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[Sacral root neuromodulation. Experience in our site: 1998-2003, concerning 18 definite neuromodulation implants].

OBJECTIVE: Sacral root neuromodulation is an effective technique for the treatment of Chronic Micturition Dysfunction (CMD) refractory to conventional therapy. New indications such as chronic pelvic pain and interstitial cystitis are currently making their way within the urologic setting. Several groups of gastric surgeons are now choosing this technique for the management of rectal diseases (constipation, sphincter dysfunction). This paper contributes our experience in the treatment of patients with CMD and the comparative results at one year from implant in all patients. MATERIAL AND METHODS: From December 1998 through July 2003, 18 neuromodulation definite implants were performed. The main indication was CMD in 62.5% patients. Follow up of patients was done at one month and three months, and every six months thereafter. Follow up is conducted through a micturition diary and QoL questionnaire. Electrode implant in the first 16 patients was achieved by open surgery. The next 2 patients had the electrode placed by a percutaneous technique using the "Tined Lead" kit. RESULTS: Results at one year after implant were compared in all patients. The total number of neuromodulation implants placed was 18, 14 (77.7%) of which were women and 4 (22.3%) men. Mean age was 52.56 years. Implant indication was CMD in 72.2% patients, mixed incontinence (urinary and faecal) in 22.1%, and interstitial cystic disease in 5.5%. Symptoms improvement at one year from implant, as determined by a micturition diary and QoL questionnaire was 76.4%. Clinical improvement was greater in patients with urgency symptoms than in patients with predominance of voiding symptoms.

Adult↗
PubMed1995

Intrinsic neuromodulation in the Tritonia swim CPG: serotonin mediates both neuromodulation and neurotransmission by the dorsal swim interneurons.

1. Neuromodulation has previously been shown to be intrinsic to the central pattern generator (CPG) circuit that generates the escape swim of the nudibranch mollusk Tritonia diomedea; the dorsal swim interneurons (DSIs) make conventional monosynaptic connections and evoke neuromodulatory effects within the swim motor circuit. The conventional synaptic potentials evoked by a DSI onto cerebral neuron 2 (C2) and onto the dorsal flexion neurons (DFNs) consist of a fast excitatory postsynaptic potential (EPSP) followed by a prolonged slow EPSP. In their neuromodulatory role, the DSIs produce an enhancement of the monosynaptic connections made by C2 onto other CPG circuit interneurons and onto efferent flexion neurons. Previous work showed that the DSIs are immunoreactive for serotonin. Here we provide evidence that both the neurotransmission and the neuromodulation evoked by the DSIs are produced by serotonin, and that these effects may be pharmacologically separable. 2. Previously it was shown that bath-applied serotonin both mimics and occludes the modulation of the C2 synapses by the DSIs. Here we find that pressure-applied puffs of serotonin mimic both the fast and slow EPSPs evoked by a DSI onto a DFN, whereas high concentrations of bath-applied serotonin occlude both of these synaptic components. 3. Consistent with the hypothesis that serotonin mediates the actions of the DSIs, the serotonin reuptake inhibitor imipramine prolongs the duration of the fast DSI-DFN EPSP, increases the amplitude of the slow DSI-DFN EPSP, and increases both the amplitude and duration of the modulation of the C2-DFN synapse by the DSIs. 4. Two serotonergic antagonists were found that block the actions of the DSIs. Gramine blocks the fast DSI-DFN EPSP, and has far less of an effect on the slow EPSP and the modulation. Gramine also diminishes the depolarization evoked by pressure-applied serotonin, showing that it is a serotonin antagonist in this system. In contrast, methysergide greatly reduces both the slow EPSP and the modulation evoked by the DSIs, but has mixed effects on the fast EPSP. Methysergide also blocks the ability of exogenous serotonin to enhance the C2-DFN EPSP, demonstrating that it antagonizes the serotonin receptors responsible for this modulation. 5. Taken together with previous work, these results indicate that serotonin is likely to be responsible for all three actions of the DSIs that were examined: the fast and slow DSI-DFN EPSPs and the neuromodulation of the C2-DFN synapse. These results also indicate that the conventional and neuromodulatory effects of the DSIs may be pharmacologically separable. In future work it may be possible to determine the functional role of each in the swim circuit.

Adrenergic Uptake Inhibitors↗
PubMed2000

Influence of sacral neuromodulation on electrosensation of the lower urinary tract.

