RESUMO
Gastrointestinal (GI) mucosal integrity is based on the balance of aggressive and protective mechanisms. Mucosal damage may occur when the injurious factors become dominant or the mucosal defensive processes are impaired. The main target of the therapy against GI mucosal injury is the reduction of aggressive factors, however, the therapeutic possibilities for stimulation of mucosal defensive processes are rather limited. This overview focuses on the gastric and intestinal mucosal protective mechanisms and discusses the main targets that increase protective processes and increase the mucosal resistance to injurious stimuli at pre-epithelial, epithelial and sub-epithelial levels.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Trato Gastrointestinal/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Trato Gastrointestinal/imunologia , HumanosRESUMO
Previous findings showed that inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), degrading enzymes of anandamide (2-AEA) and 2-arachidonoylglycerol (2-AG), reduced the nonsteroidal anti-inflammatory drug-induced gastric lesions. The present study aimed to investigate: i./whether central or peripheral mechanism play a major role in the gastroprotective effect of inhibitors of FAAH, MAGL and AEA uptake, ii./which peripheral mechanism(s) may play a role in mucosal protective effect of FAAH, MAGL and uptake inhibitors. METHODS: Gastric mucosal damage was induced by acidified ethanol. Gastric motility was measured in anesthetized rats. Catalepsy and the body temperature were also evaluated. Mucosal calcitonin gene-related peptide (CGRP), somatostatin concentrations and superoxide dismutase (SOD) activity were measured. The compounds were injected intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.). RESULTS: 1. URB 597, JZL184 (inhibitors of FAAH and MAGL) and AM 404 (inhibitor of AEA uptake) decreased the mucosal lesions significantly given either i.c.v. or i.p. 2. URB 937, the peripherally restricted FAAH inhibitor failed to exert significant action injected i.p. 3. Ethanol-induced decreased levels of mucosal CGRP and somatostatin were reversed by URB 597, JZL 184 and AM 404, the decreased SOD activity was elevated significantly by URB 597 and JZL 184. 4. Neither compounds given i.c.v. influenced gastric motility, elicited catalepsy, or hypothermia. CONCLUSION: Elevation of central endocannabinoid levels by blocking their degradation or uptake via stimulation of mucosal defensive mechanisms resulted in gastroprotective action against ethanol-induced mucosal injury. These findings might suggest that central endocannabinoid system may play a role in gastric mucosal defense and maintenance of mucosal integrity.
Assuntos
Endocanabinoides/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/lesões , Gastropatias/terapia , Análise de Variância , Animais , Ácidos Araquidônicos/farmacologia , Benzamidas/farmacologia , Benzodioxóis/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Carbamatos/farmacologia , Catalepsia/induzido quimicamente , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Etanol/toxicidade , Mucosa Gástrica/metabolismo , Motilidade Gastrointestinal/efeitos dos fármacos , Hipotermia/induzido quimicamente , Masculino , Piperidinas/farmacologia , Ratos , Ratos Wistar , Somatostatina/metabolismo , Gastropatias/induzido quimicamente , Superóxido Dismutase/metabolismoRESUMO
Gastric mucosal integrity can be influenced both by peripheral and central mechanisms. In the periphery several protective factors play a role in gastric mucosal defense. Moreover, receptors located in the gastric mucosa (e.g. toll-like receptors, proteinase-activated receptors, α2-adrenoceptors, opioid receptors) may also be involved in the regulation of gastric mucosal integrity. Activation of peripheral δ-opioid receptors by opioid peptides was shown to induce gastric mucosal defense. In contrast, the gastroprotective action mediated by α2-adrenoceptors (α2B/C-subtypes) is likely to be initiated centrally. Namely, central nervous system (CNS) is also involved in the regulation of gastrointestinal functions; hypothalamus and dorsal vagal complex (DVC) have prominent role in this process. In DVC several receptors have been identified, among others, µ and δ-opioid-, α2-adrenergic-, cannabinoid CB1- and CB2-, angiotensin II AT1-, nociceptin NOP-, neurokinin NK1- and TRH-receptors. Activation of these receptors results in gastric mucosal protection, mainly in a vagal dependent manner. In addition, glutamate (together with GABA and norepinephrine) is involved in synaptic connections between nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMNV) neurons. AP-7, a selective NMDA receptor antagonist blocked the gastroprotective effect of opioid peptides, indicating that N-Methyl-D-aspartic acid (NMDA) might play a role in centrally induced gastroprotective effect. Moreover, interactions between neuropeptides may have also importance in centrally initiated gastric mucosal protection. Clarification of the role of neuropeptides in gastric mucosal defense may serve as a basis for the development of new strategies to enhance gastric mucosal resistance against injury.
