Capsaicin-sensitive Sensory Neurons Research Articles

Interaction of Cortricotropin-Releasing Hormone and Capsaicin-Sensitive Afferent Neurons in Gastroprotection

Interaction of Cortricotropin-Releasing Hormone and Capsaicin-Sensitive Afferent Neurons in Gastroprotection

Osteosarcoma-Induced Pain Is Mediated by Glial Cell Activation in the Spinal Dorsal Horn, but Not Capsaicin-Sensitive Nociceptive Neurons: A Complex Functional and Morphological Characterization in Mice.

Bone cancer and its related chronic pain are huge clinical problems since the available drugs are often ineffective or cannot be used long term due to a broad range of side effects. The mechanisms, mediators and targets need to be identified to determine potential novel therapies. Here, we characterize a mouse bone cancer model induced by intratibial injection of K7M2 osteosarcoma cells using an integrative approach and investigate the role of capsaicin-sensitive peptidergic sensory nerves. The mechanical pain threshold was assessed by dynamic plantar aesthesiometry, limb loading by dynamic weight bearing, spontaneous pain-related behaviors via observation, knee diameter with a digital caliper, and structural changes by micro-CT and glia cell activation by immunohistochemistry in BALB/c mice of both sexes. Capsaicin-sensitive peptidergic sensory neurons were defunctionalized by systemic pretreatment with a high dose of the transient receptor potential vanilloid 1 (TRPV1) agonist resiniferatoxin (RTX). During the 14- and 28-day experiments, weight bearing on the affected limb and the paw mechanonociceptive thresholds significantly decreased, demonstrating secondary mechanical hyperalgesia. Signs of spontaneous pain and osteoplastic bone remodeling were detected both in male and female mice without any sex differences. Microglia activation was shown by the increased ionized calcium-binding adapter molecule 1 (Iba1) immunopositivity on day 14 and astrocyte activation by the enhanced glial fibrillary acidic protein (GFAP)-positive cell density on day 28 in the ipsilateral spinal dorsal horn. Interestingly, defunctionalization of the capsaicin-sensitive afferents representing approximately 2/3 of the nociceptive fibers did not alter any functional parameters. Here, we provide the first complex functional and morphological characterization of the K7M2 mouse osteosarcoma model. Bone-cancer-related chronic pain and hyperalgesia are likely to be mediated by central sensitization involving neuroinflammation via glial cell activation in the spinal dorsal horn, but not the capsaicin-sensitive sensory neuronal system.

Reduced capsaicin-induced mechanical allodynia and neuronal responses in the dorsal root ganglion in the presence of protein tyrosine phosphatase non-receptor type 6 overexpression.

Transient Receptor Potential Vanilloid 1 (TRPV1) is a nonselective cation channel expressed by pain-sensing neurons and has been an attractive target for the development of drugs to treat pain. Recently, Src homology region two domain-containing phosphatase-1 (SHP-1, encoded by Ptpn6) was shown to dephosphorylate TRPV1 in dorsal root ganglia (DRG) neurons, which was linked with alleviating different pain phenotypes. These previous studies were performed in male rodents only and did not directly investigate the role of SHP-1 in TRPV-1 mediated sensitization. Therefore, our goal was to determine the impact of Ptpn6 overexpression on TRPV1-mediated neuronal responses and capsaicin-induced pain behavior in mice of both sexes. Twelve-week-old male and female mice overexpressing Ptpn6 (Shp1-Tg) and their wild type (WT) littermates were used. Ptpn6 overexpression was confirmed in the DRG of Shp1-Tg mice by RNA in situ hybridization and RT-qPCR. Trpv1 and Ptpn6 were found to be co-expressed in DRG sensory neurons in both genotypes. Functionally, this overexpression resulted in lower magnitude intracellular calcium responses to 200nM capsaicin stimulation in DRG cultures from Shp1-Tg mice compared to WTs. In vivo, we tested the effects of Ptpn6 overexpression on capsaicin-induced pain through a model of capsaicin footpad injection. While capsaicin injection evoked nocifensive behavior (paw licking) and paw swelling in both genotypes and sexes, only WT mice developed mechanical allodynia after capsaicin injection. We observed similar level of TRPV1 protein expression in the DRG of both genotypes, however, a higher amount of tyrosine phosphorylated TRPV1 was detected in WT DRG. These experiments suggest that, while SHP-1 does not mediate the acute swelling and nocifensive behavior induced by capsaicin, it does mediate a protective effect against capsaicin-induced mechanical allodynia in both sexes. The protective effect of SHP-1 might be mediated by TRPV1 dephosphorylation in capsaicin-sensitive sensory neurons of the DRG.

