Inhibitory Effect Of Capsaicin Research Articles

Beyond Thermal Sensation: Roles of Transient Receptor Potential Vanilloid Subfamily Member 1 and Spicy Food in Cardiometabolic Diseases

Beyond Thermal Sensation: Roles of Transient Receptor Potential Vanilloid Subfamily Member 1 and Spicy Food in Cardiometabolic Diseases

In-vitro binding analysis and inhibitory effect of capsaicin on lipase

Capsaicin is the main active ingredient in chilis. This study selected capsazepine as a comparative model and revealed the binding mechanism and inhibitory effect of capsaicin on lipase in vitro. Electrochemical results showed capsaicin has a moderate affinity to lipase with a 7.413 × 104 L/mol binding constant, which is higher than capsazepine (3.388 × 104 L/mol). Structural analysis displayed that capsaicin/capsazepine caused a slight disturbance (less than 1%) to the secondary structure of lipase. The capsaicin binding epitope on the lipase was characterized by nuclear magnetic resonance. H47, H48 and H49 were the protons mainly involved in the interaction. In the comparison model, the H27 and H26 were involved in the capsazepine-lipase system. Hydrogen proton binding epitope analysis combined with molecular docking showed the main elements involved in the binding details. Enzyme kinetics results showed that capsaicin could inhibit the activity of lipase, resulting in a decrease in its ability to hydrolyze the substrate varying hydrolysis rate from 0% to 33.33% in different capsaicin concentrations. The biological model in vitro established in this study will support the development of weight-loss-related functional foods.

Capsaicin Inhibits the Expression of Melanogenic Proteins in Melanocyte via Activation of TRPV1 Channel: Identifying an Inhibitor of Skin Melanogenesis.

Chili pepper belongs to the genus Capsicum of Solanaceae family. Capsaicin is the primary capsaicinoid in placenta and flesh of chili pepper fruit, which has been shown to have various pharmacological functions, including gastric protection, anti-inflammation, and obesity treatment. Here, we revealed that capsaicin as well as chilli extract was able to inhibit synthesis of melanin in melanocytes. In cultured melanocytes, the melanin content was reduced to 54 ± 6.55% and 42 ± 7.41% with p < 0.001 under treatment of 50 μM capsaicin for 24 and 72 h, respectively. In parallel, the protein levels of tyrosinase and tyrosinase-related protein-1 were reduced to 62 ± 8.35% and 48 ± 8.92% with p < 0.001. Such an inhibitory effect of capsaicin was mediated by activation of transient receptor potential vanilloid 1-induced phosphorylation of extracellular signal-regulated kinase. This resulted in a degradation of microphthalmia-associated transcription factor, leading to reduction of melanogenic enzymes and melanin. These results revealed that capsaicin could be an effective inhibitor for skin melanogenesis. Hence, chili pepper, as our daily food, has potential in dermatological application, and capsaicin should be considered as a safe agent in treating hyperpigmentation problems.

Inhibition of LINE-1 Retrotransposition by Capsaicin.

Long interspersed nuclear element 1 (LINE-1 or L1) is a non-long terminal repeat (LTR) retrotransposon that constitutes approximately 17% of the human genome. Since approximately 100 copies are still competent for retrotransposition to other genomic loci, dysregulated retrotransposition of L1 is considered to be a major risk factor of endogenous mutagenesis in humans. Thus, it is important to find drugs to regulate this process. Although various chemicals are reportedly capable of affecting L1 retrotransposition, it is poorly understood whether phytochemicals modulate L1 retrotransposition. Here, we screened a library of compounds that were derived from phytochemicals for reverse transcriptase (RT) inhibition with an in vitro RT assay. We identified capsaicin as a novel RT inhibitor that also suppressed L1 retrotransposition. The inhibitory effect of capsaicin on L1 retrotransposition was mediated neither through its receptor, nor through its modulation of the L1 promoter and/or antisense promoter activity, excluding the possibility that capsaicin indirectly affected L1 retrotransposition. Collectively, capsaicin suppressed L1 retrotransposition most likely by inhibiting the RT activity of L1 ORF2p, which is the L1-encoded RT responsible for L1 retrotransposition. Given that L1-mediated mutagenesis can cause tumorigenesis, our findings suggest the potential of capsaicin for suppressing cancer development.

