Interplay between nitric oxide and gonadotrophin-releasing hormone in the neuromodulation of the corpus luteum during late pregnancy in the rat.

BACKGROUND: Nitric oxide and GnRH are biological factors that participate in the regulation of reproductive functions. To our knowledge, there are no studies that link NO and GnRH in the sympathetic ganglia. Thus, the aim of the present work was to investigate the influence of NO on GnRH release from the coeliac ganglion and its effect on luteal regression at the end of pregnancy in the rat. METHODS: The ex vivo system composed by the coeliac ganglion, the superior ovarian nerve, and the ovary of rats on day 21 of pregnancy was incubated for 180 min with the addition, into the ganglionic compartment, of L-NG-nitro arginine methyl ester (L-NAME), a non-selective NO synthase inhibitor. The control group consisted in untreated organ systems. RESULTS: The addition of L-NAME in the coeliac ganglion compartment decreased NO as well as GnRH release from the coeliac ganglion. In the ovarian compartment, and with respect to the control group, we observed a reduced release of GnRH, NO, and noradrenaline, but an increased production of progesterone, estradiol, and expression of their limiting biosynthetic enzymes, 3ß-HSD and P450 aromatase, respectively. The inhibition of NO production by L-NAME in the coeliac ganglion compartment also reduced luteal apoptosis, lipid peroxidation, and nitrotyrosine, whereas it increased the total antioxidant capacity within the corpora lutea. CONCLUSION: Collectively, the results indicate that NO production by the coeliac ganglion modulates the physiology of the ovary and luteal regression during late pregnancy in rats.

Botulinum Toxin Type A for Lumbar Sympathetic Ganglion Block in Complex Regional Pain Syndrome: A Randomized Trial.

BACKGROUND: The present study was designed to test the hypothesis that botulinum toxin would prolong the duration of a lumbar sympathetic block measured through a sustained increase in skin temperature. The authors performed a randomized, double-blind, controlled trial to investigate the clinical outcome of botulinum toxin type A for lumbar sympathetic ganglion block in patients with complex regional pain syndrome. METHODS: Lumbar sympathetic ganglion block was conducted in patients with lower-extremity complex regional pain syndrome using 75 IU of botulinum toxin type A (botulinum toxin group) and local anesthetic (control group). The primary outcome was the change in the relative temperature difference on the blocked sole compared with the contralateral sole at 1 postoperative month. The secondary outcomes were the 3-month changes in relative temperature differences, as well as the pain intensity changes. RESULTS: A total of 48 participants (N = 24/group) were randomly assigned. The change in relative temperature increase was higher in the botulinum toxin group than in the control group (1.0°C ± 1.3 vs. 0.1°C ± 0.8, respectively; difference: 0.9°C [95% CI, 0.3 to 1.5]; P = 0.006), which was maintained at 3 months (1.1°C ± 0.8 vs. -0.2°C ± 1.2, respectively; P = 0.009). Moreover, pain intensity was greatly reduced in the botulinum toxin group compared with the control group at 1 month (-2.2 ± 1.0 vs. -1.0 ± 1.6, respectively; P = 0.003) and 3 months (-2.0 ± 1.0 vs. -0.6 ± 1.6, respectively; P = 0.003). There were no severe adverse events pertinent to botulinum toxin injection. CONCLUSIONS: In patients with complex regional pain syndrome, lumbar sympathetic ganglion block using botulinum toxin type A increased the temperature of the affected foot for 3 months and also reduced the pain.

Parasympathetic, but not sympathetic denervation, suppressed colorectal cancer progression.

Disruption in the nerve-tumor interaction is now considered as a possible anticancer strategy for treating various cancer types, particularly colorectal cancer. However, the underlying mechanisms are not still fully understood. Therefore, the present study aimed to evaluate the effects of sympathetic and parasympathetic denervation on the inhibition of colorectal cancer progression in early and late phases and assess the involvement of nerve growth factor in denervation mediated anticancer effects. One-hundred and fifty male Wistar rats were assigned into 15 groups. Seven groups comprising the control group, 1,2-dimethylhydrazine (DMH) group, sympathetic denervation group (celiac-mesenteric ganglionectomy and guanethidine sulphate administration), parasympathetic denervation group (vagotomy and atropine administration), and combination group were used in the early-stage protocol. For the late-stage protocol, eight groups comprising the control, DMH, surgical and pharmacological sympathetic and parasympathetic denervation groups, combination group, and 5-flourouracil group were considered. After 8 weeks, sympathetic and parasympathetic denervation significantly reduced ACF numbers in rats receiving DMH. On the other hand, in the late stages, parasympathetic but not sympathetic denervation resulted in significant reductions in tumor incidence, tumor volume and weight, cell proliferation (indicated by reduced immunostaining of PCNA and ki-67), and angiogenesis (indicated by reduced immunostaining of CD31 and VEGF expression levels), and downregulated NGF, ß2 adrenergic, and M3 receptors. It can be concluded that parasympathetic denervation may be of high importance in colon carcinogenesis and suggested as a possible therapeutic modality in late stages of colorectal cancer.

