Release Of Sensory Neuropeptides Research Articles

Anti-CGRP antibody galcanezumab modifies the function of the trigeminovascular nocisensor complex in the rat

BackgroundMonoclonal antibodies directed against the neuropeptide calcitonin gene-related peptide (CGRP) are effective in the prevention of chronic and frequent episodic migraine. Since the antibodies do not cross the blood brain barrier, their antinociceptive effect is attributed to effects in meningeal tissues. We aimed to probe if such an antibody can be visualized within the dura mater and the trigeminal ganglia following its administration to rats and to examine if the activity of the trigeminovascular nocisensor complex is influenced by this treatment.MethodsEffects of the anti-CGRP antibody galcanezumab on the trigeminovascular nocisensor complex was examined by measuring release of sensory neuropeptides and histamine from the rat dura mater. Deposits of galcanezumab were visualized by fluorescence microscopy in the trigeminal ganglion and the dura mater.ResultsFluorophore-labelled galcanezumab was detected in the dura mater and the trigeminal ganglion up to 30 days after treatment affirming the long-lasting modulatory effect of this antibody. In female rats, seven days after systemic treatment with galcanezumab the capsaicin-induced release of CGRP was decreased, while that of substance P (SP) was increased in the dura mater. In control rats, release of the inhibitory neuropeptide somatostatin (SOM) was higher in females than in males. Stimulation with high concentration of KCl did not significantly change the release of SOM in control animals, while in rats treated with galcanezumab SOM release was slightly reduced. Galcanezumab treatment also reduced the amount of histamine released from dural mast cells upon stimulation with CGRP, while the effect of compound 48/80 on histamine release was not changed.ConclusionsGalcanezumab treatment is followed by multiple changes in the release of neuropeptides and histamine in the trigeminal nocisensor complex, which may contribute to the migraine preventing effect of anti-CGRP antibodies. These changes affecting the communication between the components of the trigeminal nocisensor complex may reduce pain susceptibility in migraine patients treated with CGRP targeting monoclonal antibodies.

Painful diabetic neuropathy leads to functional CaV3.2 expression and spontaneous activity in skin nociceptors of mice

Painful diabetic neuropathy occurs in approximately 20% of diabetic patients with underlying pathomechanisms not fully understood. We evaluated the contribution of the CaV3.2 isoform of T-type calcium channel to hyperglycemia-induced changes in cutaneous sensory C-fiber functions and neuropeptide release employing the streptozotocin (STZ) diabetes model in congenic mouse strains including global knockouts (KOs). Hyperglycemia established for 3–5 weeks in male C57BL/6J mice led to major reorganizations in peripheral C-fiber functions. Unbiased electrophysiological screening of mechanosensitive single-fibers in isolated hairy hindpaw skin revealed a relative loss of (polymodal) heat sensing in favor of cold sensing. In healthy CaV3.2 KO mice both heat and cold sensitivity among the C-fibers seemed underrepresented in favor of exclusive mechanosensitivity, low-threshold in particular, which deficit became significant in the diabetic KOs. Diabetes also led to a marked increase in the incidence of spontaneous discharge activity among the C-fibers of wildtype mice, which was reduced by the specific CaV3.2 blocker TTA-P2 and largely absent in the KOs. Evaluation restricted to the peptidergic class of nerve fibers - measuring KCl-stimulated CGRP release - revealed a marked reduction in the sciatic nerve by TTA-P2 in healthy but not diabetic wildtypes, the latter showing CGRP release that was as much reduced as in healthy and, to the same extent, in diabetic CaV3.2 KOs. These data suggest that diabetes abrogates all CaV3.2 functionality in the peripheral nerve axons. In striking contrast, diabetes markedly increased the KCl-stimulated CGRP release from isolated hairy skin of wildtypes but not KO mice, and TTA-P2 reversed this increase, strongly suggesting a de novo expression of CaV3.2 in peptidergic cutaneous nerve endings which may contribute to the enhanced spontaneous activity. De-glycosylation by neuraminidase showed clear desensitizing effects, both in regard to spontaneous activity and stimulated CGRP release, but included actions independent of CaV3.2. However, as diabetes-enhanced glycosylation is decisive for intra-axonal trafficking, it may account for the substantial reorganizations of the CaV3.2 distribution. The results may strengthen the validation of CaV3.2 channel as a therapeutic target of treating painful diabetic neuropathy.