Interaction of Corticotropin-Releasing Factor and Capsaicin-Sensitive Afferent Neurons in Gastroprotection

Abstract—Corticotropin-releasing factor (CRF) and capsaicin-sensitive afferent neurons with efferent-like function (CSN) make an important contribution to the regulation of the functions of the gastrointestinal tract (GIT) and gastroprotection. The aim of the review was to analyze the data of literature, including the results of our own studies on the interaction of CRF and CSN in the gastroprotection and regulation of the functions of the gastrointestinal tract, with a focus on their most studied interaction in the regulation of the motor function of the gastrointestinal tract. Based on the results obtained by the authors of the review, the contribution of CSN to the implementation of the gastroprotective effect of CRF and, conversely, the participation of CRF in the gastroprotective effect of capsacin, which activates CSN, is discussed. The contribution of glucocorticoid hormones to the implementation of the gastroprotective action of CRF and the compensatory gastroprotective role of these hormones under conditions of shutdown of CSN functioning are considered.

Therapeutic effects of p38 mitogen-activated protein kinase inhibition on hyperexcitability of capsaicin sensitive bladder afferent neurons in mice with spinal cord injury

AimsNerve growth factor (NGF) has been implicated as a key molecule of pathology-induced changes in C-fiber afferent nerve excitability, which contributes to the emergence of neurogenic detrusor overactivity due to spinal cord injury (SCI). It is also known that the second messenger signaling pathways activated by NGF utilize p38 Mitogen-Activated Protein Kinase (MAPK). We examined the roles of p38 MAPK on electrophysiological properties of capsaicin sensitive bladder afferent neurons with SCI mice. Main methodsWe used female C57BL/6 mice and transected their spinal cord at the Th8/9 level. Two weeks later, continuous administration of p38 MAPK inhibitor (0.51 μg/h, i.t. for two weeks) was started. Bladder afferent neurons were labelled with a fluorescent retrograde tracer, Fast-Blue (FB), injected into the bladder wall three weeks after SCI. Four weeks after SCI, freshly dissociated L6-S1 dorsal root ganglion neurons were prepared and whole cell patch clamp recordings were performed in FB-labelled neurons. After recording action potentials or voltage-gated K+ currents, the sensitivity of each neuron to capsaicin was evaluated. Key findingsIn capsaicin-sensitive FB-labelled neurons, SCI significantly reduced the spike threshold and increased the number of action potentials during 800 ms membrane depolarization. Densities of slow-decaying A-type K+ (KA) and sustained delayed rectifier-type K+ (KDR) currents were significantly reduced by SCI. The reduction of KA, but not KDR, current density was reversed by the treatment with p38 MAPK inhibitor. SignificanceP38 MAPK plays an important role in hyperexcitability of capsaicin-sensitive bladder afferent neurons due to the reduction in KA channel activity in SCI mice.

Sensitization of colonic nociceptors by IL-13 is dependent on JAK and p38 MAPK activity.

The effective management of visceral pain is a significant unmet clinical need for those affected by gastrointestinal diseases, such as inflammatory bowel disease (IBD). The rational design of novel analgesics requires a greater understanding of the mediators and mechanisms underpinning visceral pain. Interleukin-13 (IL-13) production by immune cells residing in the gut is elevated in IBD, and IL-13 appears to be important in the development of experimental colitis. Furthermore, receptors for IL-13 are expressed by neurons innervating the colon, though it is not known whether IL-13 plays any role in visceral nociception per se. To resolve this, we used Ca2+ imaging of cultured sensory neurons and ex vivo electrophysiological recording from the lumbar splanchnic nerve innervating the distal colon. Ca2+ imaging revealed the stimulation of small-diameter, capsaicin-sensitive sensory neurons by IL-13, indicating that IL-13 likely stimulates nociceptors. IL-13-evoked Ca2+ signals were attenuated by inhibition of Janus (JAK) and p38 kinases. In the lumbar splanchnic nerve, IL-13 did not elevate baseline firing, nor sensitize the response to capsaicin application, but did enhance the response to distention of the colon. In line with Ca2+ imaging experiments, IL-13-mediated sensitization of the afferent response to colon distention was blocked by inhibition of either JAK or p38 kinase signaling. Together, these data highlight a potential role for IL-13 in visceral nociception and implicate JAK and p38 kinases in pronociceptive signaling downstream of IL-13.