Factors associated with Successful Responses to Ganglion Impar Block: A Retrospective Study.

Background: The ganglion impar (ganglion of Walther) block has been used to manage coccygeal and perineal (perianal and genital) pain due to both benign and malignant causes. However, the factors associated with successful responses to ganglion impar block are unknown. Therefore, in the present study, we aimed to identify the independent factors associated with successful responses to ganglion impar block in patients with chronic pain in coccygeal and perineal regions. Methods: From January 2008 to December 2017, we performed a retrospective review of 106 patients who underwent ganglion impar block. Patients were considered successful responders if they reported a decrease of more than 50% or 4 points on the 11-point (0 = no pain and 10 = worst possible pain) numerical rating scale 1 month after the procedure, while others were considered non-responders. Logistic regression analysis was performed to identify factors independently associated with successful responses at 1 month after the procedure. Results: Multivariable logistic regression analysis showed that cancer-related causes were significantly associated with successful responses at 1 month after ganglion impar block (odds ratio = 2.60, 95% confidence interval = 1.05 to 6.43, P = 0.038). Conclusion: Ganglion impar block may be more effective in cancer-related pain than pain due to benign causes.

The Influence of an Adrenergic Antagonist Guanethidine on the Distribution Pattern and Chemical Coding of Caudal Mesenteric Ganglion Perikarya and Their Axons Supplying the Porcine Bladder.

This study was aimed at disclosing the influence of intravesically instilled guanethidine (GUA) on the distribution, relative frequency and chemical coding of both the urinary bladder intramural sympathetic nerve fibers and their parent cell bodies in the caudal mesenteric ganglion (CaMG) in juvenile female pigs. GUA instillation led to a profound decrease in the number of perivascular nerve terminals. Furthermore, the chemical profile of the perivascular innervation within the treated bladder also distinctly changed, as most of axons became somatostatin-immunoreactive (SOM-IR), while in the control animals they were found to be neuropeptide Y (NPY)-positive. Intravesical treatment with GUA led not only to a significant decrease in the number of bladder-projecting tyrosine hydroxylase (TH) CaMG somata (94.3 ± 1.8% vs. 73.3 ± 1.4%; control vs. GUA-treated pigs), but simultaneously resulted in the rearrangement of their co-transmitters repertoire, causing a distinct decrease in the number of TH+/NPY+ (89.6 ± 0.7% vs. 27.8 ± 0.9%) cell bodies and an increase in the number of SOM-(3.6 ± 0.4% vs. 68.7 ± 1.9%), calbindin-(CB; 2.06 ± 0.2% vs. 9.1 ± 1.2%) or galanin-containing (GAL; 1.6 ± 0.3% vs. 28.2 ± 1.3%) somata. The present study provides evidence that GUA significantly modifies the sympathetic innervation of the porcine urinary bladder wall, and thus may be considered a potential tool for studying the plasticity of this subdivision of the bladder innervation.

Inhibition of the norepinephrine transporter rescues vascular hyporeactivity to catecholamine in obstructive jaundice.

In patients with obstructive jaundice, the cardiovascular system exhibits hypotension and vascular hyporeactivity. Most norepinephrine is taken up through the neuronal norepinephrine transporter (NET), which is implicated in cardiovascular diseases. A previous study demonstrated that pharmacological NET inhibition could increase resting blood pressure. However, the role of NETs in vascular hyporeactivity induced by obstructive jaundice is poorly understood. This study used the NET inhibitor nisoxetine and a rat model of bile duct ligation (BDL) to investigate whether NET is associated with BDL-induced vascular hyporeactivity. Rats were injected with nisoxetine via the tail vein for 7 consecutive days after BDL. Samples of the superior cervical sympathetic ganglion (SCG) and thoracic aortic rings were processed for investigations. Our results showed that NET expression in the SCG was significantly increased after BDL. Nisoxetine prevented the augmentation of NET expression, increased α1-adrenoceptor activation, and enhanced the weakened contractile responses of thoracic aortic rings after BDL. Our study demonstrates that nisoxetine plays a protective role in BDL-induced vascular hyporeactivity through increased α1-adrenoceptor activation in rats.