Role of Neuro‐immune Interactions in a Cigarette Smoke‐induced Chronic Airway Inflammation Mouse Model

Chronic obstructive pulmonary disease characterized by progressive persistent airway inflammation & airway resistance is caused mainly by cigarette smoke‐triggered inflammatory cascades & tissue damage. The airways are densely innervated by capsaicin‐sensitive sensory nerves expressing Transient Receptor Potential Vanilloid 1 (TRPV1) ion channels, which play an important regulatory role in inflammation through the release of sensory neuropeptides. Pro‐inflammatory peptides, such as tachykinins (substance P, neurokinin A) encoded by the TAC1 gene induce neurogenic inflammation via NK1 & NK2 receptor activation in the innervated area. The overall significance of these mediators depends on the pathophysiological mechanisms involved in certain inflammatory processes. Therefore, we established a predictive mouse model of cigarette smoke‐induced chronic bronchitis & consequent airway hyperresponsiveness to investigate the roles of TRPV1 channel & tachikinins.We exposed TRPV1−/− & TAC1−/− gene‐deleted mice and their C57Bl/6 wildtype counterparts to cigarette smoke in a whole body smoke exposure chamber for 3 months. Bronchial responsiveness & enhanced pause (Penh) correlating with airway resistance to inhalation of 22 mM carbachol were measured with unrestrained whole body plethysmography weekly. At the end of each month inflammatory cell profile and count from the bronchoalveolar lavage fluid (BALF), semiquantitative histopathological scoring of the lung, myeloperoxidase (MPO) activity with spectrophotometry & IL‐1β concentrations with ELISA were performed.In wildtype mice mild bronchial hyperresponsiveness developed in the 1st month, then it decreased & started to increase after 10 weeks. The inflammatory cell peak in BALF was observed in the 2nd month, correlating with the histology. In the 1st month significant perivascular/peribronchial edema, in the 2nd month remarkable inflammatory cell accumulation, then increasing atelectasy, emphysema, mucus production & irregular bronchiolar mucosa were observed. Lung IL‐1β concentration gradually increased, but MPO activity only transiently elevated in the 2nd month. Hyperreactivity occured earlier & increased significantly in TRPV1−/−, but did not change in TAC1−/− mice. Remarkably more severe inflammatory histopathological parameters, higher BALF cell counts, MPO activity a& IL‐1β production were observed in TRPV1‐deficient mice. Meanwhile, some inflammatory alterations in the 1st month, & BALF cell counts in the 2nd month were significantly decreased in the TAC1 gene‐deleted mice.Neurogenic inflammatory mechanisms are not crucial in chronic cigarette smoke‐induced inflammation & hyperresponsiveness. The overall role of TRPV1 receptor is protective in smoking‐induced chronic bronchitis.Support or Funding InformationÚNKP‐18‐3 New National Excellence Program of the Ministry of Human CapacitiesThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The CGRP receptor antagonist BIBN4096 inhibits prolonged meningeal afferent activation evoked by brief local K+ stimulation but not cortical spreading depression-induced afferent sensitization.

Cortical spreading depression (CSD) is believed to promote migraine headache by enhancing the activity and mechanosensitivity of trigeminal intracranial meningeal afferents. One putative mechanism underlying this afferent response involves an acute excitation of meningeal afferents by cortical efflux of K+ and the ensuing antidromic release of proinflammatory sensory neuropeptides, such as calcitonin gene-related peptide (CGRP). We sought to investigate whether (1) a brief meningeal K+ stimulus leads to CGRP-dependent enhancement of meningeal afferent responses and (2) CSD-induced meningeal afferent activation and sensitization involve CGRP receptor signaling. Extracellular single-unit recording were used to record the activity of meningeal afferents in anesthetized male rats. Stimulations included a brief meningeal application of K+ or induction of CSD in the frontal cortex using pinprick. Cortical spreading depression was documented by recording changes in cerebral blood flow using laser Doppler flowmetery. Calcitonin gene-related peptide receptor activity was inhibited with BIBN4096 (333 μM, i.v.). Meningeal K+ stimulation acutely activated 86% of the afferents tested and also promoted in ∼65% of the afferents a 3-fold increase in ongoing activity, which was delayed by 23.3 ± 4.1 minutes and lasted for 22.2 ± 5.6 minutes. K+ stimulation did not promote mechanical sensitization. Pretreatment with BIBN4096 suppressed the K+-induced delayed afferent activation, reduced CSD-evoked cortical hyperemia, but had no effect on the enhanced activation or mechanical sensitization of meningeal afferents following CSD. While CGRP-mediated activation of meningeal afferents evoked by cortical efflux of K+ could promote headache, acute activation of CGRP receptors may not play a key role in mediating CSD-evoked headache.