PURPOSE: We prospectively investigated whether neuromodulation of the S3 root influences the sensory threshold to electrical stimulation in the lower urinary tract. MATERIALS AND METHODS: The study included 7 women and 3 men receiving S3 neuromodulation at 210 msec. and 25 Hz. with the Interstim PNE system for a mean of 5 days. Neuromodulation was done unilaterally in 6 cases and bilaterally in 4. The sensory threshold was determined by electrodes placed randomly against the mucosa of the empty bladder on the left and right sides, in the urethra in women, and in the prostatic and penile urethra in men. Thresholds were measured at each location with neuromodulation on and off. RESULTS: With bilateral neuromodulation on all 4 patients had a lower bladder threshold than with neuromodulation off. In unilateral neuromodulation the threshold was significantly lower during neurostimulation on the ipsilateral side. There was no effect on the threshold on the arm or in the urethra. The effect was noted in patients in whom neuromodulation was and was not clinically successful. CONCLUSIONS: Neuromodulation on S3 influences the nervous system involved in electrosensation of the bladder but not the skin afferent innervation or the nerves involved in urethral electrosensation. These data support the hypothesis that S3 neurostimulation is effective mainly through the afferent nervous system in the pelvic nerves.

Adult↗
PubMed2000

Sacral neuromodulation for treatment of lower urinary tract dysfunction.

Despite initial reservations, sacral neuromodulation has begun to develop as a new therapeutic tool for the treatment of lower urinary tract dysfunction. It bridges the gap between conservative treatment options and highly invasive procedures, such as urinary diversion. At present, there are no clinical variables that can reliably predict the efficacy of neuromodulation in an individual patient. All patients, regardless of indication, must therefore undergo a test stimulation before they can be offered chronic sacral neuromodulation with an implanted system. Evaluations in various clinical trials have confirmed that sacral neuromodulation, based on unilateral sacral foramen electrode implantation, has statistically significant therapeutic effects compared to controls, in patients with urge syndromes and failure to empty. The patients most likely to benefit from this treatment are those with detrusor hyperactivity or detrusor hypo-activity. Those with pain syndromes are less likely to respond and to benefit from treatment. Acute and subchronic sacral neuromodulation are associated with very low rates of complications. Complications of chronic sacral neuromodulation are caused either by surgery-related morbidity or hardware problems. Conservative treatment options should be exhausted before neuromodulation is considered. This rule has two purposes: First, it postpones surgery, with its potential morbidity, for as long as possible; second, the long-term efficacy of neuromodulation is still unclear and may be limited in some patients. A fully exploited conservative therapy, in combination with subsequent sacral neuromodulation, may therefore be the optimum way to pursue therapeutic options of relatively low invasiveness.

Electric Stimulation Therapy↗
PubMed2000

Sacral root neuromodulation in the treatment of refractory urinary urge incontinence: a prospective randomized clinical trial.

OBJECTIVES: To compare the effectiveness of sacral root neuromodulation with that of conservative management in ameliorating symptoms of refractory urinary urge incontinence and enhancing quality of life, to assess the objective response to neuromodulation as revealed by urodynamic testing, and to delineate the long-term outcomes of neuromodulation. METHODS: Forty-four patients with refractory urge incontinence were randomized to undergo neuromodulation with an implantable impulse generator (n = 21) or to continue their prior conservative management (n = 23). At 6 months the control group was eligible for crossover to implant. Patient evaluation included voiding diaries, quality of life questionnaires, urodynamic testing, and documentation of adverse events. Long-term follow-up evaluations were conducted at 6-month intervals up to 36 months. RESULTS: At 6 months mean leakage episodes, leakage severity and pad usage in the implant group were significantly lower by 88% (p < 0.0005), 24% (p = 0.047) and 90% (p < 0.0005), respectively, than the corresponding control group mean values. Improvements in leakage episodes and pad usage of >/=90% were attained by 75 and 85% of the implant group, respectively, but none of the control group. One third of implant patients, but none of the control patients, achieved >/=50% improvement in leakage severity. Over half of the implant patients (56%) were completely dry compared with 1 control patient (4%). Implant patients, but not control patients, exhibited significant improvement with respect to two quality of life measures. Neuromodulation resulted in increases of 220% (p < 0.0005) and 39% (p = 0.013), respectively, in urodynamically assessed bladder volume at first contraction and maximum fill. At 36 months the actuarial rate of treatment failure was 32.4% (95% CI, 17.0-56.0%). Adverse events most frequently involved pain at the implant site, and the incidence of serious complications was low. CONCLUSIONS: Neuromodulation is markedly more effective than conservative management in alleviating symptoms of refractory urge incontinence. Quality of life and urodynamic function are also improved by neuromodulation. The effects of neuromodulation are long-lasting, and associated morbidity is low.

