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PubMed1997

Requirement for tyrosine phosphatase during serotonergic neuromodulation by protein kinase C.

Tyrosine kinases and phosphatases are abundant in the nervous system, where they signal cellular differentiation, mediate the responses to growth factors, and direct neurite outgrowth during development. Tyrosine phosphorylation can also alter ion channel activity, but its physiological significance remains unclear. In an identified leech mechanosensory neuron, the ubiquitous neuromodulator serotonin increases the activity of a cation channel by activating protein kinase C (PKC), resulting in membrane depolarization and modulation of the receptive field properties. We observed that the effects on isolated neurons and channels were blocked by inhibiting tyrosine phosphatases. Serotonergic stimulation of PKC thus activates a tyrosine phosphatase activity associated with the channels, which reverses their constitutive inhibition by tyrosine phosphorylation, representing a novel form of neuromodulation.

Action Potentials↗

PubMed1996

Neuromodulation by Mg2+ and polyamines of excitatory amino acid currents in rodent neurones in culture.

Excitatory amino-acid currents in rodent central neurones are mediated by the activation of glutamate receptors. Ionotropic types of the receptors are divided into alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainate and N-methyl-D-aspartate (NMDA) receptors, and the former two are collectively called non-NMDA receptors. The NMDA receptor is modulated by a number of endogenous neuromodulators including Mg2+, polyamines, glycine and protons in extracellular solutions. Although it has been generally thought that each of the neuromodulators acts on a distinct site in the NMDA receptor, recent studies have revealed that these actions may be not necessarily independent of each other. The NMDA receptor response is not only inhibited but also potentiated by Mg2+, and the latter action is due to an interaction of a Mg2+ site with either glycine- or proton-binding site. In the presence of polyamines, a tonic inhibition by protons of the NMDA receptor response is relieved, resulting in a potentiation of the response. Alternatively, it has been recently revealed that there are some subtypes of non-NMDA receptors which are negatively modulated by polyamines in either extra- or intra cellular solutions. The difference in polyamine sensitivity among non-NMDA receptors is attributed to a distinction in their constituted subunits. The inhibition of non-NMDA receptor by intracellular polyamines results in inward rectification of the current-voltage relation which is not seen for polyamine-insensitive ones. This polyamine action is not mimicked by intracellular Mg2+.

Action Potentials↗

PubMedDate not supplied

[Current status of neurostimulation and neuromodulation for vesicourethral dysfunction].

OBJECTIVE: To describe the current indications, techniques and results of sacral root stimulation in patients with spinal cord lesions as a treatment for patients with high pressure bladders and/or urinary incontinence despite conservative management, as well as sacral root neuromodulation with permanent stimulators for complex bladder dysfunction: vesical instability, sensory urgency, chronic pelvic pain and chronic voiding dysfunction. METHODS/RESULTS: The literature is reviewed, both techniques are described and the results of the most significant series are discussed, with special reference to the first groups that utilized these techniques. CONCLUSIONS: There is ample experience in the application of sacral root electrical stimulation. The reported results are comparable with those achieved by other treatments, such as augmentation cystoplasty. Neurostimulation and neuromodulation techniques are simple, the complications are minimal and they do not prelude the use of other therapies.

Electric Stimulation Therapy↗

PubMed2026

Predictive value of anal sphincter electromyography for sacral neuromodulation test-phase outcomes.