Sympathetic Input to Multiple Cell Types in Mouse and Human Colon Produces Region-Specific Responses.

BACKGROUND & AIMS: The colon is innervated by intrinsic and extrinsic neurons that coordinate functions necessary for digestive health. Sympathetic input suppresses colon motility by acting on intrinsic myenteric neurons, but the extent of sympathetic-induced changes on large-scale network activity in myenteric circuits has not been determined. Compounding the complexity of sympathetic function, there is evidence that sympathetic transmitters can regulate activity in non-neuronal cells (such as enteric glia and innate immune cells). METHODS: We performed anatomical tracing, immunohistochemistry, optogenetic (GCaMP calcium imaging, channelrhodopsin), and colon motility studies in mice and single-cell RNA sequencing in human colon to investigate how sympathetic postganglionic neurons modulate colon function. RESULTS: Individual neurons in each sympathetic prevertebral ganglion innervated the proximal or distal colon, with processes closely opposed to multiple cell types. Calcium imaging in semi-intact mouse colon preparations revealed changes in spontaneous and evoked neural activity, as well as activation of non-neuronal cells, induced by sympathetic nerve stimulation. The overall pattern of response to sympathetic stimulation was unique to the proximal or distal colon. Region-specific changes in cellular activity correlated with motility patterns produced by electrical and optogenetic stimulation of sympathetic pathways. Pharmacology experiments (mouse) and RNA sequencing (human) indicated that appropriate receptors were expressed on different cell types to account for the responses to sympathetic stimulation. Regional differences in expression of α-1 adrenoceptors in human colon emphasize the translational relevance of our mouse findings. CONCLUSIONS: Sympathetic neurons differentially regulate activity of neurons and non-neuronal cells in proximal and distal colon to promote distinct changes in motility patterns, likely reflecting the distinct roles played by these 2 regions.

Long-term potentiation is differentially expressed in rostral and caudal neurons in the superior cervical ganglion of normal and hypertensive rats.

Neurons in the superior cervical ganglia (SCG) are classified as rostral and caudal according to their regional locations. Although diverse phenotypes have been reported for these two subpopulations, differences in neuroplasticity, like long-term potentiation (LTP), have not been characterized. Here, we explored possible regional differences of LTP expression in rostral and caudal neurons of the SCG in control rats, Wistar and Wistar Kyoto (WKy), and in the spontaneously hypertensive rats (SHR) as a model of hypertension. We characterized the expression of gLTP evoked by a tetanic train (40 Hz, 3 s) in an in vitro SCG preparation. gLTP was recorded in rostral and caudal neurons at 8-weeks-old (wo) in Wistar rats, 6-wo and 12-wo in SHR and WKy rats. We found that gLTP was differentially expressed; gLTP was larger in caudal neurons in Wistar and adult WKy rats. In adult 12-wo hypertensive SHR, gLTP was expressed in caudal but not in rostral neurons. In contrast, in 6-wo pre-hypertensive SHR, gLTP was expressed in rostral but not in caudal neurons; while in 6-wo WKy, gLTP was expressed in caudal but not in rostral neurons. The lack of gLTP expression in caudal neurons of 6-wo SHR was not due to a GABAergic modulation because several GABA-A receptor antagonists failed to unmask gLTP. Data show that neuroplasticity, particularly gLTP expression, varied according to the ganglionic region. We propose that differential regional expression of gLTP may be correlated with selective innervation on different target organs.

Resiniferatoxin reduces ventricular arrhythmias in heart failure via selectively blunting cardiac sympathetic afferent projection into spinal cord in rats.