Assuntos
Sistema Nervoso Central/metabolismo , Mucosa Gástrica/metabolismo , Animais , Aminoácidos Excitatórios/metabolismo , Humanos , Neuropeptídeos/metabolismo , Óxido Nítrico/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Opioides/metabolismoRESUMO
The role of α(2)-adrenoceptors in regulation of gastric motility has been well documented. However, only few data are available on the adrenoceptor subtype that mediates this effect. The purpose of the present work was to identify the α(2)-adrenoceptor subtype(s) responsible for the inhibition of gastric motor activity in isolated fundus strip of the mouse. It was shown that (i) the electrically evoked contraction of the gastric fundus strip of the mouse was inhibited by the non-selective α(2)-adrenoceptor stimulant clonidine (EC(50): 0.019±0.001µM), the α(2A)-adrenoceptor subtype selective agonist oxymetazoline (EC(50): 0.004±0.001µM) and the α(2B)-adrenoceptor subtype preferring ST-91 (EC(50): 0.029±0.004µM), (ii) the inhibitory effect of clonidine (1µM), oxymetazoline (0.1µM) and ST-91 (1µM) on the contractions of gastric fundus strip was reversed by the non-selective α(2)-adrenoceptor antagonist idazoxan and α(2A)-adrenoceptor antagonist BRL 44408, but not by the α(2B/2C)-adrenoceptor antagonist ARC-239. (iii) Clonidine and ST-91 inhibited the electrically induced gastric contractions in C57BL/6 wild type mice as well as in α(2B)- and α(2C)-adrenoceptor deficient mice in a concentration-dependent manner; however, neither of them was effective in α(2A)-deficient mice. As a conclusion, it was first demonstrated that the inhibitory effect of α(2)-adrenoceptor agonists on the gastric motor activity of isolated stomach strip of the mouse is mediated purely by α(2A)-adrenoceptors.
Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Atividade Motora/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Estômago/efeitos dos fármacos , Animais , Clonidina/análogos & derivados , Clonidina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Estômago/fisiologiaRESUMO
BACKGROUND AND PURPOSE: This study was undertaken to compare the analgesic activity of antagonists acting at P2X1, P2X7, and P2Y12 receptors and agonists acting at P2Y1, P2Y2, P2Y4, and P2Y6 receptors in neuropathic, acute, and inflammatory pain. EXPERIMENTAL APPROACH: The effect of the wide spectrum P2 receptor antagonist PPADS, the selective P2X7 receptor antagonist Brilliant Blue G (BBG), the P2X1 receptor antagonist (4,4',4'',4-[carbonylbis(imino-5,1,3-benzenetriyl-bis(carbonylimino))]tetrakis-1,3-benzenedisulfonic acid, octasodium salt (NF449) and (8,8'-[carbonylbis(imino-3,1-phenylenecarbonylimino)]bis-1,3,5-naphthalene-trisulphonic acid, hexasodium salt (NF023), the P2Y12 receptor antagonist (2,2-dimethyl-propionic acid 3-(2-chloro-6-methylaminopurin-9-yl)-2-(2,2-dimethyl-propionyloxymethyl)-propylester (MRS2395), the selective P2Y1 receptor agonist ([[(1R,2R,3S,4R,5S)-4-[6-amino-2-(methylthio)-9H-purin-9-yl]-2,3-dihydroxybicyclo[3.1.0]hex-1-yl]methyl] diphosphoric acid mono ester trisodium salt (MRS2365), the P2Y2/P2Y4 agonist uridine-5'-triphosphate (UTP), and the P2Y4/P2Y6 agonist uridine-5'-diphosphate (UDP) were examined on mechanical allodynia in the Seltzer model of neuropathic pain, on acute thermal nociception, and on the inflammatory pain and oedema induced by complete Freund's adjuvant (CFA). KEY RESULTS: MRS2365, MRS2395 and UTP, but not the other compounds, significantly alleviated mechanical allodynia in the neuropathic pain model, with the following rank order of minimal effective dose (mED) values: MRS2365 > MRS2395 > UTP. All compounds had a dose-dependent analgesic action in acute pain except BBG, which elicited hyperalgesia at a single dose. The rank order of mED values in acute pain was the following: MRS2365 > MRS2395 > NF449 > NF023 > UDP = UTP > PPADS. MRS2365 and MRS2395 had a profound, while BBG had a mild effect on inflammatory pain, with a following rank order of mED values: MRS2395 > MRS2365 > BBG. None of the tested compounds had significant action on oedema evoked by intraplantar injection of CFA. CONCLUSIONS AND IMPLICATIONS: Our results show that antagonism at P2X1, P2Y12, and P2X7 receptors and agonism at P2Y1 receptors define promising therapeutic strategies in acute, neuropathic, and inflammatory pain respectively.