BACKGROUND: Sacral neuromodulation (SNM) is an established therapy for refractory pelvic organ dysfunction. Anal sphincter electromyography (EMG) is commonly used preoperatively to assess sacral and peripheral nerve integrity. However, the prognostic significance of chronic neurogenic EMG changes for SNM outcomes remains unclear. OBJECTIVE: To evaluate whether chronic neurogenic changes on preoperative anal sphincter EMG predict the outcome of the SNM test phase. METHODS: We retrospectively analysed 62 consecutive patients with bladder and/or bowel dysfunction or pelvic pain who were candidates for SNM treatment and who underwent preoperative anal sphincter EMG. EMG findings were classified as normal or showing chronic neurogenic changes. SNM test-phase success was defined as a ≥50% improvement of symptoms at 24 days. Outcomes were compared between EMG groups. RESULTS: Of the 62 patients (49 women, 13 men), 30 (48%) had normal EMG findings and 32 (52%) showed chronic neurogenic changes. Overall, the SNM test phase was successful in 47 patients (76%). Success rates were similar in patients with normal EMG (72%) and neurogenic EMG changes (79%), with no statistically significant difference (p = 0.878). Sex-stratified analyses revealed no significant association between EMG findings and test-phase success in women or men. CONCLUSIONS: Chronic neurogenic changes on anal sphincter EMG do not predict SNM test-phase outcomes. These findings suggest that abnormal sphincter EMG results should not be used as a standalone criterion to exclude patients from SNM therapy. SIGNIFICANCE: Signs of neurogenic damage on anal sphincter EMG are not an indicator of reduced neuromodulatory capacity or diminished clinical response to SNM.

Humans↗

PubMed2026

Assessment of blinding in pharmacotherapy and noninvasive neuromodulation randomized controlled trials for neuropathic pain in adults.

In randomized controlled trials (RCTs), study participants and research personnel are often blinded to minimize biases related to knowing treatment allocation. To determine if blinding was effective, participants may be asked which treatment they believe they received ("treatment guess"). This descriptive review characterized blinding assessment (BA) reporting in pharmacotherapy and neuromodulation neuropathic pain RCTs. Of 288 papers, 36 (12.5%) reported a BA. One paper reported the results of 2 studies, so in total 37 studies with a BA were assessed. Of these, 19 were crossover, 17 parallel, and 1 partial crossover in design. All 37 studies assessed participant blinding, and 10 also assessed investigator blinding. Approximately 27% included an "unsure" answer option for treatment guess, and 38% asked the reason for the guess. There were no clear patterns in BA reporting across time nor based on treatment type. Seventeen trials provided sufficient data to calculate Bang Blinding Index (BI) to determine blinding success. Participants remained blinded (BI = 0 ± 0.2) in 10/17 placebo and 10/17 treatment arms, 6 placebo and 5 treatment arms had a BI > 0.2 suggesting possible unblinding, whereas 1 placebo and 2 treatment arms had a BI < -0.2 suggesting misinformed guessing. Overall, we found that BAs are done in a minority of published neuropathic pain trials and with variable methodology. Given the importance of minimizing risk of bias because of treatment unblinding, future studies should consider including BAs, and further consensus building is necessary to determine if and how BAs should be conducted and interpreted in analgesic clinical trials.

Bias↗

PubMed2000

Neuromodulation of ligand- and voltage-gated channels in the amphibian retina.

To understand information processing in the retina, it is important to identify and characterize the types of synaptic receptors and intrinsic ion channels in retinal neurons. In order to achieve a high degree of adaptability, retinal synapses have evolved multiple neuromodulatory mechanisms. Light or modulatory agents can alter the efficacies of both electrical and chemical synaptic transmission in the retina. Recent studies indicate that interaction of voltage-gated channels with those activated by neurotransmitters plays a significant role in shaping the light-evoked postsynaptic responses of retinal neurons. The fact that both types of channels are subject to modulation by multiple second messenger-mediated intracellular processes is a clear indicator of the importance of neuromodulation in retinal function. The whole-cell patch clamp technique provides a means to study mechanisms of regulation of ion channels by controlling intracellular as well as the extracellular environment. This review describes the experimental evidence, mostly obtained in our laboratory, which indicates the important role of Ca-dependent neuromodulatory processes in the regulation of signal transmission in the vertical pathway of the amphibian retina.

Animals↗

PubMed1985

Phosphorylative neuromodulation of the regulatory subunit of cyclic AMP-dependent protein kinase type II in skeletal muscle.