Excessive sympathetic activity is associated with heart failure and ventricular arrhythmias, which regulated by enhanced cardiac sympathetic afferent reflex, which can be blunted by resiniferatoxin, a selective receptor agonist of transient vanilloid potential 1 (TRPV1) + primary sensory afferents. The present study is aimed to determine whether intrathecal resiniferatoxin application affect cardiac sympathetic tone and electrophysiology, furtherly create a new effective strategy to prevent lethal arrhythmias in chronic heart failure. Four weeks after coronary artery occlusion to induce heart failure in rats, RTX (2µg/10 µl) or vehicle was injected intrathecally into the T2/T3 interspace. Cardiac sympathetic nerve activities (CSNA) and cardiac electrophysiology were evaluated two weeks later. Intrathecal resiniferatoxin significantly and selectively abolished the afferent markers expression (TRPV1 and calcitonin gene-related peptide) in dorsal horn and reduced overactivated CSNA. Electrophysiological studies revealed that resiniferatoxin administration intrathecally significantly reversed the prolongation of action potential duration (APD) and APD alternan, reduced the inducibilities of ventricular arrhythmias. Moreover, the over-activated calcium handling related protein CaMKII and RyR2 in heart failure was reversed by resiniferatoxin administration. In conclusion, these results firstly demonstrate that central chemo-ablation of the TRPV1+ afferents in spinal cord prevent heart from ventricular arrhythmias in heart failure via selectively blunting cardiac sympathetic afferent projection into spinal cord, which suggest a novel promising therapeutic method for anti-arrhythmia in heart failure.

Ganglionic Long-Term Potentiation in Prehypertensive and Hypertensive Stages of Spontaneously Hypertensive Rats Depends on GABA Modulation.

The sympathetic nervous system (SNS) regulates body functions in normal and pathological conditions and is characterized by the presence of a neuroplastic phenomenon, termed ganglionic long-term potentiation (gLTP). In hypertension, either in spontaneously hypertensive rats (SHR) or in humans, sympathetic hyperfunction, such as elevated SNS outflow and changes in synaptic plasticity have been described. Because enhanced SNS outflow is detected in the hypertensive stage and, more importantly, in the prehypertensive phase of SHR, here we explored whether synaptic plasticity, particularly gLTP, was modified in the superior cervical ganglia (SCG) of prehypertensive SHR. Furthermore, considering that GABA modulates sympathetic synaptic transmission and gLTP in Wistar rats, we studied whether GABA might modulate gLTP expression in SHR. We characterized gLTP in the SCG of young prehypertensive 6-week-old (wo) and adult hypertensive (12 wo) SHR and in the SCG of Wistar Kyoto (WKy) normotensive control rats of the same ages. We found that gLTP was expressed in 6 wo SHR, but not in 12 wo rats. By contrast, in WKy, gLTP was expressed in 12 wo, but not in 6 wo rats. We also found that gLTP depends on GABA modulation, as blockade of GABA-A subtype receptors with its antagonist bicuculline unmasked gLTP expression in adult SHR and young WKy. We propose that (1) activity-dependent changes in synaptic efficacy are altered not only during hypertension but also before its onset and (2) GABA may play a modulatory role in the changes in synaptic plasticity in SHR, because the blockade of GABA-A receptors unmasked the expression of gLTP. These early changes in neuroplasticity and GABA modulation of gLTP could be part of the sympathetic hyperfunction observed in hypertension.

C-Arm Guided Percutaneous Radiofrequency Thoracic Sympathectomy for Treatment of Primary Palmar Hyperhidrosis in Comparison with Local Botulinum Toxin Type A Injection, Randomized Trial.