Capsaicin Inhibited Aggressive Phenotypes through Downregulation of Tumor-Associated NADH Oxidase (tNOX) by POU Domain Transcription Factor POU3F2.

Capsaicin has been reported to preferentially inhibit the activity of tumor-associated NADH oxidase (tNOX), which belongs to a family of growth-related plasma membrane hydroquinone oxidases in cancer/transformed cells. The inhibitory effect of capsaicin on tNOX is associated with cell growth attenuation and apoptosis. However, no previous study has examined the transcriptional regulation of tNOX protein expression. Bioinformatic analysis has indicated that the tNOX promoter sequence harbors a binding motif for POU3F2, which is thought to play important roles in neuronal differentiation, melanocytes growth/differentiation and tumorigenesis. In this study, we found that capsaicin-mediated tNOX downregulation and cell migration inhibition were through POU3F2. The protein expression levels of POU3F2 and tNOX are positively correlated, and that overexpression of POU3F2 (and the corresponding upregulation of tNOX) enhanced the proliferation, migration and invasion in AGS (human gastric carcinoma) cells. In contrast, knockdown of POU3F2 downregulates tNOX, and the cancer phenotypes are affected. These findings not only shed light on the molecular mechanism of the anticancer properties of capsaicin, but also the transcription regulation of tNOX expression that may potentially explain how POU3F2 is associated with tumorigenesis.

The inhibitory effect of capsaicin on streptozocin-induced apoptosis of rat retinal cells

Background Diabetes mellitus (DM) can provoke the apoptosis of retinal cells and downregulate the expression of calcitonin gene related peptide (CGRP) in the retina.Capsaicin promotes the release of CGRP and elicits protective effects on human organs.However,whether CGRP protects retinal cells in diabetic retinopathy (DR) is still unclear.Objective The study was designed to examine the effect of capsaicin on the apoptosis of retinal cells in diabetic rats and its relationship with CGRP.Methods Forty clean healthy adult male Sprague-Dawey rats were randomly divided into the diabetes group,capsaicin pretreated group,streptozocin (STZ)control group,capsaicin control group and plain control group,with 8 rats per group.The diabetic model was established by the intraperitoneal injection of 60 mg/kg in all rats except those of the plain control group.0.4 mL of a 1％ capsaicin injected at 20 mg/kg was subcutaneously injected for 3 consecutive days prior to model establishment in the capsaicin pretreated group,after which 1.2 mL of STZ was intraperitoneally injected on the fourth day.Rats from the STZ control group were administered intraperitoneally 1.2 mL of 0.1 mol/L,pH 4.5,citrate buffer.The capsaicin control group received subcutaneous injections of 0.4 mL of 1％ capsaicin at 20 mg/kg for 3 consecutive days,after which 1.2 mL of 0.1 mol/L,pH 4.5,citrate buffer was administered intraperitoneally.The rats were sacrificed at the tenth week after model establishment and retinal specimens were prepared for the apoptosis assay by TUNEL staining and the quantitative analysis of caspase-3 activity.Expression of CGRP in the retina and serum was detected using ELISA.The use of experimental animals followed the Regulations for the Administration of Affairs Concerning Experimental Animals by State Science and Technology Commission.Results Retinal cell apoptosis was mainly localized to the retinal ganglion cell (RGC) layer.The apoptosis rate of RGCs was (43.4±5.0)％ in the DR model group and (30.0±5.1)％ in the capsaicin pretreated group,showing a significant difference (t =5.930,P＜0.01).Compared with the DR model group and capsaicin pretreated group,the apoptosis rates of the DR control group (12.4±9.9) ％ and the capsaicin control group (17.6-±6.1) ％ were significantly lower (t =8.800,t =4.925,P＜0.01).The apoptosis rate of the plain control group was (16.2±6.9)％,exhibiting significant differences in comparison with the DR control group and capsaicin control group (t =-0.989,t =0.951,P＞0.05).The specific activity of caspase-3 was (2.19±0.86) in the DR model group and (1.96±0.56) in the capsaicin pretreated group,presenting a significant difference (t =-0.515,P＜0.05).Those of the DR control group and capsaicin control group were (1.47±0.14) and (0.74±0.27),respectively,with considerable decline in comparison with the DR model group and capsaicin pretreated group (t=2.142,t=2.797,P＜0.05).The retinal and serum CGRP levels were (424.4±44.2)and (148.8±39.1) ng/L,respectively,displaying significantly lower levels than (543.2±74.4) and (237.5±78.7) ng/L (t =3.070,2.359,P＜0.05) from the capsaicin pretreated group.Conclusions Apoptosis of retinal ganglion cells occurs in the STZ-induced diabetic rats.Pretreatment of capsaicin reduces retinal cell apoptosis,which may be associated with an increase of CGRP in the retina. Key words: Calcitonin gene related peptide/ capsaicin; Apoptosis; Diabetic retinopathy; Neurodegeneration