Understanding migraine: Potential role of neurogenic inflammation.

Neurogenic inflammation, a well-defined pathophysiologial process is characterized by the release of potent vasoactive neuropeptides, predominantly calcitonin gene-related peptide (CGRP), substance P (SP), and neurokinin A from activated peripheral nociceptive sensory nerve terminals (usually C and A delta-fibers). These peptides lead to a cascade of inflammatory tissue responses including arteriolar vasodilation, plasma protein extravasation, and degranulation of mast cells in their peripheral target tissue. Neurogenic inflammatory processes have long been implicated as a possible mechanism involved in the pathophysiology of various human diseases of the nervous system, respiratory system, gastrointestinal tract, urogenital tract, and skin. The recent development of several innovative experimental migraine models has provided evidence suggestive of the involvement of neuropeptides (SP, neurokinin A, and CGRP) in migraine headache. Antidromic stimulation of nociceptive fibers of the trigeminal nerve resulted in a neurogenic inflammatory response with marked increase in plasma protein extravasation from dural blood vessels by the release of various sensory neuropeptides. Several clinically effective abortive antimigraine medications, such as ergots and triptans, have been shown to attenuate the release of neuropeptide and neurogenic plasma protein extravasation. These findings provide support for the validity of using animal models to investigate mechanisms of neurogenic inflammation in migraine. These also further strengthen the notion of migraine being a neuroinflammatory disease. In the clinical context, there is a paucity of knowledge and awareness among physicians regarding the role of neurogenic inflammation in migraine. Improved understanding of the molecular biology, pharmacology, and pathophysiology of neurogenic inflammation may provide the practitioner the context-specific feedback to identify the novel and most effective therapeutic approach to treatment. With this objective, the present review summarizes the evidence supporting the involvement of neurogenic inflammation and neuropeptides in the pathophysiology and pharmacology of migraine headache as well as its potential significance in better tailoring therapeutic interventions in migraine or other neurological disorders. In addition, we have briefly highlighted the pathophysiological role of neurogenic inflammation in various other neurological disorders.

The influence of pemirolast on autonomic imbalance in rat cystitis model

Abstract Cyclophosphamide (CP) treatment is associated with the risk of haemorrhagic cystitis (HC). Moreover, CP-induced HC is complicated by autonomic nervous system (ANS) dysfunction. Pemirolast is thought to be a mast cell stabiliser that inhibits the release of many inflammatory mediators and sensory neuropeptides, and thus, it may be considered a potential chemoprotective HC agent. The aim of the study was to indirectly estimate the effect of pemirolast in experimental HC by measuring ANS activity with the heart rate variability (HRV) method. In CP-treated rats, we found a decreasing trend of overall autonomic activity, together with an imbalance between the main components, and a dominant very low frequency (VLF) power component. Pemirolast treatment did not improve the total HRV power value or the main non-normalized HRV components. Moreover, CP-HC animals treated with pemirolast displayed a different disproportion of normalized spectral components as compared to both control and CP-HC animals without pemirolast treatment, with the balance between normalized low frequency (nLF) and normalized high frequency (nHF) shifted towards nLF. This finding, together with a relatively high VLF tension, indicates that the pemirolast treatment resulted in high sympathetic activity that may contribute to HC exacerbation; thus, this agent seems to be ineffective in CP-induced HC.

GW24-e2192 NK-1 Receptor-mediated Renal Injury during DOCA-salt Hypertension

ObjectivesSalt-sensitive hypertension is a leading risk factor contributing to the development of chronic renal disease. We found that high-salt intake activated sensory nerves, leading to release of sensory neuropeptides including...