BACKGROUND: Hyperhidrosis is a disorder associated with detrimental effects on patients' quality of life, occupational activities, and social interactions. OBJECTIVES: This study compares C-arm guided percutaneous radiofrequency (RF) ablation of the second and third thoracic sympathetic ganglions and local intradermal botulinum toxin type A (BTX-A) injection for the treatment of primary palmar hyperhidrosis. It focuses on clinical effectiveness, patient satisfaction, quality of life, safety, and the time at which repetition of the procedure is needed over one-year follow-up. STUDY DESIGN: This is a randomized single-blinded trial. SETTING: This study took place in a single hospital. METHODS: Eighty patients with primary palmar hyperhidrosis were randomly assigned to one of 2 interventions: local intradermal BTX-A injection (n = 40) or C-arm guided percutaneous RF ablation (n = 40). The Dermatology Life Quality Index (DLQI) questionnaire and the Hyperhidrosis Disease Severity Scale (HDSS) were used for assessment at one week, one month, and 2, 6, and 12 months after intervention. The number of patients who required repetition of the procedure later on and the time at which they needed it were recorded, and possible side effects were assessed. RESULTS: HDSS scores in the RF group were statistically significantly lower than in the BTX-A group at one week, one month, and 2, 6, and 12 months of follow-up. DLQI scores in the RF group were statistically significantly lower than in the BTX-A group at 6- and 12-month follow-up, whereas at one week, one month, and 2 months of follow-up, there was no statistically significant difference between both groups. The number of patients who required that the procedure be repeated was statistically significantly lower in the RF group than in the BTX-A group. The time at which patients needed repetition of the procedure in the BTX-A group was about 3 to 7 months after the first intervention. All patients in this group showed an increase in HDSS scores within this one-year follow-up. In the RF group, however, only one patient complained of increased HDSS scores after 8 months. There was no statistically significant difference in side effects between both groups. LIMITATIONS: The first limitation of this study is that results were based on subjective scales. The second is the radiation exposure associated with the technique described. CONCLUSIONS: This study supports percutaneous C-arm guided RF ablation of the second and third thoracic sympathetic ganglions and local intradermal BTX-A injection as safe, effective options and rapid lines of treatment of primary palmar hyperhidrosis. However, percutaneous RF ablation proved to be more effective, with longer effectiveness time and better patient satisfaction, compared to local intradermal BTX-A injection. KEY WORDS: Botulinum toxin, hyperhidrosis, quality, radiofrequency ablation.

Functional Pathway Between Cervical Spinal and Sympathetic Ganglia: A Neurochemical Foundation Between Neck Pain and Vertigo.

BACKGROUND: Cervical vertigo commonly concurs in patients with neck pain, but the concurrent mechanism of these 2 symptoms still remains unclear. We previously reported a bidirectional segmental nerve fiber connection between cervical spinal and sympathetic ganglia, which provided a hypothesis that this connection between the 2 ganglia may be the anatomic basis for the concurrence of neck pain and cervical vertigo. However, this concurrent mechanism needs biochemical and functional evidence. OBJECTIVES: This study aimed to investigate a possible noradrenergic pathway between cervical spinal and sympathetic ganglia. STUDY DESIGN: We performed both clinical and laboratory research. Clinical observation was a prospective case-control study. SETTING: Clinical study took place in our hospital; laboratory study was in an orthopedic laboratory. METHODS: Cervical lamina block therapy used in patients with cervical vertigo was clinically evaluated; norepinephrine (NE) expressions in cervical sympathetic ganglia were analyzed using immunohistochemical staining after electrical stimulation to the cervical spinal ganglia; the influence of phentolamine local injection to the vertebrobasilar artery flow was experimentally measured. RESULTS: Cervical lamina block therapy could significantly shorten the clinical hospital stays of patients with cervical vertigo (P = 0.000) and improve vertebral artery flow (P < 0.05). NE expressions in superior cervical sympathetic ganglia (SCG) or inferior cervical sympathetic ganglia (ICG) increased significantly when ipsilateral C2 to C3 or C6 to C8 spinal ganglia were electrically stimulated, respectively. Adrenergic receptor block with phentolamine significantly inhibited the decrease of basilar artery (BA) flow induced by electrical stimulation of the cervical spinal ganglia. The change range of BA flow caused by stimulations of C2 to C3 and C6 to C8 spinal ganglia was more than that of C4 and C5. LIMITATIONS: The inpatients observed in this clinical study might be influenced by some factors including emotion, diet, sleep, and others. The limitations of the laboratory study included animal species and small sample size. CONCLUSIONS: Adrenergic system could play a part in cervical spinal ganglia altering the vertebrobasilar artery system. It could provide a neurochemical foundation between neck pain and vertigo, and that segmental functional connections exist between cervical spinal and sympathetic ganglia. KEY WORDS: Cervical vertigo, neck pain, cervical sympathetic ganglia, cervical spinal ganglia, noradrenaline.

The NADPH oxidase inhibitor apocynin improves cardiac sympathetic nerve terminal innervation and function in heart failure.