Capsazepine reversible inhibition of opioid receptors by capsaicin

Event Abstract Back to Event Capsazepine reversible inhibition of opioid receptors by capsaicin Maria Wollemann1, Eniko Ioja1 and Sándor Benyhe1* 1 Institute of Biochemistry, Hungarian Academy of Sciences, Hungary Capsaicin inhibited the binding of endogenous opioid and opioid-like ligands (endomorphin-1, nociceptin and dynorphin-(1-17) in rat brain membrane preparations in vitro. The affinity decrease was most pregnant using endomorphin-1, followed by nociceptin and dynorphin. The inhibition of capsaicin on opioid binding was not observed using non endogenous peptides and synthetic ligands (DAMGO, morphine, naloxone). In the [3H]endomorphin binding assay capsazepine antagonized the inhibitory effect of capsaicin in rat brain membranes, which suggests that capsaicin acts on opioid receptors through the vanilloid receptor (TRPV1). In Chinese hamster ovary cells stable expressing -opioid receptors and lacking TRPV1 receptors, the inhibitory effect of capsaicin on the binding of [3H]endomorphin-1 was not present. It was concluded that the inhibitory effect of capsaicin on the affinity of opioid endogenous peptides in rat brain membrane preparations is not a direct effect, but indirectly other intermediate factors like protein kinases play an important role. Conference: 12th Meeting of the Hungarian Neuroscience Society, Budapest, Hungary, 22 Jan - 24 Jan, 2009. Presentation Type: Poster Presentation Topic: Pathophysiology and neurology - non-degenerative disorders Citation: Wollemann M, Ioja E and Benyhe S (2009). Capsazepine reversible inhibition of opioid receptors by capsaicin. Front. Syst. Neurosci. Conference Abstract: 12th Meeting of the Hungarian Neuroscience Society. doi: 10.3389/conf.neuro.01.2009.04.120 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 04 Mar 2009; Published Online: 04 Mar 2009. * Correspondence: Sándor Benyhe, Institute of Biochemistry, Hungarian Academy of Sciences, Szeged, Hungary, benyhe@brc.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Maria Wollemann Eniko Ioja Sándor Benyhe Google Maria Wollemann Eniko Ioja Sándor Benyhe Google Scholar Maria Wollemann Eniko Ioja Sándor Benyhe PubMed Maria Wollemann Eniko Ioja Sándor Benyhe Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Capsaicin induced apoptosis and the enhanced anticancer effect of anticancer drugs in cancer cells