1016 PARTIAL BLADDER OUTLET OBSTRUCTION MODULATES THE RELEASE OF SENSORY NEUROPEPTIDES SUBSTANCE P AND CALCITONIN GENE RELATED PEPTIDE FROM PENILE AFFERENT FIBERS

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Basic Research (II)1 Apr 20131016 PARTIAL BLADDER OUTLET OBSTRUCTION MODULATES THE RELEASE OF SENSORY NEUROPEPTIDES SUBSTANCE P AND CALCITONIN GENE RELATED PEPTIDE FROM PENILE AFFERENT FIBERS Qi Lei, Xiao-Qing Pan, Shaohua Chang, Ariana Smith, Allen Seftel, and Anna Malykhina Qi LeiQi Lei Glenolden, PA More articles by this author , Xiao-Qing PanXiao-Qing Pan Glenolden, PA More articles by this author , Shaohua ChangShaohua Chang Camden, NJ More articles by this author , Ariana SmithAriana Smith Philadelphia, PA More articles by this author , Allen SeftelAllen Seftel Camden, NJ More articles by this author , and Anna MalykhinaAnna Malykhina Glenolden, PA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.601AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Erectile dysfunction (ED) and benign prostatic hyperplasia (BPH) are common problems in aging males worldwide. Despite the epidemiological evidence of the link between BPH and ED, the mechanisms underlying this co-morbidity are still unclear. The objective of this work was to evaluate the effects of partial bladder outlet obstruction (PBOO) on function of sensory terminals innervating the corpus cavernosum (CC), and release of sensory neuropeptides Substance P (SP) and calcitonin gene related peptide (CGRP) in the CC using an animal model of PBOO. METHODS Experiments were conducted on adult male Sprague Dawley rats divided into two groups: sham operated and PBOO surgery. PBOO was surgically induced by a partial ligation of the bladder neck during laparotomy. Concentration of the sensory neuropeptides SP and CGRP was measured by ELISA. Contractility and relaxation of the CCSM was studied in vitro and expression of nitric oxide synthase (NOS) was evaluated by Western blotting. RESULTS The results of neuropeptide analysis established that the release of SP and CGRP in the pelvic viscera is tissue dependent. Concentration of SP in the CC was higher (2.01±0.23 ng/ml, n=10) in comparison to the urinary bladder (0.3±0.05 ng/ml, n=8, p≤0.001) under normal physiological conditions. However, basal concentration of CGRP was significantly elevated in the urinary bladder reaching 120.6±37.2 pg/ml in comparison to 14.5±0.9 pg/ml in the CC (p≤0.01). PBOO caused impairment in SP release from sensory terminals as evidenced by a 5-fold down-regulation of SP in the CC (n=10, p≤0.001) without significant changes in the obstructed bladder. Additionally, concentration of CGRP was down-regulated in the urinary bladder by PBOO without parallel changes in the CC, however, the decrease did not reach the level of statistical significance. The contractile responses of CC muscle strips to KCl and phenylephrine were decreased after PBOO, followed by a reduced relaxation response to nitroprusside. A significant decrease in nNOS expression was also detected in the CC of obstructed animals. CONCLUSIONS Our results provide evidence that PBOO leads to the impairment of bladder neck afferent innervation followed by a decrease in CC smooth muscle relaxation, down-regulation of nNOS expression and reduced release of sensory neuropeptides in the CC smooth muscle. These results suggest that nerve damage in PBOO may contribute to LUTS-ED comorbidity and trigger secondary changes in the contraction/relaxation mechanisms of CCSM. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e416-e417 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Qi Lei Glenolden, PA More articles by this author Xiao-Qing Pan Glenolden, PA More articles by this author Shaohua Chang Camden, NJ More articles by this author Ariana Smith Philadelphia, PA More articles by this author Allen Seftel Camden, NJ More articles by this author Anna Malykhina Glenolden, PA More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

1017 ADRENOMEDULLIN AND ANGIOPOIETIN-1 HAVE A INTEGRATED RESTIRATION ACTIVITY ON ERECTILE FUNCTION IN DIABETIC RATS: COMPARISON WITH THE COMBINATION THERAPY WITH VASCULAR ENDOTHELIAL GROWTH FACTOR AND ANGIOPOIETIN-1