Adult↗
PubMed2000

Neuromodulation reduces c-fos gene expression in spinalized rats: a double-blind randomized study.

PURPOSE: Neuromodulation of the sacral nerve roots is effective to treat various voiding dysfunctions, but the underlying mechanism of neuromodulation is not known. The objective of this study is to evaluate whether inhibition of afferent c-fiber activity is the underlying mechanism of sacral nerve root neuromodulation. MATERIALS AND METHODS: Twenty-nine female Sprague-Dawley rats weighing 220 to 250 gm. were divided into 4 groups: normal control (normal rats without any procedure; n = 5), sham with saline (spinalized rats at T9 with saline bladder instillation; n = 7), sham with acetic acid (spinalized rats at T9 with acetic acid bladder instillation; n = 8) and stimulation group (spinalized rats at T9 with acetic acid bladder instillation plus electrical stimulation; n = 9). A cystometrogram was performed 10 days after spinal cord transection to confirm the development of bladder hyperreflexia. Bilateral electrode wires were implanted into S1 dorsal foramina and electrical stimulation was performed 8 hours a day for three weeks. The rats were perfused with 4% paraformaldehyde and an immunocytochemical method was used to stain fos-protein that was encoded by c-fos gene. A double-blind method was used in counting fos-protein positive neurons. RESULTS: Bladder hyperreflexia developed in all spinalized rats 10 days after spinal cord transection. Peak bladder pressure was found significantly reduced after neuromodulation (30.4 +/- 4.2 cm. water) compared with the same rats before neuromodulation (82.4 +/- 10.2 cm. water; p = 0. 007). The number of fos-protein positive neurons in the L6 spinal cord segment in the neuromodulation group (93.2 +/- 13.3 cells/section) decreased significantly when compared with the sham with acetic acid group (160.6 +/- 25.0 cells/section; p = 0.02). There was no significant difference in c-fos expression between the sham with saline group (90.5 +/- 15.6 cells/section) and the neuromodulation group (p = 0.92). CONCLUSIONS: Sacral dorsal root neuromodulation reduces c-fos gene expression and bladder hyperreflexia in spinalized rats, through inhibition of afferent c-fiber activity.

Animals↗
PubMed1986

Neuromodulators and transmitters in respiratory control.

The respiratory control system is influenced by classical neurotransmitters and by neuromodulators. The neuromodulators are neuroactive substances that can be secreted at a distance from their receptors and must diffuse to their site of action. Their function can be nonsynaptic and long lasting, and their effect can be direct or indirect via other neuroactive substances. In the central nervous system, a variable degree of mismatch exists between sites of neuromodulator secretion and reception. The assignment of a natural role for a neuromodulator in respiratory control is strengthened by evidence from a variety of experimental approaches, including localization of receptor sites in respiratory-related areas and evidence for natural binding of neuromodulators to these receptors, neurophysiological and respiratory responses to the neuromodulators and their antagonists, and, finally, modulation of specific respiratory responses by neuromodulator antagonists to document the role of the endogenous modulator in eliciting the original response. Neuromodulators that are considered seriously as natural participants in respiratory control include dopamine in peripheral chemoreception and adenosine, endorphins (including enkephalins), serotonin, and substance P in central respiratory regulation.

Adenosine↗
PubMed2005

Expanding indications for neuromodulation.