Purpose : Capsaicin, the major pungent ingredient in red pepper, has long been used in spices and food additives. It has been recently shown to induce apoptosis in several cell lines through a not well known mechanism. The aim of this study was to investigate the apoptosis-inducing effect of capsaicin on gastric cancer cells, and to provide valuable information concerning the application of capsaicin for therapeutic purposes. Methods : Cultured SNU-668 cells were treated with capsaicin. We analyzed cell survival by trypan blue and crystal violet analysis, cell cytotoxicity by MTT assay, apoptosis by nuclear condensation and DNA fragmentation, bcl-2 and bax mRNA expression by RT-PCR, and the expression of apoptosis related proteins by Western immunoblot analysis. In order to assess whether the growth inhibitory effect of anticancer drugs is enhanced by capsaicin, we investigated the effects of cell cytotoxicity and the expression of apoptosis related proteins of etoposide and adriamycin treated with capsaicin in cells. Results : Capsaicin inhibited growth of SNU-668 cells in a dose-dependent manner. This inhibitory effect of capsaicin on cell growth was mainly due to the induction of apoptosis as evidenced by DNA fragmentation, nuclear condensation and the expression of apoptosis related proteins. Furthermore, capsaicin prominently reduced the ratio of anti-apoptotic Bcl-2 to pro-apoptotic Bax and consequently increased caspase-3 activity. The cells treated with capsaicin were more sensitive to death induced by etoposide and adriamycin than the cells without capsaicin. Conclusion : These results demonstrate that capsaicin efficiently induced apoptosis in SNU-668 cells through a caspase- 3-dependent mechanism and sensitizes cancer cells to anticancer drugs toward apoptotic cell death, which may contribute to its anticancer effect and chemosensitizer function against gastric cancer.

Inhibitory Effect of Capsaicin against Carcinogen-induced Oxidative Damage in Rats

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a major pungent component of hot pepper, is known to exert antioxidative properties. In this study, we investigated the protective effects of capsaicin against chemical carcinogen-induced oxidative damage in rats. Male Sprague Dawley rats weighting 230～250 g were treated with chemical carcinogens such as 2-nitropropane (2NP) or n-methyl-N'-nitro-N-nitrosoguanidine (MNNG) after (or before) the administration of capsaicin at doses of 0.5, 1, 5 mg/kg. The level of lipid peroxidation in rat liver was estimated by measuring the amounts of thiobarbituric acid reactive substances. The degree of oxidative DNA damage was evaluated by measuring a DNA adduct, 8-hydroxydeoxyguanosine (8-OHdG), in urine. Antioxidative activities of capsaicin, its metabolites in vitro were determined by the measurement of DPPH (1,1-diphenyl-2-picrylhydrazyl), a radical quencher. Significant inhibition of 2-NP induced lipid peroxidation was observed in the liver of the rat when treated with capsaicin. MNNG-induced urinary excretion of 8-OHdG was decreased by capsaicin treatment. Capsaicin, its metabolites inhibited not only the formation of free radicals, but also lipid peroxidation in vitro. Our results show that capsaicin may function as a free radical scavenger against chemical carcinogen-induced oxidative cellular damage in vivo. The observed antioxidative activities of capsaicin may play an important role in the process of chemoprevention.

Capsaicin-induced apoptosis in SK-Hep-1 hepatocarcinoma cells involves Bcl-2 downregulation and caspase-3 activation

Hepatocellular carcinoma is one of the most lethal malignancies and there is no effective preventive measure in this highly malignant disease to date. In the present study, we investigated the chemopreventive potential of capsaicin (8-methyl- N- vanillyl-6-nonenamide), the principal pungent ingredient found in hot red pepper, in SK-Hep-1 hepatocellular carcinoma cells. Treatment of capsaicin inhibited growth of SK-Hep-1 cells in a concentration-dependent manner while 4-methoxy capsaicin (Met-capsaicin) was less potent. This inhibitory effect of capsaicin on SK-Hep-1 cell growth was mainly due to the induction of apoptosis as evidenced by DNA fragmentation and nuclear condensation. Furthermore, capsaicin prominently reduced the ratio of anti-apoptotic Bcl-2 to pro-apoptotic Bax and consequently increased caspase-3 activity. These results demonstrate that capsaicin efficiently induced apoptosis in SK-Hep-1 cells through a caspase-3-dependent mechanism, which may contribute to its chemopreventive function.