The phosphorylative neuromodulation of the regulatory subunit of protein kinase type II (R-II) in cytosolic fractions from denervated and sham-operated, contralateral soleus muscles of the rat was evaluated. The denervation-induced increase in the 32P-phosphorylation of R-II is not related to an increased dephosphorylation by cation-dependent or cation-independent protein phosphatases in the cytosolic fractions. The level of 32P-phosphorylation of an exogenous heptapeptide substrate (Kemptide) by dissociated catalytic subunits of cyclic AMP-dependent protein kinase in cytosolic fractions from denervated and sham-operated solei did not differ. Also, no change in the concentration of cytosolic R-II assessed by competitive enzyme-linked immunosorbent assays (ELISA) was found after denervation. However, the in vitro 32P-phosphorylation of R-II in these samples was increased. Taken together, our results suggest that the increased availability of autophosphorylatable sites reflects an in vivo modulation of R-II phosphorylation rather than a significant change in total R-II content.

Animals↗

PubMed1984

Generation of specific behaviors in a locust by local release into neuropil of the natural neuromodulator octopamine.

The natural insect neuromodulator octopamine (OCT) was released iontophoretically into regions of neuropil in locust metathoracic ganglia. A narrowly-defined site was found on one side of the ganglion at which release caused a prolonged bout of repetitive flex-extend-flex movements of the tibia on the injected side, at a frequency of from 2-3.5 Hz. When a bout had terminated, repetition of the OCT release caused an extremely similar bout to occur, and again with further treatments, indefinitely. OCT iontophoresis at the equivalent site on the contralateral side caused the contralateral flexor to make stepping movements. Two sites were found, in each half of the ganglion, at which similar OCT release evoked a bout of flight motor activity at 10 Hz. The flight bout involved both sides synchronously and nearly equally, except for a slightly greater motor output on the injected side. Evoked bouts lasted from 20 sec to 25 min depending on the preparation and amount of OCT released. At a site in the 6th abdominal ganglion of mature female locusts OCT release suppressed ongoing rhythmic oviposition digging evoked by severing the ventral nerve cord. A number of previously undescribed DUM neurons was encountered and their dendritic patterns, which are distinctive, determined following dye injection. A hypothesis, termed the Orchestration Hypothesis is presented, which considers how modulator neurons such as locust octopaminergic neurons, might be involved in the generation of specific behaviors.

Animals↗

PubMed1990

Phenylethylamine in the CNS: effects of monoamine oxidase inhibiting drugs, deuterium substitution and lesions and its role in the neuromodulation of catecholaminergic neurotransmission.

Phenylethylamine is present in brain in tiny quantities, it is heterogeneously distributed and present in synaptosomes, and it is synthesized and degraded very quickly. If deuterium is substituted for hydrogen on the alpha carbon of the side chain then it exhibits profound isotope effects to MAO and its penetration and persistence in the brain is considerably enhanced. In the presence of MAO-B inhibitors treatment with reserpine causes reciprocal changes to PE and DA suggesting a functional relationship between them and after unilateral lesions of the substantia nigra an ipsilateral reduction in striatal PE is seen suggesting again a co-relationship with DA. Following iontophoresis PE has been shown to exhibit indirect sympathomimetic effects but in addition when applied at low currents concurrently with DA or NA it causes post synaptically a substantial potentiation in the actions of the latter amines. As a result of this and other data PE has been proposed to be a neuromodulator of catecholaminergic transmission.

Animals↗

PubMed1995

Neuromodulation of rhythmic motor patterns in the blue crab Callinectes sapidus by amines and the peptide proctolin.

The blue crab Callinectes sapidus, provides an opportunity to study neuromodulation of three variations of rhythmic behavior produced by the same appendages. These behaviors are sideways swimming, backward swimming and courtship display (CD). Each behavior has a different context, and despite similarities among them, each is quantifiably distinguishable. CD behavior occurs in males, is stimulated naturally by pheromone, and elements of the behavior are evoked by proctolin and dopamine. Sideways and backward swimming do not share these characteristics. Bath-applied proctolin, combined with either electrical or pheromonal stimulation, was used to search for interneurons influencing motor outflows from the fifth legs. Interneurons were found which, when stimulated electrically, initiated rhythmic behavior. At least one of these neurons responded to pheromonal stimulation. Application of proctolin combined with stimulation of descending 'trigger' cells resulted in changes from a backward swimming motor pattern toward a CD pattern. Dopamine applied with proctolin lowered the concentration threshold for proctolin-evoked changes in motor outflows. Octopamine co-applied with proctolin extinguished the proctolin effect unless dopamine was co-applied. Combinations of modulators appear to play critical roles in shaping patterns of rhythmic motor activity of the fifth legs.