ity are still unclear. The objective of this work was to evaluate the effects of partial bladder outlet obstruction (PBOO) on function of sensory terminals innervating the corpus cavernosum (CC), and release of sensory neuropeptides Substance P (SP) and calcitonin gene related peptide (CGRP) in the CC using an animal model of PBOO. METHODS: Experiments were conducted on adult male Sprague Dawley rats divided into two groups: sham operated and PBOO surgery. PBOO was surgically induced by a partial ligation of the bladder neck during laparotomy. Concentration of the sensory neuropeptides SP and CGRP was measured by ELISA. Contractility and relaxation of the CCSM was studied in vitro and expression of nitric oxide synthase (NOS) was evaluated by Western blotting. RESULTS: The results of neuropeptide analysis established that the release of SP and CGRP in the pelvic viscera is tissue dependent. Concentration of SP in the CC was higher (2.01 0.23 ng/ml, n 10) in comparison to the urinary bladder (0.3 0.05 ng/ml, n 8, p 0.001) under normal physiological conditions. However, basal concentration of CGRP was significantly elevated in the urinary bladder reaching 120.6 37.2 pg/ml in comparison to 14.5 0.9 pg/ml in the CC (p 0.01). PBOO caused impairment in SP release from sensory terminals as evidenced by a 5-fold down-regulation of SP in the CC (n 10, p 0.001) without significant changes in the obstructed bladder. Additionally, concentration of CGRP was down-regulated in the urinary bladder by PBOO without parallel changes in the CC, however, the decrease did not reach the level of statistical significance. The contractile responses of CC muscle strips to KCl and phenylephrine were decreased after PBOO, followed by a reduced relaxation response to nitroprusside. A significant decrease in nNOS expression was also detected in the CC of obstructed animals. CONCLUSIONS: Our results provide evidence that PBOO leads to the impairment of bladder neck afferent innervation followed by a decrease in CC smooth muscle relaxation, down-regulation of nNOS expression and reduced release of sensory neuropeptides in the CC smooth muscle. These results suggest that nerve damage in PBOO may contribute to LUTS-ED comorbidity and trigger secondary changes in the contraction/relaxation mechanisms of CCSM.

Hydrogen Sulfide Mediated Inhibitory Neurotransmission to the Pig Bladder Neck: Role of KATP Channels, Sensory Nerves and Calcium Signaling

Because neuronal released endogenous H2S has a key role in relaxation of the bladder outflow region, we investigated the mechanisms involved in H2S dependent inhibitory neurotransmission to the pig bladder neck. Bladder neck strips were mounted in myographs for isometric force recording and simultaneous measurement of intracellular Ca(2+) and tension. On phenylephrine contracted preparations electrical field stimulation and the H2S donor GYY4137 evoked frequency and concentration dependent relaxation, which was reduced by desensitizing capsaicin sensitive primary afferents with capsaicin, and the blockade of adenosine 5'-triphosphate dependent K(+) channels, cyclooxygenase and cyclooxygenase-1 with glibenclamide, indomethacin and SC560, respectively. Inhibition of vanilloid, transient receptor potential A1, transient receptor potential vanilloid 1, vasoactive intestinal peptide/pituitary adenylyl cyclase-activating polypeptide and calcitonin gene-related peptide receptors with capsazepine, HC030031, AMG9810, PACAP6-38 and CGRP8-37, respectively, also decreased electrical field stimulation and GYY4137 responses. H2S relaxation was not changed by guanylyl cyclase, protein kinase A, or Ca(2+) activated or voltage gated K(+) channel inhibitors. GYY4137 inhibited the contractions induced by phenylephrine and by K(+) enriched (80 mM) physiological saline solution. To a lesser extent it decreased the phenylephrine and K(+) induced increases in intracellular Ca(2+). H2S produces pig bladder neck relaxation via activation of adenosine 5'-triphosphate dependent K(+) channel and by smooth muscle intracellular Ca(2+) desensitization dependent mechanisms. H2S also promotes the release of sensory neuropeptides and cyclooxygenase-1 pathway derived prostanoids from capsaicin sensitive primary afferents via transient receptor potential A1, transient receptor potential vanilloid 1 and/or related ion channel activation.

Insulin resistance occurs in parallel with sensory neuropathy in streptozotocin-induced diabetes in rats: differential response to early vs late insulin supplementation

We investigated whether progressive sensory neuropathy was accompanied by changes in whole-body insulin sensitivity (WBIS) in rats made diabetic by streptozotocin (STZ). The effects of early and late insulin supplementation were also studied. The STZ-treated rats failed to gain weight and exhibited stable hyperglycemia and low plasma insulin levels with a decrease in nerve conduction velocity (NCV) measured in A and C fibers of the saphenous nerve. A decreased sensory neuropeptide (SNP) release such as that of substance P, somatostatin, and calcitonin gene–related peptide determined from organ fluid of tracheal preparations subjected to electrical field stimulation also occurred in diabetic animals. These features were accompanied by a decrease in WBIS measured by hyperinsulinemic-euglycemic glucose clamping and a decrease in insulin-stimulated glucose uptake in cardiac and gastrocnemius muscle. When insulin supplementation with slow-release implants (2 IU/d) was started 4 weeks after STZ injection, blood glucose level normalized. Both insulin sensitivity and sensory nerve function reflected in either NCV or SNP release completely recovered by the 12th post-STZ week. When the insulin implants were applied from the eighth post-STZ week, both WBIS and glucose uptake remained significantly decreased, with a seriously impaired NCV and SNP release with strong hyperglycemia. Late insulin supplementation, however, even by using double implantation from the 10th post-STZ week, was unable to restore blood glucose, WBIS, NCV, and SNP release by the 12th week. Insulin resistance occurs in parallel with sensory neuropathy in STZ-diabetic rats. Both can be improved by early but not late insulin supplementation.