TRPA1, but not TRPV1, is involved in the increase of the non-adrenergic non-cholinergic outflow induced by hydrogen sulfide in pithed rats

Hydrogen sulfide (H2S) is a gasotransmitter that modulates the peripheral transmission regulating the vascular tone. In vitro studies have suggested that H2S induces vasodilation by stimulating capsaicin-sensitive sensory neurons. This study was designed to determine the effects of H2S on the non-adrenergic/non-cholinergic (NANC) outflow in the pithed rat, and the underlying mechanisms. For that purpose, 72 male Wistar rats were anesthetized, pithed and the carotid, femoral and jugular veins were cannulated and then divided into two main sets. The first set of animals (n = 48) was used to determine the effect of NaHS (H2S donor) on the vasodepressor responses induced by: 1) NANC outflow electrical stimulation (n = 24); and 2) i.v. bolus of α-CGRP (n = 24) and subdivided into 4 groups (n = 6 each): 1) control group (without infusion); continuous infusion of: 2) PBS (vehicle; 0.02 ml/kg·min); 3) NaHS 10 μg/kg·min; and 4) NaHS 18 μg/kg·min. The second set of animals (n = 24) received an i.v. bolus of either (1) HC 030031 (TRPA1 channel antagonist; 18 μg/kg; n = 12) or (2) capsazepine (TRPV1 channel antagonist; 100 μg/kg; n = 12) in presence and absence of 18 µg/kg·min NaHS i.v. continuous infusion to determine the underlying mechanism of the NaHS effect on the NANC outflow. Our results show that NaHS infusion increased the vasodepressor responses induced by electrical stimulation, but not by α-CGRP, effect that was abolished by HC030031 and remained unaffected after capsazepine. These data suggest that activation of TRPA1 channels, but no TRPV1, is responsible for the NaHS-induced NANC neurotransmission stimulation.

Involvement of Hypothalamo-Hypophyseal-Adrenocortical System Hormones in Gastroprotection in Rats on Sensitization and Desensitization of Capsaicin-Sensitive Afferent Neurons

Involvement of Hypothalamo-Hypophyseal-Adrenocortical System Hormones in Gastroprotection in Rats on Sensitization and Desensitization of Capsaicin-Sensitive Afferent Neurons

Участие гормонов гипоталамо-гипофизарно-адренокортикальной системы крыс в гастропротекции при сенситизации и десенситизации капсаицин-чувствительных афферентных нейронов

The aim of this work was to study: a) the contribution of glucocorticoids to gastroprotection induced by sensitization of capsaicin-sensitive afferent neurons (CSN), b) gastroprotective effect of corticotropin-releasing factor (CRF) in rats with desensitization of CSN and possible corticosterone participation in this effect. The study was performed in male Sprague Dawley rats weighing 260-300 g. The immobilization at 10° C (3 h) or indomethacin (35 mg/kg) were used as ulcerogenic stimuli. Sensitization of CSN was induced by administration of capsaicin at the doses of 1 and 10 mg/kg, 1h before the onset of ulcerogenic stimulus. Desensitization was performed by administration of capsaicin in a total dose of 100 mg/kg (20+30+50) in 3 subsequent days, 2 weeks before the start of the experiment. CRF was injected at the dose of 2.5 mg/kg, i. p., 30 minutes before indomethacin in rats with CSN desensitization. To estimate the involvement of corticosterone in the gastroprotective effects, metyrapone (inhibitor of glucocorticoid synthesis) at the dose of 30 mg/kg was used. Capsaicin, administered at doses of 1 and 10 mg/kg, caused a gastroprotective effect in both ulcerogenic models. The metyrapone administration 30 minutes before capsaicin eliminated its gastroprotective effect for the 1 mg/kg dose, but not 10 mg/kg dose. The CRF administration caused a gastroprotective effect in both control rats, and rats with CSN desensitization. The results obtained in experiments with metyrapone indicate that CRF gastroprotective effect observed in rats with desensitization of CSN are at least partially mediated by corticosterone.

The effect of apelin-13 on gastric ischemia/reperfusion injury: the roles of sensory nerves and vagus nerve.