Neuromodulation in one form or another has been studied for decades for various disease states. Although its mechanism of action remains un-explained, numerous clinical success stories suggest it is a therapy with efficacy and durability. Controlled studies have led to the approval of sacral neuromodulation for urinary urgency and frequency, urinary retention, and urinary urge incontinence. The future holds hopeful possibilities for the application of neuromodulation, namely in the areas of interstitial cystitis, in-tractable pain syndromes, fecal incontinence and constipation, spinal cord injury, and erectile dysfunction. Neuromodulators have also been used in nonurologic conditions, including chronic headaches and intractable chest pain. In adults and children, in the neurologically intact and neurologically impaired, neuromodulation has been shown to improve the quality of life of those suffering chronic disease states. Neuromodulation is changing the future of urology. Treatment of voiding dysfunction and likely other disorders, such as pelvic pain, sexual dysfunction, and bowel disorders, will no longer rely only on medications that are "OK" or destructive-reconstructive procedures that suffer from significant complications. Rather, by modulating the nerves, the urologists will treat these disorders in a minimally invasive fashion and neuromodulation will become the first-line therapy before any major surgery is undertaken.

Adult↗
PubMed2002

Neuromodulation through sacral nerve roots 2 to 4 with a Finetech-Brindley sacral posterior and anterior root stimulator.

STUDY DESIGN: Investigation of five patients receiving an implant, using laboratory cystometry and self-catheterisation at home. OBJECTIVES: To use the established Finetech-Brindley sacral root stimulator to increase bladder capacity by neuromodulation, eliminating the need for posterior rhizotomy, as well as achieving bladder emptying by neurostimulation. SETTING: Spinal Injuries Unit, Royal National Orthopaedic Hospital, Stanmore, Middlesex, UK. METHODS: Five patients underwent implantation of a Finetech-Brindley stimulator without rhizotomy of the posterior roots. This was either a two channel extradural device (four cases) or a three channel intrathecal device (one case). In each patient, the implant was configured as a Sacral Posterior and Anterior Root Stimulator (SPARS). Postoperatively, repeated provocations using rapid instillation of 60 ml saline were used to determine the relative thresholds for neuromodulation using each channel. The effect of continuous neuromodulation was examined in the laboratory using slow fill cystometrograms, and conditional stimulation was also studied (neuromodulation for 1 min to suppress hyperreflexic contractions as they occurred). In one patient, neuromodulation was applied continuously at home, and volumes at self catheterisation recorded in a diary. RESULTS: Reflex erections were preserved in each patient. In three patients, detrusor hyperreflexia persisted postoperatively and neuromodulation via the implant was studied. In these three patients, the configuration was: S2 mixed roots bilaterally (channel B), and S34 bilaterally (channel A). Both channels could be used to suppress provoked hyperreflexic contractions, with the S2 channel effective at a shorter pulse width than S34 in a majority of cases. Continuous stimulation more than doubled bladder capacity in two out of three patients during slow fill cystometry. Conditional stimulation was highly effective. In the one patient who used continuous stimulation at home, bladder capacity was more than doubled and the effect was comparable with anticholinergic medication. Bladder pressures >70 cm water could be achieved with intense stimulation in three patients, but detrusor-external urethral sphincter dyssynergia (DSD) prevented complete emptying. CONCLUSIONS: Neuromodulation via a SPARS was effective and may replace the need for posterior rhizotomy. However, persisting DSD may prevent complete bladder emptying and warrants further investigation.

Adult↗
PubMed1994

Multiple modes of activity in a model neuron suggest a novel mechanism for the effects of neuromodulators.

1. Previous examination of the phase space of a mathematical model of a bursting molluscan neuron has demonstrated the existence of multiple stable oscillatory modes. The present study examined the extent to which multistability could be regulated by known modulatory agents, the consequences of that regulation on the response of the neuron to synaptic inputs, the effects of noise, and the potential of multistability to enrich the repertoire of neuromodulatory effects. 2. Coexisting stable attractors may appear when a change is made in a voltage-dependent conductance in a manner that simulates the application of a neuromodulator. A small transient perturbation can shift the model neuron between stable modes, greatly amplifying the original perturbation. Thus the model becomes more sensitive to conventional synaptic inputs. These mode shifts are robust in the presence of low-amplitude synaptic noise. 3. In response to random high-amplitude synaptic noise, a model neuron rendered multistable by a simulated application of a neuromodulator produces apparently random activity, whereas in response to the same synaptic noise, a monostable model neuron produces barely perturbed regular activity. Thus an increase in the number of attractors enhances sensitivity to both conventional synaptic inputs and noise. Conversely, a decrease is associated with a reduction in sensitivity. 4. The response of a neuron to a subsequent transient perturbation in the level of neuromodulator depends on the steady-state level of the neuromodulator. For example, if the steady-state level is associated with a multistable neuron, a mode shift produced by such a transient change in the level of neuromodulator (manifested in our model as a conductance change) can persist after the conductance is returned gradually to its original value. Thus multistable dynamic activity permits the effects of a neuromodulator to persist when the neuromodulator is no longer present. 5. The mechanism of mode shifting between coexisting stable oscillatory modes introduces a number of novel possibilities with potentially profound implications for information processing and storage in a single neuron.