N-Methylated sst2 Selective Somatostatin Cyclic Peptide Analogue as a Potent Candidate for Treating Neurogenic Inflammation.

A focused multiply N-methylated library of a cyclic hexapeptidic somatostatin analogue: MK678 cyclo(-MeAYwKVF-) was generated, which resulted in the unexpected observation of an efficacious tetra-N-methylated analogue, cyclo(-MeAYMewMeKVMeF-) with a potent inhibitory action on sensory neuropeptide release in vitro and on acute neurogenic inflammatory response in vivo. The analogue shows selectivity toward somatostatin receptor subtype 2 (sst2). Extensive 2D NMR spectroscopy and molecular dynamics simulation revealed the solution conformation of the analogue, which can be adopted as a lead for the further structure-activity relationship studies targeting neurogenic inflammation.

The sythetic endomorphin-1 analog, CYT-1010, inhibits sensory neuropeptide release, acute neurogenic inflammation and heat injury-induced thermal hyperalgesia in rodent models

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An emerging problem in clinical practice: how to treat chronic headache patients

In this issue, an interesting article by Farinelli and coworkers [1] debates an important emerging and not yet resolved problem: how to treat the chronic headaches complicated by medication overuse. Headache is the most common neurological disease in clinical practice. In Europe, this affects about 51% of the population, of which 31% are tension-type headache and 14% are migraine sufferers; 2% of these patients become chronic sufferers, more than 15/day/month, and chronic daily headache (CDH). 4–5% of general population suffers from a chronic form (CDH), with prevalence between 1.7 and 2.1% in men and between 2.8 and 6.8% in women [2]; within this group of patients in the US general population ranges around 1.3–2% of chronic migraine (CM). A number of possible pathophysiological mechanisms for the transformation from episodic to chronic headache have been proposed including a progressive damage of the central nociceptive system. One physiopathological hypothesis is the activation of N-methyl-D-aspartate (NMDA) and nonNMDA receptors glutamate, released by central nociceptive terminations, induces calcium entry in dorsal horn neurons, as well as in the trigeminal nucleus caudalis. Calcium entry leads to the activation of nitric oxide (NO) synthetase causing NO synthesis. These neurotransmitters produce the release of sensory neuropeptides, such as CGRP and substance P, which support the development of hyperalgesia and maintain central sensitization [3–5]. Medication near-daily use and subsequent medication overuse headache (MOH) have been described by the revised International Classification of Headache Disorders (ICHDs)-IIR criteria as the use of each drug for at least 3 months, for a certain number of days per month, and is one of the most critical parameters in the process of

Hydrogen sulfide promotes transient receptor potential vanilloid 1-mediated neurogenic inflammation in polymicrobial sepsis*

To investigate the interaction and involvement of hydrogen sulfide and transient receptor potential vanilloid type 1 in the pathogenesis of sepsis. Hydrogen sulfide has been demonstrated to be involved in many inflammatory states including sepsis. Its contribution in neurogenic inflammation has been suggested in normal airways and urinary bladder. However, whether endogenous hydrogen sulfide would induce transient receptor potential vanilloid type 1-mediated neurogenic inflammation in sepsis remains unknown. Prospective, experimental study. Research laboratory. Male Swiss mice. Mice were subjected to cecal ligation and puncture-induced sepsis and treated with transient receptor potential vanilloid type 1 antagonist capsazepine (15 mg/kg subcutaneous) 30 mins before cecal ligation and puncture. To investigate hydrogen sulfide-mediated neurogenic inflammation in sepsis, DL-propargylglycine (50 mg/kg intraperitoneal), an inhibitor of hydrogen sulfide formation was administrated 1 hr before or 1 hr after the induction of sepsis, whereas sodium hydrosulfide (10 mg/kg intraperitoneal), a hydrogen sulfide donor, was given at the same time as cecal ligation and puncture. Lung and liver myeloperoxidase activities, liver cystathionine-gamma-lyase activity, plasma hydrogen sulfide level, histopathological examination, and survival studies were determined after induction of sepsis. Capsazepine treatment attenuates significantly systemic inflammation and multiple organ damage caused by sepsis, and protects against sepsis-induced mortality. Similarly, administration of sodium hydrosulfide exacerbates but capsazepine reverses these deleterious effects. In the presence of DL-propargylglycine, capsazepine causes no significant changes to the attenuation of sepsis-associated systemic inflammation, multiple organ damage, and mortality. In addition, capsazepine has no effect on endogenous generation of hydrogen sulfide, suggesting that hydrogen sulfide is located upstream of transient receptor potential vanilloid type 1 activation, and may play a critical role in regulating the production and release of sensory neuropeptides in sepsis. The present study shows that hydrogen sulfide induces systemic inflammation and multiple organ damage characteristic of sepsis via transient receptor potential vanilloid type 1-mediated neurogenic inflammation.