Apelin is a peptide that plays a role in physiological processes such as angiogenesis, apoptosis, and proliferation. The aim of this study was to investigate the role of capsaicin-sensitive afferent neurons and vagus in the effect of apelin against ischemia/reperfusion (I/R) injury. The experimental groups were (1) control, (2) I/R, (3) apelin + I/R, (4) vagotomy + I/R, (5) vagotomy + apelin + I/R, (6) capsaicin + I/R, (7) capsaicin + apelin + I/R, (8) lorglumide + I/R, and (9) lorglumide + apelin + I/R. To test the potential gastroprotective effect of apelin-13, apelin-13 (2 mg/kg i.v.) was administered just before both ischemia and reperfusion. A vagotomy was performed 1 week before I/R in the vagotomized groups; capsaicin (125 mg/kg s.c.) was administrated 2 weeks before I/R in the capsaicin-treated groups and lorglumide (5 mg/kg i.p.) was administered 30 min before I/R in the lorglumide-treated groups. After I/R, a variety parameters in gastric tissue were analyzed. cfos expression was determined in brainstem samples. In the I/R group, the lesion index, myeloperoxidase activity, lipid peroxidation, nitric oxide, and tumor necrosis factor-α increased, and mucosal blood flow, prostaglandin-E2, and calcitonin gene related peptide decreased. Apelin prevented the damaging effects of I/R and increased cfos expression in brainstem areas. Vagotomy, capsaicin, and lorglumide largely eliminated the gastroprotective effects of apelin-13. This study showed that sensory nerves and the vagus play regulatory roles in apelin-induced gastroprotection. Cholecystokinin may play a role in the effect of apelin through sensory neurons.

Presence and upregulation of Transient Receptor Potential Vanilloid 1 (TRPV1) and Ankyrin 1 (TRPA1) in translational rat endometriosis model

Abstract The Transient Receptor Potential Vanilloid 1 (TRPV1) and Ankyrin 1 (TRPA1) are non-selective cation channels predominantly localized on capsaicin-sensitive sensory neurons; however both receptors have been described in non-neuronal tissues. It has been published that both receptors upregulated in peritoneal endometriosis in humans. Our research group demonstrated that TRPA1 and TRPV1 expression is elevated in human deep infiltrating endometriosis (DIE) lesions and the receptors have an estrogen-dependent expression pattern in rat endometrium. Here, we investigated the expression changes of TRPA1/V1 and the role of the capsaicin-sensitive sensory-nerve endings in a rat model of peritoneal endometriosis. Peritoneal endometriosis was surgically induced in 8-week-old female rats (n=7-7) for 2-weeks (acute condition) and 8-weeks (chronic condition). TRPA1/V1 mRNAs were quantified with quantitative polymerase chain reaction (qPCR). The expression levels were compared with the results obtained earlier from human DIE samples. The blockade of the TRPA1/V1 expressing capsaicin-sensitive nerve endings was induced with resiniferatoxin (RTX), followed by the measurement of the weight and size of the endometriosis lesions. We detected TRPV1 and TRPA1 mRNA in normal rat endometrium, their expression was not altered in sham-operated animals. In chronic, but not in acute endometriosis the expression was significantly elevated in the lesions, which results are consistent with our previous findings in human DIE. The elimination of capsaicin-sensitive nerve endings decreased the weight of the endometriosis lesions while the size of the ectopic tissue was not altered. Taken together, our results obtained from the rat endometriosis model are consistent with the previous human results, therefore this model is considered to have translational significance and it is suitable for functional analysis of the ion channels. The local, non-neuronal TRPA1 and TRPV1 might play a role in inflammation and sensory neuronal activation in endometriosis related pain, which is mediated by a broad range of pro-inflammatory molecules.

Role of TRPV1 and TRPA1 Ion Channels in Inflammatory Bowel Diseases: Potential Therapeutic Targets?

Inflammatory bowel diseases (IBD) have long been recognized to be accompanied by pain resulting in high morbidity. Transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) ion channels located predominantly on the capsaicin-sensitive sensory neurons play a complex role in hyperalgesia and neurogenic inflammation. This review provides an overview of their expression and role in intestinal inflammation, in particular colitis, that appears to be virtually inconsistent based on the thorough investigations of the last twenty years. However, preclinical results with pharmacological interventions, as well as scarcely available human studies, more convincingly point out the potential therapeutic value of TRPV1 and TRPA1 antagonists in colitis and visceral hypersensitivity providing future therapeutical perspectives through a complex, unique mechanism of action for drug development in IBD.