NEW FINDINGS: What is the central question of this study? Does NADPH oxidase activation mediate cardiac sympathetic nerve denervation and dysfunction in heart failure. What is the main findings and its importance? Cardiac sympathetic nerve terminal density and function were reduced in heart failure after myocardial infarction in rabbits. The NADPH oxidase inhibitor apocynin prevented the reduction in cardiac sympathetic nerve terminal density and function in heart failure. This suggest that NADPH oxidase activation mediates cardiac sympathetic nerve terminal abnormalities in heart failure. NADPH oxidase may be a potential therapeutic target for cardiac sympathetic denervation and dysfunction in heart failure. ABSTRACT: Congestive heart failure (CHF) is characterized by cardiac sympathetic nerve terminal abnormalities, as evidenced by decreased noradrenaline transporter (NAT) density and cardiac catecholaminergic and tyrosine hydroxylase (TH) profiles. These alterations are associated with increased reactive oxygen species (ROS). NADPH oxidase is a major source of ROS in CHF. In this study, we tested the hypothesis that NADPH oxidase activation mediates cardiac sympathetic nerve terminal abnormalities in CHF. CHF was produced by myocardial infarction (MI) in rabbits. Rabbits with MI or a sham operation were randomized to orally receive an NADPH oxidase inhibitor, apocynin (6 mg kg-1  day-1 ), or placebo for 30 days. MI rabbits exhibited left ventricular dilatation, systolic dysfunction, and increases in NADPH oxidase activity and 4-hydroxynonenal expression in the remote non-infarcted myocardium, all of which were prevented by treatment with apocynin. Cardiac catecholaminergic histofluorescence profiles and immunostained TH and PGP9.5 expression were decreased, and the decreases were ameliorated by apocynin treatment. NAT, TH and PGP9.5 protein and mRNA expression were reduced and the reduction was mitigated by apocynin treatment. The effects of apocynin were confirmed by utilizing the NADPH oxidase inhibitor diphenyleneiodonium in a separate experiment. In conclusion, the NADPH oxidase inhibitor apocynin attenuated increased myocardial oxidative stress and decreased cardiac sympathetic nerve terminals in CHF after MI in rabbits. These findings suggest that the activation of NADPH oxidase mediates cardiac sympathetic nerve terminal abnormalities in CHF, and the inhibition of NADPH oxidase may be beneficial for the treatment of heart failure.

Intrathecal Administration of Losartan Reduces Directly Recorded Cardiac Sympathetic Nerve Activity in Ovine Heart Failure.

Early and preferential activation of cardiac sympathetic nerve activity (CSNA) is one of the strongest prognostic markers of heart failure (HF) in patients. Our previous studies have implicated central angiotensin mechanisms as playing a critical role in generating this increase in cardiac sympathetic drive. However, it is unclear if inhibition of AT1R (angiotensin type-1 receptors) in different neural groups in the sympathetic pathway to the heart, such as the sympathetic preganglionic neurons in the intermediolateral column of the spinal cord, can reduce cardiac sympathetic drive. We hypothesized that in HF, localized intrathecal administration of the AT1R antagonist losartan, specifically into the T1-2 subarachnoid space, would decrease CSNA. In normal conscious sheep, intrathecal infusion of Ang II (angiotensin II; 3.0 nmol/mL per hour), significantly increased mean arterial pressure and CSNA; this effect was abolished by prior administration of losartan (1 mg/h). In an ovine rapid ventricular pacing model of HF, the resting levels of heart rate and CSNA were significantly elevated compared with normals. Intrathecal infusion of losartan (1 mg/h) in HF significantly reduced CSNA and heart rate but did not change arterial pressure. The AT1R binding density in the spinal cord was also elevated in the HF group. Our data suggest that AT1Rs within the spinal cord are responsible, in part, for the increased CSNA in HF and may represent a target for the selective reduction of CSNA in HF.

Age-Dependent Effects of NO on Rhythmic Activity of Postganglionic Sympathetic Fibers.

We studied the effects of exogenous NO donor (sodium nitroprusside) and NO synthesis blocker (100 µM L-NAME) on baseline electrical activity of postganglionic fibers in the sympathetic superior cervical in rats during postnatal ontogeny. Starting the age of 20 days, sodium nitroprusside increased the mean discharge amplitude and the spectrum power in the respiratory (0.7-1.5 Hz) and cardiac (4-7 Hz) frequency bands. In contrast, application of L-NAME for 1 h decreased the spectrum power in these bands. Both agents produced no significant effect on the rhythmic sympathetic discharges at frequencies >8 Hz.

Cardiac Afferent Denervation Abolishes Ganglionated Plexi and Sympathetic Responses to Apnea: Implications for Atrial Fibrillation.