Inhibitory effect of capsaicin on cholinergic transmission in ovine airways: evidence for non-cholinergic contractions

Electrical stimulation of ovine trachealis smooth muscle and bronchial ring segments induced neurogenic and monophasic atropine-sensitive contractions. Pretreatment of the tissues with capsaicin (100 μM) significantly reduced these contractions indicating a possible contribution of a peptidergic neurotransmitter to the contractions. The effect of capsaicin on electrically induced contractions was significantly inhibited by capsazepin indicating an action on vanilloid receptors. In both preparations, electrically induced contractions were not modified by tachykinin NK 1- and NK 2-receptor antagonists singly and in combination. It was therefore concluded that a component of the atropine-sensitive electrically induced contractions of ovine airways smooth muscles involved the release of a peptide neurotransmitter which is probably not a tachykinin. However, an action of capsaicin on prejunctional vanilloid receptors located on cholinergic nerves cannot be ruled out.

Effects of Capsaicin and Capsaicin Desensitization on Alanine Accumulation in Rat Hemidiaphragms

1. Alanine accumulation in rat hemidiaphragms is significantly inhibited by capsaicin in a dose-dependent pattern that produced maximal effect at 1 mM. 2. The inhibitory effect of capsaicin on alanine accumulation by rat hemidiaphragms was enhanced upon preincubation with 5 mM ouabain. However, preincubation with 1 mM Verapamil did not alter the inhibitory effect of capsaicin. 3. Chemical ablation of the capsaicin-sensitive primary afferent fibers abolished the inhibitory effect of capsaicin on alanine accumulation in the rat hemidiaphragms.

Capsaicin can alter the expression of tumor forming-related genes which might be followed by induction of apoptosis of a Korean stomach cancer cell line, SNU-1

Capsaicin (CAP) has been known to inhibit some tumor development in vivo (J.J. Jang, S.H. Kim, T.K. Yun, Inhibitory effect of capsaicin on mouse lung tumor development, in vivo, J. Korean Med. Sci. 3 (1989) 49–53; J.J. Jang, K.J. Cho, Y.S. Lee, J.H. Bae, Different modifying responses of capsaicin in a wide-spectrum initiation model of F344 rat, J. Korean Med. 6 (1991) 31–36) [1, 2]even though its mechanism of action is not well understood. The objectives of this study were to examine the effect of CAP on expression of tumor forming-related genes in a Korean stomach tumor cell, SNU-1. We used slot blot hybridization to investigate its effect on a wide spectrum of proto-oncogenes. It was found that CAP enhanced the transcripts of two proto-oncogenes (c- myc and c-Ha- ras) and tumor suppressor gene p53. While a low concentration of CAP (0.01 μM) did not significantly increase the level of p53 transcript in SNU-1, it did increase it by a factor of 3.5 at a 10 μM dose of CAP. Consequently, SNU-1 cells are sensitive to CAP in the overexpression of tumor suppressor gene, p53 and proto-oncogenes, c- myc and c-Ha- ras, but not those of c- erbB-2, c- jun and bcl-2 genes. Both cell death and DNA fragmentation were shown in SNU-1 cells with treatment of CAP. Our results suggest that CAP induces apoptotic cell death in human gastric cancer cells (SNU-1) in vitro which may be possibly mediated by the overexpression of p53 and/or c- myc genes. Because cell suicide is arguably the most potent natural defense against cancer, the correlation between the induction of apoptosis and the change of tumor forming-related gene expression after CAP treatment should be further studied in detail.

Effect of phytochemicals on the mutagenicity of the tobacco‐specific nitrosamine 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK) in Salmonella typhimurium strain TA1535

AbstractFive phytochemicals with potential chemopreventive activity were tested to determine their antimutagenic effects toward the tobacco‐specific nitrosamine 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK) in Salmonella typhimurium strain TA1535. NNK at a concentration of 80 mM was metabolically activated by hamster liver microsomes. Three phytochemicals; capsaicin, diallyl sulphide and silymarin, exhibited antimutagenic activity toward NNK in a dose‐dependent manner. At the highest nontoxic concentration tested (0.5 mmole/plate), the inhibitory effect of capsaicin, diallyl sulphide and silymarin was 85%, 23% and 48%, respectively. D‐limonene and tannic acid were also tested but did not show antimutagenic activity toward NNK in TA1535. These results suggest that capsaicin, diallyl sulphide and silymarin inhibited the activation of NNK and indicate that further studies of the efficacy of these phytochemicals in the chemoprevention of NNK‐induced carcinogenesis are warranted.