Animals↗

PubMed1987

Immunohistochemical and biological evidence for a neuromodulator function of neuropeptide Y in the human oviduct.

By means of the peroxidase-antiperoxidase technique the existence of neuropeptide Y-immunoreactivity (NPY-IR) in nerve fibers of the normal human uterine tube was established. NPY-IR fibers are found to supply vascular and non-vascular smooth muscles of the uterine tube. In both systems the density of NPY-IR nerves is markedly high. The NPY-IR nerves exhibit a predominance for the arterial portion of the oviductal vasculature in the serosal, the muscle and the mucosal layer. Furthermore in the mucosal layer, some NPY-IR fibers occur in contact with the surface epithelium. In-vitro experiments with helical strips of the human uterine tube reveal no significant effects of NPY alone of the different parameters (resting tension, frequency and amplitude of spontaneous contractions) of mechanical activity while it seems to act in combination with acetylcholine. Thus, the distinct innervation patterns of the NPY-IR nerve fibers as well as the results obtained by bioassay may suggest a neuromodulator function of this neuropeptide in the human uterine tube. In this respect, NPY may play an important role in the transport of the eggs through the tube.

Arteries↗

PubMedDate not supplied

Neuromediators and neuromodulators. Evolution of compounds and evolution of hypotheses.

The probable features of the evolution of neuromediators (NM) and neuromodulators (NR) of different types are discussed. The assumption concerning the high rate of evolution of peptide NM and NR and the greater potentialities of the formation of new NM and NR of this type is substantiated. Monomolecular NM and NR are presumably more conservative, but have an advantage as regards the strict individualism of the systems of synthesis and degradation. Peptides, individual amino acids, and ATP are probably among the oldest NM and NR.

Adenosine Triphosphate↗

PubMed1996

Taurine as osmoregulator and neuromodulator in the brain.

Taurine has been assumed to function as an osmoregulator and neuromodulator in the brain. The pertinent studies are now reviewed in an attempt to formulate a unifying hypothesis as to how taurine could simultaneously act in both roles. Neuromodulatory actions of taurine may also underlie its protective effects against neuronal overexcitation and glutamate agonist-induced neurotoxicity.

Animals↗

PubMed2001

Neuromodulation for fecal incontinence: outcome in 16 patients with definitive implant. The initial Italian Sacral Neurostimulation Group (GINS) experience.

PURPOSE: Sacral nerve modulation appears to offer a valid treatment option for some patients with fecal incontinence and functional defects of the internal anal sphincter or of the striated muscle. METHODS: Sixteen patients with fecal incontinence (4 males; mean age, 51.4 (range, 27-79) years) with intact or surgically repaired (n = 1) anal sphincter underwent permanent sacral nerve stimulation implant. Cause was traumatic in two patients, and associated disorders included scleroderma (2 patients) and spastic paraparesis (1 patient); eight (50 percent) of the patients also had urinary incontinence, and two (12.5 percent) had nonobstructive urinary retention. All patients were selected on the basis of positive findings from at least one peripheral nerve evaluation. The stimulating electrode was positioned in the S2 (1 patient), S3 (14 patients), or S4 (1 patient) sacral foramen. RESULTS: Mean follow-up was 15.5 (range, 3-45) months. Mean preimplant Williams score decreased from 4.1 +/- 0.9 (range, 2-5) to 1.25 +/- 0.5 (range, 1-2) (P = 0.01, Wilcoxon test), and the number of incontinence accidents for liquid or solid stool in 14 days decreased from 11.5 +/- 4.8 (range, 2-20) before implant to 0.6 +/- 0.9 (range, 0-2) at the last follow-up. Important manometric data were an increase in mean maximal pressure at rest of 37.7 +/- 14.9 mmHg (implantable pulse generator 49.1 +/- 18.7, P = 0.04) and in mean maximal pressure during squeeze (prestimulation 67.3 +/- 21.1 mmHg, implantable pulse generator 82.6 +/- 21.0, P = 0.09). CONCLUSIONS: Neuromodulation can be considered an option for fecal incontinence. However, an accurate clinical and instrumental evaluation and careful patient selection are required to optimize outcome.