Влияние сенситизации и десенситизации капсаицин-чувствительных нейронов на образование эрозий в слизистой оболочке желудка, индуцированных индометацином, у крыс: роль глюкокортикоидных гормонов

The aim of this work was to study the effect of sensitization and desensitization of capsaicin-sensitive afferent neurons (CSN) on the vulnerability of the rat gastric mucosa to the ulcerogenic action of indomethacin (35 mg/kg) and to evaluate the participation of glucocorticoids in this effect. Sensitization of CSN was caused by a single administration of capsaicin at the small doses, 0.1-10.0 mg/kg, desensitization was performed by administration of capsaicin in a total dose of 100 mg/kg (20, 30, 50 мг/кг, 2 weeks before indomethacin). Capsaicin (0.1-10.0 mg/kg) was administered 1 h before indomethacin. To evaluate the participation of corticosterone in the effects of capsaicin, the inhibitor of glucocorticoid synthesis metyrapone (30 mg/kg) was used. Desensitization of CSN with a large dose of capsaicin led to the aggravation of the ulcerogenic effect of indomethacin. The administration of capsaicin at the doses of 0.5-10.0 mg/kg, dose-dependently decreased the area of indomethacin-induced gastric erosions, as well as resulted in an increase in the blood level of corticosterone and glucose. Metyrapone administration prevented both the increase in the corticosterone level in response to capsaicin and gastroprotective effect of capsaicin (1 mg/kg). The results obtained suggest that glucocorticoids participate in realization of the gastroprotective effect of capsaicin

PD19-10 P38 MITOGEN-ACTIVATED PROTEIN KINASE INHIBITOR REDUCES HYPEREXCITABILITY OF CAPSAICIN SENSITIVE BLADDER AFFERENT NEURONS IN MICE WITH SPINAL CORD INJURY

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Basic Research & Pathophysiology I1 Apr 2018PD19-10 P38 MITOGEN-ACTIVATED PROTEIN KINASE INHIBITOR REDUCES HYPEREXCITABILITY OF CAPSAICIN SENSITIVE BLADDER AFFERENT NEURONS IN MICE WITH SPINAL CORD INJURY Takahisa Suzuki, Takahiro Shimizu, Nobutaka Shimizu, Jianshu Ni, Shinsuke Mizoguchi, Eiichiro Takaoka, Hideaki Miyake, Anthony J Kanai, and Naoki Yoshimura Takahisa SuzukiTakahisa Suzuki More articles by this author , Takahiro ShimizuTakahiro Shimizu More articles by this author , Nobutaka ShimizuNobutaka Shimizu More articles by this author , Jianshu NiJianshu Ni More articles by this author , Shinsuke MizoguchiShinsuke Mizoguchi More articles by this author , Eiichiro TakaokaEiichiro Takaoka More articles by this author , Hideaki MiyakeHideaki Miyake More articles by this author , Anthony J KanaiAnthony J Kanai More articles by this author , and Naoki YoshimuraNaoki Yoshimura More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.1000AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Nerve growth factor (NGF) has been implicated as an important mediator to induce C-fiber bladder afferent hyperexcitability, which contributes to the emergence of neurogenic detrusor overactivity following spinal cord injury (SCI). It is also known that the second messenger signaling pathways activated by NGF utilize p38 Mitogen-Activated Protein Kinase (MAPK). We examined whether p38 MAPK inhibition using SB203580 (p38 MAPK inhibitor) normalizes the SCI-induced changes in electrophysiological properties of capsaicin-sensitive C-fiber bladder afferent neurons in the mouse SCI model. METHODS The spinal cord was transected at the Th8/9 level in 8-9 weeks old female C57BL/6 mice. Two weeks later, SB203580 (1 mg/ml) was injected intrathecally using an osmotic pump at infusion rate of 0.51 µl/hr for 2 weeks. Instead of SB203580, artificial cerebrospinal fluid was injected in separate groups of spinal intact (SI) and SCI mice as controls. Bladder afferent neurons were labeled with axonal transport of Fast Blue (FB), a fluorescent retrograde tracer, injected into the bladder wall 3 weeks after SCI. Dissociated L6 and S1 dorsal root ganglion neurons were prepared 4 weeks after SCI. Whole cell patch clamp recordings were performed in FB-labeled bladder afferent neurons, and the data were compared among control SI, SCI and SCI treated with p38 MAPK inhibitor mice. After recording action potentials (AP) or voltage-gated K+ (Kv) currents, the sensitivity of each neuron to capsaicin was evaluated. RESULTS In capsaicin-sensitive bladder afferent neurons, the threshold for eliciting AP was significantly reduced in control SCI compared to SI mice. Also, SCI increased the number of AP during 800 ms membrane depolarization. These SCI induced hyperexcitability was reversed by p38 MAPK inhibitor. Densities of slow decaying KA and sustained KDR currents evoked by depolarization to 0 mV were significantly reduced after SCI. The treatment with a p38 MAPK inhibitor reversed the SCI-induced reduction in the KA current density, but not in the KDR. CONCLUSIONS In SCI mice, p38 MAPK signaling pathways play an important role in hyperexcitability of capsaicin sensitive C-fiber bladder afferent neurons due to KA current reduction. Thus, p38 MAPK-targeting therapies could be effective for treatment of afferent hyperexcitability in SCI. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e399-e400 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Takahisa Suzuki More articles by this author Takahiro Shimizu More articles by this author Nobutaka Shimizu More articles by this author Jianshu Ni More articles by this author Shinsuke Mizoguchi More articles by this author Eiichiro Takaoka More articles by this author Hideaki Miyake More articles by this author Anthony J Kanai More articles by this author Naoki Yoshimura More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