Animals↗
PubMed1996

Intrinsic neuromodulation: altering neuronal circuits from within.

There are two sources of neuromodulation for neuronal circuits: extrinsic inputs and intrinsic components of the circuits themselves. Extrinsic neuromodulation is known to be pervasive in nervous systems, but intrinsic neuromodulation is less recognized, despite the fact that it has now been demonstrated in sensory and neuromuscular circuits and in central pattern generators. By its nature, intrinsic neuromodulation produces local changes in neuronal computation, whereas extrinsic neuromodulation can cause global changes, often affecting many circuits simultaneously. Studies in a number of systems are defining the different properties of these two forms of neuromodulation.

Animals↗
PubMed1998

A urodynamic study of surface neuromodulation versus sham in detrusor instability and sensory urgency.

PURPOSE: We studied the effect of surface neuromodulation on cystometric pressure and volume parameters in women with detrusor instability or sensory urgency. Electrical current was delivered to the suprapubic region and third sacral foramina via a transcutaneous electrical nerve stimulator with sham neuromodulation control. MATERIALS AND METHODS: A consecutive series of women with proved detrusor instability or sensory urgency were randomized to 3 surface neuromodulation groups. Volume and pressure parameters were the main outcomes of transcutaneous electrical nerve stimulation applied during second cystometric fill. RESULTS: Sham transcutaneous electrical nerve stimulation did not alter the outcome measures. However, neuromodulation delivered across the suprapubic and sacral skin effected a reduction in mean maximum height of detrusor contraction. A current which inhibits motor activity was not superior to that which inhibits sensory perception in reducing detrusor pressure. Response in sensory urgency was poor. CONCLUSIONS: Results from our sham controlled study suggest that short-term surface neuromodulation via transcutaneous electrical nerve stimulation may have a role in the treatment of detrusor instability. Future studies must examine the clinical effect of long-term surface neuromodulation.

Adult↗
PubMed2004

Urodynamic study of women in urinary retention treated with sacral neuromodulation.

PURPOSE: We investigated the action of sacral neuromodulation in restoring voiding function in women with urinary retention attributable to sphincter overactivity (Fowler's syndrome). MATERIALS AND METHODS: We recruited women within retention who were able to void following neuromodulation by temporary test stimulation or a permanent implant. Urethral pressure profiles, cystometry and sphincter electromyography were performed before and after neuromodulation. RESULTS: A total of 30 women 19 to 52 years old were recruited, including 21 with a permanent implant and 9 undergoing temporary stimulation. Mean maximum urethral closure pressure was elevated compared to expected pressure and it did not change significantly after neuromodulation. The electromyographic abnormality persisted during neuromodulation and voiding was often done with an interrupted flow. There was a slight increase in detrusor contractility. CONCLUSIONS: This evidence suggests that neuromodulation does not restore voiding in these patients by a direct relaxant effect on the sphincter. The modest increase in detrusor pressure appears to be sufficient to overcome the resistance of the overactive sphincter.

Adult↗
PubMed2006

Current opinion on the working mechanisms of neuromodulation in the treatment of lower urinary tract dysfunction.

PURPOSE OF REVIEW: Neuromodulation is a successful treatment for patients with refractory lower urinary tract dysfunction. In the recent years, more applications of various types and ways have been developed and put into clinical practice. It is important, therefore, for urologists to know the existing theories on the working mechanisms that explain the effect. Although much research has been devoted to this subject for the past 35 years, the working mechanism is still unknown. This review presents an overview of the different theories and research into the physiological background of neuromodulation during the past 3 decades with emphasis on recent developments. RECENT FINDINGS: Specific receptors in the spinal cord have been identified, which are involved in the working mechanism of neuromodulation. The maximal effect of neuromodulation is not directly reached, indicating that neuromodulation induces learning changes (i.e. neural plasticity). The carry-over effect could be caused by negative modulation of excitatory synapses in the central micturition reflex pathway. SUMMARY: Neuromodulation in the treatment of stress incontinence probably induces physiological changes in the sphincter muscles and pelvic floor. In the treatment of overactive bladder syndrome, nonobstructive voiding dysfunction and chronic pelvic pain, the mechanism of action seems to be more complicated. Most likely, it is a combination of the different suggested modes of action, involving the neuroaxis at different levels.