Mechanism of inhibitory action of capsaicin on particulate axoplasmic transport in sensory neurons in culture.

The inhibitory effect of capsaicin on axoplasmic transport in cultured dorsal root ganglion cells was analyzed by video-enhanced contrast microscopy. Capsaicin inhibited particle transports in a dose-dependent manner, irrespective of the diameter of axons. The effect of capsaicin was reversible at low concentrations. Capsaicin affected both the anterograde and retrograde transport. Large organelles were more sensitive to capsaicin than small ones in the retrograde transport. An experiment using calcium-sensitive dye, Fura 2, indicated that capsaicin raised the intraneuronal free calcium concentration preceding the inhibition of the transport. Electron microscopy revealed that microtubules and neurofilaments are disorganized and disoriented by capsaicin. We reached a conclusion that capsaicin inhibits fast axoplasmic transport of both anterograde and retrograde directions in all types of somatosensory neurons in culture by disorganizing intraaxonal cytoskeletal structures, through the elevated intracellular Ca2+ concentration.

Inhibitory effect of capsaicin on the ascending pathway of the guinea-pig ileum and antagonism of this effect by ruthenium red

A segment of guinea-pig ileum, which was continuous with a strip of longitudinal muscle-myenteric plexus (LM-MP) at the anal end, was used to examine the effect of capsaicin on ascending excitatory pathways. Electrical field stimulation of the LM-MP caused an ascending contraction of the segment. After initially causing contraction capsaicin (3 μM) inhibited the ascending contraction. This inhibitory effect of capsaicin exhibited rapid desensitization and was abolished after extrinsic (mesentrric) denervation. Desensitization to calcitonin gene-related peptide (CGRP) prevented the capsaicin-induced inhibition without affecting the ascending contraction. Neither naloxone nor α- and β-adrenoceptor antagonists affected the capsaicin-induced inhibition. CGRP (25 nM) also inhibited the ascending contraction, mimicking the inhibition induced by capsaicin. Ruthenium red (0.1–3 μM) antagonized the capsaicin-induced inhibition in a concentration-related manner, but did not affect the CGRP-induced inhibition. These findings suggest that the inhibitory effect of capsaicin on the ascending pathways might be mediated via the release of CGRP from extrinsic nerve terminals, and that the site of the antagonism of the action of capsaicin by ruthenium red is prejunctional.

Effects of capsaicin on the circular muscle motility of the isolated guinea-pig ileum.

Effects of capsaicin on the circular muscle motility of the isolated guinea-pig ileum were investigated. Capsaicin produced a contraction followed by a relaxation of the circular muscle. Both responses were easily desensitized. As the late relaxation response was not sufficiently intense to be analyzed, the inhibitory effect of capsaicin on substance P-induced contractions was explored. Capsaicin abolished the substance P-induced contractions. This inhibitory effect was not affected by tetrodotoxin, and the effect was desensitized. Therefore, all effects of capsaicin on circular muscle motility seem to be due to the release of sensory neuropeptides, similarly to those elicited in the longitudinal muscle.

Intragastric capsaicin protects against aspirin-induced lesion formation and bleeding in the rat gastric mucosa