A prospective multicenter trial of S-1 with lafutidine vs S-1 as adjuvant chemotherapy for gastric cancer in Japan: AEOLUS.

91 Background: From the result of ACTS-GC study, adjuvant chemotherapy with S-1 for one year is standard therapy of gastric cancer in Japan. In this study, completion rate of pre-planned S-1 treatment was 65.8% and there is still room for improvement on this rate. Lafutidine is a H2 blocker and enhances submucosal blood flow via capsaicin-sensitive afferent neurons. Alleviating effect of lafutidine on toxicity of 5FU leading to discontinuation of adjuvant treatment could be expected. Methods: Patients with histologically confirmed stage II (excluding T1 cases), IIIA, or IIIB (Japanese Classification of Gastric Carcinoma 13th) who underwent gastrectomy with D2 lymphadenectomy were randomly assigned to receive S-1 with lafutidine(L) or S-1 (S). All patients were given S-1 (40mg/m2) for 4 weeks with 2 weeks rest, repeated for 1 year after surgery. Patients of L group received lafutidine (20mg/day) every day for 1 year with S-1. The primary end point was treatment completion rate (TCR) of S-1. Definition of treatment completion was S-1 continuation for 1 year with over 70% planned dose. The secondary end points were toxicity (CTCAE v3.0) and relative total administration dose (RD) of S-1. Results: We randomly assigned 101 patients to the L group and 101 patients to the S group between February 2010 and December 2012 from 17 centers in Japan. After randomization, two patients were found to be ineligible in L group (the absence of cytologic examination of the peritoneal fluid, stageIB) and 1 in S group (allocation violation). TCR was 68.3% in the L group and 60.4% in the S group (p = 0.072, Cochran-Mantel-Haenzel test at a pre-specified one-sided significance level of 0.1). Adverse events of grade 3/4 excluding ineligible example was 30.0% in the L group, and 36.0% in the S group. Patients who require a dose reduction and/or delay of S-1 was 41.6% in the L group, and 51.5% in the S group. RD was 83.9% (range: 1.6-103.7) in the L group, and 84.0% (range: 1.7-103.8) in the S group. No any toxicity of lafutidine was observed. Conclusions: Lafutidine may increase a completion rate of adjuvant chemotherapy using S-1 within a 30% dose reduction for gastric cancer. This result need to be confirmed in double-blind placebo control study. Clinical trial information: UMIN000002703.

Su1819 - Allyl Isothiocyanate, a Pungent Ingredient of Wasabi, Induces Gastric Low-Grade Inflammation in Rats to Lead to the Impaired Gastric Motility; Involvement of Prostaglandin, Capsaicin-Sensitive Sensory Neurons, and Nitric Oxide

Su1819 - Allyl Isothiocyanate, a Pungent Ingredient of Wasabi, Induces Gastric Low-Grade Inflammation in Rats to Lead to the Impaired Gastric Motility; Involvement of Prostaglandin, Capsaicin-Sensitive Sensory Neurons, and Nitric Oxide

MP42-03 EFFECTS OF NERVE GROWTH FACTOR NEUTRALIZATION ON HYPEREXCITABILITY OF CAPSAICIN SENSITIVE BLADDER AFFERENT NEURONS IN MICE WITH SPINAL CORD INJURY