Adult↗

PubMedDate not supplied

VIP as a cell-growth and differentiation neuromodulator role in neurodevelopment.

In addition to its commonly recognized status as a neuromodulator of virtually all vital functions, including neurobiological, the neuropeptide VIP plays a role in the control of cell growth and differentiation and of neuronal survival. Through these actions, VIP, whose impact appears early in ontogeny, may possess developmental functions. VIP can be stimulatory or inhibitory on cell growth in function of the model considered. The growth regulatory actions of VIP, which are often independent of cAMP, are most likely significant when mitogenic or trophic factors, eventually released by nontarget cells, are simultaneously present in the extracellular medium. The intracellular mechanisms that mediate these actions of VIP may involve different transduction cascades triggered by subsets of VIP binding sites that may coexist in the same tissue.

Animals↗

PubMed2006

Urinary retention following tension-free vaginal tape successfully treated by sacral neuromodulation.

Postoperative urinary retention following anti-incontinence surgery has traditionally been thought to be due to overcorrection. There is increasing evidence, however, that a neurogenic component may also play a significant role. This is a case report of a 72-year-old woman who developed delayed partial urinary retention following a tension-free vaginal tape which resolved with initial sacral neuromodulation.

Aged↗

PubMed2000

Chemical neuromodulation of frontal-executive functions in humans and other animals.

Neuromodulation of frontal-executive function is reviewed in the context of experiments on rats, monkeys and human subjects. The different functions of the chemically identified systems of the reticular core are analysed from the perspective of their possible different interactions with the prefrontal cortex. The role of dopamine in spatial working memory is reviewed, taking account of its deleterious as well as facilitatory effects. Baseline-dependent effects of dopaminergic manipulation are described in rats on an attentional task, including evidence of enhanced function following infusions of D1 receptor agonists into the prefrontal cortex. The precise nature of the cognitive task under study is shown to be a powerful determinant of the effects of mesofrontal dopamine depletion in monkeys. Parallels are identified in human subjects receiving drugs such as the indirect catecholamine agonists L-dopa, methylphenidate and the dopamine D2 receptor blocker sulpiride. The effects of these drugs on different types of cognitive function sensitive to frontal lobe dysfunction are contrasted with those of a manipulation of 5-HT function, dietary tryptophan depletion. Hypotheses are advanced that accord the ascending systems a greater deal of specificity in modulating prefrontal cortical function than has hitherto been entertained, and clinical and theoretical implications of this hypothesis are discussed.

Animals↗

PubMed2003

The role of the carbachol test and concomitant diseases in patients with nonobstructive urinary retention undergoing sacral neuromodulation.

The aim of this study was to evaluate the percutaneous nerve evaluation (PNE) test success in patients with nonobstructive urinary retention. A total of 24 PNE tests were performed in patients with nonobstructive urinary retention and in 18 patients, a carbachol test was performed during urodynamics. The diagnosis relating to the acontractile detrusor was also assessed and compared to the outcome of the PNE test. The PNE test was successful in eight of 24 patients (33.3%) with the the highest success rate being observed in patients after hysterectomy (80%). It was successful in five of 12 patients with negative carbachol tests and in three of six patients with positive carbachol tests. We conclude that sacral neuromodulation is an effective treatment option in patients with nonobstructive urinary retention. PNE tests should be performed in all patients with therapy resistant nonobstructive urinary retention, because predictive factors do not exist.

Adult↗