Intravesical Liposome Versus Oral Pentosan Polysulfate for Interstitial Cystitis/Painful Bladder Syndrome

We evaluated the safety and efficacy of intravesical liposomes, a mucosal protective agent, compared to oral pentosan polysulfate sodium for interstitial cystitis/painful bladder syndrome. We performed a prospective longitudinal study of the effect of 2 independent treatments (intravesical liposomes and oral pentosan polysulfate sodium) in patients with interstitial cystitis/painful bladder syndrome. Ten possible responses (or measures) to treatment were monitored at 3 time points, including baseline, and weeks 4 and 8. A total of 24 patients with interstitial cystitis/painful bladder syndrome were evaluated in a 1:1 ratio to intravesical liposomes (80 mg/40 cc distilled water) once weekly or to oral pentosan polysulfate sodium (100 mg) 3 times daily for 4 weeks each. No patient had urinary incontinence, retention or infection due to liposome instillation. There were no unanticipated adverse events and no significant worsening of symptoms during followup. Statistically significant decreases in urinary frequency and nocturia were observed in each treatment group. Statistically significant decreases in pain, urgency and the O'Leary-Sant symptom score were observed in the liposome group. Decreased urgency in the liposome group had the most profound effect of the ordinal measures. Each glycosaminoglycan directed treatment seemed beneficial. Liposome intravesical instillation is safe for interstitial cystitis/painful bladder syndrome with potential improvement after 1 course of therapy for up to 8 weeks. Intravesical liposomes achieved efficacy similar to that of oral pentosan polysulfate sodium. Further large-scale placebo controlled studies are needed. Intravesical liposomes appear to be a promising new treatment for interstitial cystitis/painful bladder syndrome.

Bladder Sensation Measures and Overactive Bladder

We performed a prospective multicomponent study to determine whether subjective and objective bladder sensation instruments may provide data on sensory dysfunction in patients with overactive bladder. We evaluated 70 prospectively enrolled patients with urodynamics and questionnaires on validated urgency (Urgency Perception Score), general overactive bladder (Urogenital Distress Inventory) and quality of life (Incontinence Impact Questionnaire). We first sought a correlation between sensory specific (Urgency Perception Score) and quality of life questionnaire scores. We then assessed a correlation between sensory questionnaire scores and urodynamic variables, exploring the hypothesis that certain urodynamic parameters may be bladder sensation measures. We evaluated 2 urodynamic derivatives (first sensation ratio and bladder urgency velocity) to increase sensory finding discrimination. We noted a moderate correlation between the Urgency Perception Score (0.56) and the Urogenital Distress Inventory (0.74) vs the Incontinence Impact Questionnaire (each p <0.01). A weak negative correlation was seen between Urgency Perception Score and bladder capacity (-0.25, p <0.05). No correlation was noted for the other urodynamics parameters. First sensation ratio and bladder urgency velocity statistically significantly correlated with the Urgency Perception Score despite the lesser or absent correlation associated with the individual components of these derivatives. Bladder sensation questionnaires may be valuable to identify patients with sensory dysfunction and provide additional data not obtained in generalized symptom questionnaires. Urodynamic variables correlated with bladder sensation questionnaire scores and may be an objective method to assess sensory dysfunction.