You have accessJournal of UrologyBladder & Urethra: Anatomy, Physiology & Pharmacology I1 Apr 2017MP42-03 EFFECTS OF NERVE GROWTH FACTOR NEUTRALIZATION ON HYPEREXCITABILITY OF CAPSAICIN SENSITIVE BLADDER AFFERENT NEURONS IN MICE WITH SPINAL CORD INJURY Takahiro Shimizu, Tsuyoshi Majima, Takahisa Suzuki, Nobutaka Shimizu, Naoki Wada, Shun Takai, Eiichiro Takaoka, Joonbeom Kwon, Pradeep Tyagi, Motoaki Saito, and Naoki Yoshimura Takahiro ShimizuTakahiro Shimizu More articles by this author , Tsuyoshi MajimaTsuyoshi Majima More articles by this author , Takahisa SuzukiTakahisa Suzuki More articles by this author , Nobutaka ShimizuNobutaka Shimizu More articles by this author , Naoki WadaNaoki Wada More articles by this author , Shun TakaiShun Takai More articles by this author , Eiichiro TakaokaEiichiro Takaoka More articles by this author , Joonbeom KwonJoonbeom Kwon More articles by this author , Pradeep TyagiPradeep Tyagi More articles by this author , Motoaki SaitoMotoaki Saito More articles by this author , and Naoki YoshimuraNaoki Yoshimura More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1292AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Nerve growth factor (NGF) has been implicated as an important mediator to induce C-fiber bladder afferent hyperexcitability, which contributes to the emergence of neurogenic detrusor overactivity (NDO) following spinal cord injury (SCI). In this study, we examined whether NGF neutralization using anti-NGF antibody normalizes the SCI-induced changes in electrophysiological properties of capsaicin-sensitive C-fiber bladder afferent neurons in the mouse model. METHODS In female C57BL/6 mice, the spinal cord was transected at the Th8/9 level. Two weeks later, an osmotic pump was placed subcutaneously to administer anti-NGF antibody at 10 µg/kg/h for 2 weeks. Bladder afferent neurons were labeled with axonal transport of Fast Blue (FB), a fluorescent retrograde tracer, injected into the bladder wall 3 weeks after SCI. Four weeks after SCI, freshly dissociated L6-S1 dorsal root ganglion neurons were prepared. Whole cell patch clamp recordings were then performed in FB-labeled bladder afferent neurons, and the data were compared between SCI and spinal intact (SI) mice. After recording action potentials (AP) or voltage-gated K+ (Kv) currents, the sensitivity of each neuron to capsaicin was evaluated. RESULTS In capsaicin-sensitive bladder afferent neurons, the resting membrane potentials and the peak and duration of AP did not changed by SCI. On the other hand, the threshold for eliciting AP was significantly reduced in SCI vs. SI mice. Also, SCI increased the number of AP during 800 ms membrane depolarization. These SCI induced changes were reversed by NGF neutralization. SCI induced significant increases in the diameter and cell input capacitance of capsaicin-sensitive bladder afferent neurons, which were not reversed by NGF neutralization. Densities of slow decaying KA and sustained KDR currents evoked by depolarization to 0 mV were significantly reduced by SCI. NGF neutralization reversed the SCI-induced reduction in the KA current density. CONCLUSIONS In SCI mice, NGF plays an important role in hyperexcitability of capsaicin sensitive C-fiber bladder afferent neurons due to KA current reduction. Thus, NGF-targeting therapies could be effective for treatment of afferent hyperexcitability and NDO in SCI. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e544-e545 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Takahiro Shimizu More articles by this author Tsuyoshi Majima More articles by this author Takahisa Suzuki More articles by this author Nobutaka Shimizu More articles by this author Naoki Wada More articles by this author Shun Takai More articles by this author Eiichiro Takaoka More articles by this author Joonbeom Kwon More articles by this author Pradeep Tyagi More articles by this author Motoaki Saito More articles by this author Naoki Yoshimura More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Effect of capsaicin-sensitive sensory neurons on bone architecture and mechanical properties in the rat hindlimb suspension model

SummaryBackground/ObjectiveThe participation of sensory neural regulation in bone metabolism has been widely studied. However, the physiological role of sensory neural regulation in the functional adaptation to weight bearing is not clear. This study was conducted to investigate the effect of capsaicin-induced sensory neuron lesions on cancellous architecture properties in a hindlimb suspension (HLS) model.MethodsThirty-two female rats were randomly assigned to four groups. Groups b and d underwent systemic capsaicin treatment, whereas Groups a and c were treated with vehicle. Then, Groups c and d were subjected to HLS, whereas Groups a and b were allowed hindlimbs full loading. The proximal trabecular and mid-shaft cortical bone structure were evaluated via microcomputed tomography, and the biomechanical properties of the tibial mid-shaft were assessed using the four-point bending test.ResultsThe trabecular bone volume was reduced by 40% and 50% in Groups b and c, respectively, and was also reduced significantly in Group d. Trabecular thickness and trabecular separation in Group b were not significantly different from those of Group a. The cortical bone area fraction showed no significant difference among all groups. Compared with Group a, the ultimate strength in Group b decreased by 20.3%, whereas it did not change significantly in Group c.ConclusionThe results suggest that capsaicin-sensitive sensory neurons play an important role in bone modelling. The effect of capsaicin is similar to HLS. However, HLS has no add-on effect to capsaicin in the reduction of bone density and mechanical properties.Translational potential of this article: This study gives clues to the function of sensory neurons in bone modelling.