Animals↗
PubMed2005

Interaction between neurotransmitter antagonists and effects of sacral neuromodulation in rats with chronically hyperactive bladder.

OBJECTIVE: To investigate to what extent antagonists of spinal neurotransmitters interact with the effects of sacral neuromodulation in a rat model of a chronically hyperactive urinary bladder. MATERIALS AND METHODS: In female rats the urinary bladder was instilled with turpentine oil 2.5% to induce cystitis. After surviving for 10 days the rats were anaesthetized with urethane, the bladder catheterized and connected to a pressure transducer. Stimulating electrodes were placed in the sacral foramina bilaterally. The spinal cord was exposed by a laminectomy, and a small pool was placed on the cord for intrathecal administration of neurotransmitter antagonists. Sacral neuromodulation was applied before and after administering the antagonists. The antagonists used were: memantine, an antagonist for N-methyl-D-aspartate (NMDA) receptors; CNQX, an antagonist for non-NMDA receptors, and L-NAPNA, a blocker of nitric oxide synthase. RESULTS: With no electrical neuromodulation, memantine and L-NAPNA abolished the cystitis-induced bladder contractions for approximately 4 and approximately 37 min, respectively. The effect of CNQX was similar to that of artificial cerebrospinal fluid. Electrical sacral modulation with no antagonists also transiently abolished the bladder contractions; at the highest intensity used, the pause was 2-3 min. Superfusion of the spinal cord with CNQX reduced this effect of neuromodulation significantly, whereas memantine had no influence, and L-NAPNA increased the neuromodulation-induced pause. CONCLUSIONS: The results suggest that non-NMDA receptors are involved in the effects of sacral neuromodulation, whereas NMDA receptors appear to have no role. Nitric oxide is essential for maintaining the chronic hyperactive state of the urinary bladder.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1990

Activity-dependent neuromodulation in Aplysia neuron R15: intracellular calcium antagonizes neurotransmitter responses mediated by cAMP.

1. The effect of electrical activity on the response to the neuromodulators serotonin (5-HT) and the neuropeptide egg-laying hormone (ELH) was studied in the Aplysia bursting pacemaker neuron R15. 2. Previous work has shown that 5-HT and ELH augment R15s bursting activity by enhancing two ionic currents, an inwardly rectifying K+ current (IR) and a voltage-gated Ca2+ current (ICa), and that the enhancement of the currents is mediated by the intracellular second-messenger adenosine 3',5'-cyclic monophosphate (cAMP). Here we show that both spontaneous action potentials and voltage-clamp depolarizations suppress the modulation by 5-HT and ELH of these currents. Both spontaneous and evoked depolarizations decrease the magnitude and dramatically speed the decay of the modulation of IR and ICa. 3. The depolarization-induced suppression is blocked by intracellular ethylene glycol-bis(beta-aminoethyl ether)N,N,N',N',-tetraacetic acid (EGTA), indicating that the suppression is Ca-dependent. The suppression is specific for responses mediated by cAMP; a non-cyclic AMP-mediated response to acetylcholine is not affected by depolarizing pulses. 4. The Ca-dependent suppression of IR modulation differs from the Ca-dependent suppression of ICa modulation. Ca2+ influx decreases the sensitivity of IR to neuromodulators without reducing the maximal response elicited by high concentrations of neuromodulators. In contrast, Ca2+ not only decreases the sensitivity of ICa but also reduces the maximal effect elicited by high concentrations of neuromodulators. We have shown previously that intracellular Ca2+ also inactivates the basal IR and ICa in neuron R15 by distinct mechanisms. The inactivation of IR is due to an antagonistic action of Ca2+ on cAMP metabolism, whereas the inactivation of the basal ICa is due primarily to a more direct action of Ca2+, perhaps on the Ca channels themselves. 5. We also studied the interaction between action potentials and neuromodulator released onto R15 from an endogenous source: bag cell neurons, which release large amounts of ELH during an intense "afterdischarge." IR and ICa become greatly enhanced during the afterdischarge, even though R15 continually fires action potentials. In addition, Ca-dependent inactivation of IR is suppressed during the afterdischarge. We suggest that the bag cells release an amount of ELH sufficient to temporarily saturate the cAMP-mediated enhancement of IR and that this temporarily prevents the suppressive effects of Ca2+ on IR. 6. The activity-dependent suppression of neuromodulation in neuron R15 is an example of neuronal plasticity that results from interactions between intracellular messengers.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed2002

Modulating the modulators: parasites, neuromodulators and host behavioral change.