Background The autonomic nervous system response to apnea and its mechanistic connection to atrial fibrillation (AF) are unclear. We hypothesize that sensory neurons within the ganglionated plexi (GP) play a role. We aimed to delineate the autonomic response to apnea and to test the effects of ablation of cardiac sensory neurons with resiniferatoxin (RTX), a neurotoxic TRPV1 (transient receptor potential vanilloid 1) agonist. Methods Sixteen dogs were anesthetized and ventilated. Apnea was induced by stopping ventilation until oxygen saturations decreased to 80%. Nerve recordings from bilateral vagal nerves, left stellate ganglion, and anterior right GP were obtained before and during apnea, before and after RTX injection in the anterior right GP (protocol 1, n=7). Atrial effective refractory period and AF inducibility on single extrastimulation were assessed before and during apnea, and before and after intrapericardial RTX administration (protocol 2, n=9). GPs underwent immunohistochemical staining for TRPV1. Results Apnea increased anterior right GP activity, followed by clustered crescendo vagal bursts synchronized with heart rate and blood pressure oscillations. On further oxygen desaturation, a tonic increase in stellate ganglion activity and blood pressure ensued. Apnea-induced effective refractory period shortening from 110.20±31.3 ms to 90.6±29.1 ms ( P<0.001), and AF induction in 9/9 dogs versus 0/9 at baseline. After RTX administration, increases in GP and stellate ganglion activity and blood pressure during apnea were abolished, effective refractory period increased to 126.7±26.9 ms ( P=0.0001), and AF was not induced. Vagal bursts remained unchanged. GP cells showed cytoplasmic microvacuolization and apoptosis. Conclusions Apnea increases GP activity, followed by vagal bursts and tonic stellate ganglion firing. RTX decreases sympathetic and GP nerve activity, abolishes apnea's electrophysiological response, and AF inducibility. Sensory neurons play a role in apnea-induced AF.

Target validation: Weak selectivity of LY341495 for mGluR2 over mGluR4 makes glutamate a less selective agonist.

Metabotropic glutamate receptors (mGluRs) are class C G protein coupled receptors with widespread expression in the central nervous system. There are eight mGluRs in the mammalian genome. Research on mGluRs relies on the availability of selective compounds. While many selective allosteric compounds have been described, selectivity of orthosteric agonists and antagonists has been more difficult due to the similarity of the glutamate binding pocket across the mGluR family. LY341495 has been used for decades as a potent and selective group II mGluR antagonist. The selectivity of LY341495 was investigated here between mGluR2, a group II mGluR, and mGluR4, a group III receptor, heterologously expressed in adult rat sympathetic neurons from the superior cervical ganglion (SCG), which provides a null-mGluR background upon which mGluRs were examined in isolation. The compound does in fact selectively inhibit mGluR2 over mGluR4, but in such a way that it makes signaling of the two receptors more difficult to distinguish. The glutamate potency of mGluR2 is about 10-fold higher than mGluR4. 50 nmol L-1 LY341495 did not alter mGluR4 signaling but shifted the mGluR2 glutamate dose-response about 10-fold, such that it overlapped more closely with that of mGluR4. Increasing the LY341494 dose to 500 nmol L-1 further shifted the glutamate dose-response of mGluR2 by another ~10-fold, but also shifted that of mGluR4 similarly. Thus, while glutamate is a moderately selective agonist of mGluR2 over mGluR4 when applied alone, in the presence of increasing concentrations of LY341495, this selectivity of glutamate is lost.

Ganglionic and ovarian action of acetylcholine during diestrous II in rats. Neuroendocrine control of the luteal regression.

Our aim was to investigate if acetylcholine (Ach), added to the celiac ganglion-superior ovarian nerve-ovary system (CG-SON-ovary) or in ovary incubations, modifies the release of progesterone (P4), androstenedione (A2), dopamine (DA), norepinephrine (NE), gonadotropin-releasing hormone (GnRH), and alters the expression of 3ß-hydroxysteroid dehydrogenase (3ß-HSD), 20α-hydroxysteroid dehydrogenase (20α-HSD), and apoptotic genes in ovarian tissue during the diestrous II (DII) in rats. The CG-SON-ovary system or the ovary alone were removed and placed into separate cuvettes both containing Krebs-Ringer solution (control groups). In experimental groups, 10-6 M Ach was added into the ganglion compartment or into the ovary compartment. P4, A2 and GnRH were measured by RIA, mRNA expression by RT-PCR, and catecholamines by HPLC. In addition, a routine histological technique was applied. In ex-vivo system, 10-6 M Ach into the ganglion compartment decreased P4 and NE release, altered 3ß-HSD and 20α-HSD expression, and decreased bax/bcl-2 ratio, while increasing the release of A2 and DA, and bcl-2 expression. In ovary incubations, 10-6 M Ach decreased P4 and GnRH release, decreased 3ß-HSD and bcl-2 expression, increased A2 release, increased 20α-HSD and bax expression, and the bax/bcl-2 ratio, and induced disorganization of the corpus luteum structure. The peripheral nervous system protected the ovary from the apoptotic mechanisms while in the ovary incubation the effect was reversed. Our results indicate that Ach in DII regulates steroidogenesis and apoptosis in the ovary, by modulating the concentration of neurotransmitters. In vivo, an alteration in the extrinsic cholinergic innervation of the ovary could disrupt the endocrine control of the reproductive function.