The Airway Neurogenic Inflammation: Clinical and Pharmacological Implications

Bronchial airway microvasculature consists in a developed network of vessels, which plays an important role in normal homeostasis as well as in inflammatory airway processes. Its airway autonomic neural control includes cholinergic and adrenergic innervation, as well as nonadrenergic noncholinergic system. The nerve/vessel interplay is complex and not yet completely clarified. In response to inspired air conditions, the sensory nerves can recruit appropriate reflexes, which can induce different vascular processes, such as vasodilatation, vasoconstriction, plasma extravasation and exudation. Additionally, the stimulation of C fibres may result in an axon local reflex with antidromic conduction down afferent nerve collaterals and release of sensory neuropeptides, which in turn may act on the mucosal vasculature to promote vasodilatation and microvascular leakage. The neurogenic inflammation may play a key role in allergic diseases, such as asthma, as well as in COPD, a smoking-related disease. This review deals with the interactions of vessels and nerves within the airway mucosa under healthy conditions and in inflammatory diseases. The clinical and pharmacological implications are also described.

Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1

Prostaglandins (PG) are known to induce pain perception indirectly by sensitizing nociceptors. Accordingly, the analgesic action of nonsteroidal anti-inflammatory drugs (NSAIDs) results from inhibition of cyclooxygenases and blockade of PG biosynthesis. Cyclopentenone PGs, 15-d-PGJ(2), PGA(2), and PGA(1), formed by dehydration of their respective parent PGs, PGD(2), PGE(2), and PGE(1), possess a highly reactive alpha,beta-unsaturated carbonyl group that has been proposed to gate the irritant transient receptor potential A1 (TRPA1) channel. Here, by using TRPA1 wild-type (TRPA1(+/+)) or deficient (TRPA1(-/-)) mice, we show that cyclopentenone PGs produce pain by direct stimulation of nociceptors via TRPA1 activation. Cyclopentenone PGs caused a robust calcium response in dorsal root ganglion (DRG) neurons of TRPA1(+/+), but not of TRPA1(-/-) mice, and a calcium-dependent release of sensory neuropeptides from the rat dorsal spinal cord. Intraplantar injection of cyclopentenone PGs stimulated c-fos expression in spinal neurons of the dorsal horn and evoked an instantaneous, robust, and transient nociceptive response in TRPA1(+/+) but not in TRPA1(-/-) mice. The classical proalgesic PG, PGE(2), caused a slight calcium response in DRG neurons, increased c-fos expression in spinal neurons, and induced a delayed and sustained nociceptive response in both TRPA1(+/+) and TRPA1(-/-) mice. These results expand the mechanism of NSAID analgesia from blockade of indirect nociceptor sensitization by classical PGs to inhibition of direct TRPA1-dependent nociceptor activation by cyclopentenone PGs. Thus, TRPA1 antagonism may contribute to suppress pain evoked by PG metabolites without the adverse effects of inhibiting cyclooxygenases.

Botulinum toxin type A inhibits sensory neuropeptide release in rat bladder models of acute injury and chronic inflammation

To determine the effect of botulinum toxin type A (BTX-A) on the release of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) from isolated bladder preparations after acute injury with HCl and the induction of cyclophosphamide (CYP)-induced cystitis, as neurogenic inflammation has been increasingly identified in urological disorders such as interstitial cystitis. Adult rats had either an intraperitoneal injection with CYP or saline over a 10-day period to induce chronic bladder inflammation, after which the bladder was harvested, or normal bladder explants were injured acutely with incubation (20 s) in HCl (0.4 m). To measure the effect of BTX-A on the release of neurotransmitters, harvested bladders were incubated in an organ bath containing BTX-A (10 U) or vehicle. Bladders were transferred to a subsequent bath (physiological saline) and incubated for 15 min, and the bathing medium analysed to measure neurotransmitter release, as determined by radioimmunoassay. Bladder specimens from sham treatment, controls and experimental rats were compared histologically. Acute injury with HCl caused a significantly greater release of both CGRP and SP release (1235 and 1655 pg/g, respectively) than in controls (183 and 449 pg/g, respectively; P < 0.001). This increase in neurotransmitter release was partly inhibited by exposure to BTX-A (870 and 1033 pg/g (P < 0.05 and <0.01). CYP-induced chronic inflammation caused significantly greater release of SP than in the controls (1060 and 605 pg/g, respectively; P < 0.005). Exposure to BTX-A partly inhibited the release of SP after CYP-induced cystitis (709 pg/g, P < 0.05). The application of BTX-A inhibits the release of sensory neurotransmitters from isolated bladder preparations in rat bladder models of both acute injury and chronic inflammation, suggesting a potential clinical benefit of BTX-A in the treatment of neurogenic inflammation.