Neuromodulators can resculpt neural circuits, giving an animal the behavioral flexibility it needs to survive in a complex changing world. This ability, however, provides parasites with a potential mechanism for manipulating host behavior. This paper reviews three invertebrate host-parasite systems to examine whether parasites can change host behavior by secreting neuromodulators. The parasitic wasp, Cotesia congregata, suppresses host feeding partly by inducing the host (Manduca sexta) to increase the octopamine concentration in its hemolymph. The increased octopamine concentration disrupts the motor pattern produced by the frontal ganglion, preventing the ingestion of food. Polymorphus paradoxus (Acanthocephalan) alters the escape behavior of its host, Gammarus lacustris (Crustacea), possibly through an effect on the host's serotonergic system. The trematode Trichobilharzia ocellata inhibits egg-laying in its snail host (Lymnaea stagnalis), partly by inducing the host to secrete schistosomin. Schistosomin decreases electrical excitability of the caudodorsal cells. The parasite also alters gene expression for some neuromodulators within the host's central nervous system. In at least two of these three examples, it appears that the host, not the parasite, produces the neuromodulators that alter host behavior. Producing physiologically potent concentrations of neuromodulators may be energetically expensive for many parasites. Parasites may exploit indirect less energetically expensive methods of altering host behavior. For example, parasites may induce the host's immune system to produce the appropriate neuromodulators. In many parasites, the ability to manipulate host behavior may have evolved from adaptations designed to circumvent the host's immune system. Immune-neural-behavioral connections may be pre-adapted for parasitic manipulation.

Animals↗
PubMed1998

MAP kinase-independent signaling in angiotensin II regulation of neuromodulation in SHR neurons.

Angiotensin II (Ang II), via its interaction with the angiotensin type 1 (AT1) receptor subtype, causes enhanced stimulation of norepinephrine (NE) neuromodulation. This involves increased transcription of NE transporter, tyrosine hydroxylase, and dopamine ss-hydroxylase genes in Wistar-Kyoto rat (WKY) brain neurons. AT1 receptor-mediated regulation of certain signaling events (such as activation of the Ras-Raf-1-mitogen activated protein (MAP) kinase signaling pathway, nuclear translocation of transcription factors such as Fos and Jun, and the interactions of these factors with AP-1 binding sites) is involved in this NE neuromodulation (Lu et al. J Cell Biol. 1996;135:1609-1617). The aim of this study was to compare the signal transduction mechanism of Ang II regulation of NE neuromodulation in WKY and spontaneously hypertensive rat (SHR) brain neurons, in view of the fact that AT1 receptor expression and Ang II stimulation of NE neuromodulation are higher in SHR neurons compared with WKY neurons. Despite this hyperactivity, Ang II stimulation of Ras, Raf-1, and MAP kinase activities was comparable between the neurons from WKY and SHR. Similarly, central injections of Ang II caused a comparable stimulation of MAP kinase in the hypothalamic and brain stem areas of adult WKY and SHR. Inhibition of MAP kinase by either an MAP kinase kinase inhibitor (PD98059) or an MAP kinase antisense oligonucleotide completely attenuated the stimulatory effects of Ang II on [3H]-NE uptake, NE transporter mRNA, and tyrosine hydroxylase mRNA levels in WKY neurons. These treatments resulted in only 43% to 50% inhibition of [3H]-NE uptake and NE transporter and tyrosine hydroxylase mRNAs in SHR neurons. Thus, Ang II stimulation of NE neuromodulation was completely blocked by MAP kinase inhibition in WKY neurons and only partially blocked in the SHR neurons. These observations suggest the presence of an additional signal transduction pathway involved in NE neuromodulation in SHR neurons that is independent of the MAP kinase pathway.

Angiotensin II↗