a molecular mass of 37 kDa and requires pyridoxal 5'-phosphate for its activity. The enzyme is highly selective toward L-serine, failing to racemize any other amino acid tested. Properties such as pH optimum, Km values, and the requirement for pyridoxal phosphate resemble those of bacterial racemases, suggesting that the biosynthetic pathway for D-amino acids is conserved from bacteria to mammalian brain.

Amino Acid Isomerases↗
PubMed2005

A peripheric neuromodulation technique for curing detrusor overactivity: Stoller afferent neurostimulation.

OBJECTIVE: To perform Stoller afferent neurostimulation (SANS) with and without a low-dose anticholinergic (oxybutynin hydrochloride) in patients with detrusor overactivity and compare the results obtained with the two therapeutic approaches. MATERIAL AND METHODS: A total of 43 patients with symptoms of detrusor overactivity (frequency, urgency, urge incontinence) underwent urodynamic studies (UDS). Those in whom UDS revealed phasic detrusor overactivity were evaluated using a quality of life questionnaire and voiding diaries. Patients were randomized into two groups: Group 1 received SANS alone; Group 2 received SANS combined with a low-dose anticholinergic (5 mg of oral oxybutynin hydrochloride). Both groups were re-evaluated following 8 weeks of therapy. RESULTS: There were 21 patients in Group 1 and 22 in Group 2. The treatment response rate was 61.6% and 83.2% in Groups 1 and 2, respectively. In both groups, the best symptomatic improvements were obtained in patients with urge incontinence. The percentage decreases in the mean number of symptoms of frequency and urgency were 36.7% and 46.1%, respectively in Group 1 and 44.2% and 61.1%, respectively in Group 2. However, there were no statistically significant differences in the effects on frequency and urgency between the two groups. The anticholinergic drug was well tolerated by all patients in Group 2. One patient reported local tenderness, and a small hematoma developed in another following SANS therapy. CONCLUSION: SANS is an easy and inexpensive therapeutic method with low morbidity in patients with an overactive bladder. Combination with a low-dose anticholinergic increases the success rate without causing any significant side-effects.

Administration, Oral↗