Activation of endogenous TRPV1 fails to induce overstimulation-based cytotoxicity in breast and prostate cancer cells but not in pain-sensing neurons

Vanilloids including capsaicin and resiniferatoxin are potent transient receptor potential vanilloid type 1 (TRPV1) agonists. TRPV1 overstimulation selectively ablates capsaicin-sensitive sensory neurons in animal models in vivo. The cytotoxic mechanisms are based on strong Na+ and Ca2+ influx via TRPV1 channels, which leads to mitochondrial Ca2+ accumulation and necrotic cell swelling. Increased TRPV1 expression levels are also observed in breast and prostate cancer and derived cell lines. Here, we examined whether potent agonist-induced overstimulation mediated by TRPV1 might represent a means for the eradication of prostate carcinoma (PC-3, Du 145, LNCaP) and breast cancer (MCF7, MDA-MB-231, BT-474) cells in vitro. While rat sensory neurons were highly vanilloid-sensitive, normal rat prostate epithelial cells were resistant in vivo. We found TRPV1 to be expressed in all cancer cell lines at mRNA and protein levels, yet protein expression levels were significantly lower compared to sensory neurons. Treatment of all human carcinoma cell lines with capsaicin didn't lead to overstimulation cytotoxicity in vitro. We assume that the low vanilloid-sensitivity of prostate and breast cancer cells is associated with low expression levels of TRPV1, since ectopic TRPV1 expression rendered them susceptible to the cytotoxic effect of vanilloids evidenced by plateau-type Ca2+ signals, mitochondrial Ca2+ accumulation and Na+- and Ca2+-dependent membrane disorganization. Moreover, long-term monitoring revealed that merely the ectopic expression of TRPV1 stopped cell proliferation and often induced apoptotic processes via strong activation of caspase-3 activity. Our results indicate that specific targeting of TRPV1 function remains a putative strategy for cancer treatment.

Transient receptor potential ankyrin 1 (TRPA1) receptor is involved in chronic arthritis: in vivo study using TRPA1-deficient mice.

BackgroundThe transient receptor potential ankyrin 1 (TRPA1) is a calcium-permeable cation channel that is expressed on capsaicin-sensitive sensory neurons, endothelial and inflammatory cells. It is activated by a variety of inflammatory mediators, such as methylglyoxal, formaldehyde and hydrogen sulphide. Since only few data are available about the role of TRPA1 in arthritis and related pain, we investigated its involvement in inflammation models of different mechanisms.MethodsChronic arthritis was induced by complete Freund’s adjuvant (CFA), knee osteoarthritis by monosodium iodoacetate (MIA) in TRPA1 knockout (KO) mice and C57Bl/6 wildtype mice. For comparison, carrageenan- and CFA-evoked acute paw and knee inflammatory changes were investigated. Thermonociception was determined on a hot plate, cold tolerance in icy water, mechanonociception by aesthesiometry, paw volume by plethysmometry, knee diameter by micrometry, weight distribution with incapacitance tester, neutrophil myeloperoxidase activity and vascular leakage by in vivo optical imaging, and histopathological alterations by semiquantitative scoring.ResultsCFA-induced chronic mechanical hypersensitivity, tibiotarsal joint swelling and histopathological alterations, as well as myeloperoxidase activity in the early phase (day 2), and vascular leakage in the later stage (day 7), were significantly reduced in TRPA1 KO mice. Heat and cold sensitivities did not change in this model. Although in TRPA1 KO animals MIA-evoked knee swelling and histopathological destruction were not altered, hypersensitivity and impaired weight bearing on the osteoarthritic limb were significantly decreased. In contrast, carrageenan- and CFA-induced acute inflammation and pain behaviours were not modified by TRPA1 deletion.ConclusionsTRPA1 has an important role in chronic arthritis/osteoarthritis and related pain behaviours in the mouse. Therefore, it might be a promising target for novel analgesic/anti-inflammatory drugs.