The efficacy of the ganglion impar block in perineal and pelvic cancer pain.

BACKGROUND: Visceral pain conducted by sympathetic fibers with pelvic and perineal origin can be treated using ganglion impar (GIB) or Walters' block in a simple and effective manner. This article aims to evaluate the effectiveness, security, and performance difficulty of GIB in patients with pelvic and perineal oncological pain. METHODS: A retrospective study between January 2016 and August 2017. Patients with poorly controlled pelvic oncological pain and patients experimenting opioid side effects in which GIB was performed ambulatory were included. Prognostic GIB was performed, under echographic and fluoroscopic control, with local anesthetic and corticoid. The neurolytic block was performed under fluoroscopic guidance. The technique was performed by the same anesthetist with pain management competence. For statistical analysis, Microsoft Excel 2013® and IBM SPSS Statistics version 22.0 were used. RESULTS: Fifteen patients were included. One patient was excluded. A statistical significant basal pain score reduction was observed ((median of the verbal numerical scale (VNS) 7 (p25 = 7; p75 = 8)) compared with 72 h median VNS 4 ((p25 = 3; p75 = 5.3) p = 0.001, and 3 months (median VNS 4 (p25 = 3, p75 = 7)) p = 0.003 after the procedure. Regarding morphine consumption, a statistically significant reduction was observed 3 months after GIB performance (p = 0.012). DISCUSSION/CONCLUSION: GIB is a safe and easy-to-perform technique achieving satisfactory and statistically significant results, regarding pain control improvement and opioid consumption reduction in patients which meet selection criteria. Prospective, randomized studies with more patients are needed for further conclusions.

Combined Celiac Ganglia and Plexus Neurolysis Shortens Survival, Without Benefit, vs Plexus Neurolysis Alone.

BACKGROUND & AIMS: Pancreatic cancer produces debilitating pain that opioids often ineffectively manage. The suboptimal efficacy of celiac plexus neurolysis (CPN) might result from brief contact of the injectate with celiac ganglia. We compared the effects of endoscopic ultrasound-guided celiac ganglia neurolysis (CGN) vs the effects of CPN on pain, quality of life (QOL), and survival. METHODS: We performed a randomized, double-blind trial of patients with unresectable pancreatic ductal adenocarcinoma and abdominal pain; 60 patients (age 66.4±11.6 years; male 66%) received CPN and 50 patients (age 66.8±10.0 years; male 56%) received CGN. Primary outcomes included pain control and QOL at week 12 and survival (overall median and 12 months). Secondary outcomes included morphine response, performance status, secondary neurolytic effects, and adverse events. RESULTS: Rates of pain response at 12 weeks were 46.2% for CGN and 40.4% for CPN (P = .84). There was no significant difference in improvement of QOL between the techniques. The median survival time was significantly shorter for patients receiving CGN (5.59 months) compared to (10.46 months) (hazard ratio for CGN, 1.49; 95% CI, 1.02-2.19; P = .042), particularly for patients with non-metastatic disease (hazard ratio for CGN, 2.95; 95% CI, 1.61-5.45; P < .001). Rates of survival at 12 months were 42% for patients who underwent CPN vs 26% for patients who underwent CGN. The number of adverse events did not differ between techniques. CONCLUSION: In a prospective study of patients with unresectable pancreatic ductal adenocarcinoma and abdominal pain, we found CGN to reduce median survival time without improving pain, QOL, or adverse events, compared to CPN. The role of CGN must be therefore be reassessed. Clinicaltrials.gov no: NCT01615653.