Previous work has indicated that capsaicin-sensitive afferent neurons are involved in gastric mucosal defense mechanisms. The present study investigated whether stimulation of these neurons by intragastric administration of capsaicin would protect against aspirin-induced mucosal damage in the luminally perfused rat stomach. Capsaicin (25–640 μM), administered together with acidified (pH 1.5) aspirin (25 mM), inhibited macroscopically visible lesion formation and gastric bleeding in a concentration-dependent fashion. Capsaicin (160 μM) also attenuated the aspirin-induced fall in the gastric potential difference. An inhibitory effect of capsaicin (160 μM) on aspirin-induced gastric injury was also seen by light and scanning electron microscopy. Aspirin alone caused a vast ablation of the gastric surface epithelium, resulting in exposure of the lamina propria. In the presence of capsaicin, the depth of mucosal injury, the area totally deprived of surface epithelial cells, and the severity of surface desquamation were diminished. As capsaicin is a selective stimulant of thin afferent neurons, it would appear that these neurons participate in mechanisms of gastric defense against aspirin injury. Prevention of hemorrhagic damage seems to be the primary effect of afferent nerve-mediated gastroprotection, although injury to the surface epithelium is also reduced to some degree.

Neural pathways and pharmacological modulation of defecation reflex in rats

1. 1. A new method was developed for quantitative studies on defecation reflex in urethane-anesthetized rats which involves the continuous infusion of saline (0.1 ml/min) to distend a balloon placed in the rectum. At threshold values, the balloon was expelled during an active rectal contraction. 2. 2. Balloon expulsion was greatly delayed or even abolished by i.v. hexamethonium. Cord transection at the upper cervical level increased defection threshold but a functional, hexamethonium-sensitive response was still elicited in spinal rats. 3. 3. Various parameters of the defecation response were modulated by drugs (phentolamine, picrotoxin, naloxone) expected to interfere (either centrally or peripherally), with neural pathways controlling the autonomic outflow for the reflex response. 4. 4. In capsaicin-pretreated rats (50 mg/kg s.c. on 2nd day of life, experiments performed at 2 months), daily fecal production was unchanged as compared to vehicle-treated, age-matched controls. However, under urethane-anesthesia, defecation threshold was increased at higher-than-normal values by capsaicin-pretreatment. 5. 5. In in vitro experiments, capsaicin (1 μM) induced a transient inhibition of field stimulation-induced contractions of the rat isolated rectum. This effect was mimicked by application of calcitonin gene—related peptide (CGRP) (0.1 μM) while Substance P (0.1 μM) had an opposite effect. In preparations desensitized to exogenous CGRP, the inhibitory effect of capsaicin was almost abolished. 6. 6. These findings indicate that in rats, reflex defecation is mainly organized at spinal level, although the participation of supraspinal centers may modify the functional response. Capsaicin-sensitive afferents may be involved in the initiation of certain forms of reflex defecation, although capsaicin-resistant mechanisms are capable of activating the normal excretory function.

Visceromotor responses to calcitonin gene-related peptide (CGRP) in the rat lower urinary tract: evidence for a transmitter role in the capsaicin-sensitive nerves of the ureter

Either intra-arterial or topical administration of calcitonin gene-related peptide (CGRP) had little effect on motility of the urinary bladder in urethane-anaesthetized rats. Only a high concentration (50 μM) of topical CGRP activated the micturition reflex and potentiated the response to exogenous substance P (SP). In the isolated rat bladder CGRP had inconsistent effects on spontaneous or field-stimulated contractions. CGRP neither produced any significant plasma extravasation (Evans blue leakage) in the rat lower urinary tract, nor potentiated the response to exogenous SP. CGRP inhibited motility in the rat isolated proximal urethra and ureters and counteracted the contractile response to neurokinins. An inhibitory effect of capsaicin on stimulated motility of the urethra was observed in all preparations and a small contractile response was evident in about 40% of cases. Lack of desensitization to the action of CGRP prevented the study of its interaction with capsaicin. The inhibitory effect of CGRP in the ureter exhibited a specific desensitization: if the preparations were pre-exposed to exogenous CGRP, the inhibition of motility produced by antidromic activation of the capsaicin-sensitive nerve terminals (field stimulation) as well as the response to capsaicin (1 μM) was prevented but the inhibitory response to isoprenaline was unaffected. These findings indicate that CGRP is able to influence markedly the motility of the rat lower urinary tract, but exhibits marked regional differences in its action. Endogenous CGRP could be the inhibitory transmitter which, when released from capsaicin-sensitive fibers, participate in the control of ureteral motility.