Assuntos
Analgésicos/farmacologia , Neuralgia/tratamento farmacológico , Dor/tratamento farmacológico , Receptores Purinérgicos P2/efeitos dos fármacos , Analgésicos/administração & dosagem , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Edema/fisiopatologia , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Ligantes , Masculino , Neuralgia/fisiopatologia , Dor/fisiopatologia , Medição da Dor , Ratos , Ratos Wistar , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2XRESUMO
Our previous findings suggest that alpha(2)-adrenoceptor stimulants induce gastroprotective action, the effect is likely to be mediated by alpha(2B)-adrenoceptor subtype. Clonidine (0.094 micromol/kg p.o.) and rilmenidine (0.014 micromol/kg p.o.) in gastroprotective dose range, as well as ST-91 (2.2 micromol/kg p.o.), a clonidine analogue showing higher affinity to alpha(2B)-adrenoceptor subtype than to alpha(2A)-one, inhibited the carrageenan-induced hyperalgesia in Randall-Selitto test, the antinociceptive action was reversed by yohimbine (5 micromol/kg s.c.) and the alpha(2B)-adrenoceptor antagonist prazosin (0.24 micromol/kg i.p.). Similarly, clonidine and rilmenidine in the same dose range reduced the oedema formation induced by carrageenan, yohimbine and the alpha(2A)-adrenoceptor antagonist BRL-44408 (3 micromol/kg i.p.) inhibited the anti-inflammatory effect; however, prazosin failed to affect it. These results suggest that alpha(2B/C)-like adrenoceptor subtype may be involved in the antihyperalgesic action, but not in the antiphlogistic effect of alpha(2)-adrenoceptor stimulants. The later effect may be mediated by alpha(2A)-like adrenoceptor subtype.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 2 , Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antiulcerosos/uso terapêutico , Edema/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Úlcera Gástrica/tratamento farmacológico , Antagonistas de Receptores Adrenérgicos alfa 2 , Agonistas alfa-Adrenérgicos/uso terapêutico , Animais , Clonidina/análogos & derivados , Clonidina/uso terapêutico , Modelos Animais de Doenças , Edema/induzido quimicamente , Motilidade Gastrointestinal/efeitos dos fármacos , Motilidade Gastrointestinal/fisiologia , Hiperalgesia/induzido quimicamente , Masculino , Oxazóis/uso terapêutico , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa 2/fisiologia , Rilmenidina , Úlcera Gástrica/induzido quimicamenteRESUMO
Increasing number of evidence suggest that gastric mucosal protection can be induced also centrally. Several neuropeptides, such as TRH, amylin, adrenomedullin, enkephalin, beta-endorphin, nociceptin, nocistatin, ghrelin or orexin given centrally induce gastroprotection and the dorsal vagal complex and vagal nerve may play prominent role in this centrally initiated effect. Since also cannabinoid receptors are present in the dorsal vagal complex, we aimed to study whether activation of central cannabinoid receptors result in gastric mucosal defense and whether there is an interaction between cannabinoids and endogenous opioids. Gastric mucosal damage was induced by 100% ethanol in rats. The cannabinoids were given intravenously (i.v.) or intracerebroventricularly (i.c.v.), while the antagonists were given i.c.v or intracisternally (i.c.). Gastric lesions were evaluated macroscopically 60 min later. Anandamide, methanandamide and WIN55,212-2 reduced ethanol-induced mucosal lesions after both peripheral (0.28-5.6 micromol/kg, 0.7-5.6 micromol/kg and 0.05-0.2 mumol/kg i.v., respectively) and central (2.9-115 nmol/rat, 0.27-70 nmol/rat and 1.9-38 nmol/rat i.c.v., respectively) administration. The gastroprotective effect of anandamide and methanandamide given i.c.v. or i.v.was reversed by the CB(1) receptor antagonist SR141716A (2.16 nmol i.c.v.). Naloxone (27.5 nmol i.c.v.) also antagonized the effect of i.c.v. or i.v. injected anandamide and WIN55,212-2, but less affected that of methanandamide. The gastroprotective effect of anandamide was diminished also by endomorphin-2 antiserum. In conclusion it was first demonstrated that activation of central CB(1) receptors results in gastroprotective effect. The effect is mediated at least partly by endogenous opioids.
Assuntos
Analgésicos Opioides/uso terapêutico , Antiulcerosos/uso terapêutico , Canabinoides/uso terapêutico , Mucosa Gástrica/efeitos dos fármacos , Neuropeptídeos/uso terapêutico , Úlcera Gástrica/prevenção & controle , Analgésicos Opioides/administração & dosagem , Animais , Antiulcerosos/administração & dosagem , Agonistas de Receptores de Canabinoides , Antagonistas de Receptores de Canabinoides , Moduladores de Receptores de Canabinoides/administração & dosagem , Canabinoides/administração & dosagem , Relação Dose-Resposta a Droga , Etanol/toxicidade , Concentração de Íons de Hidrogênio , Injeções Intraventriculares , Masculino , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/farmacologia , Neuropeptídeos/administração & dosagem , Oligopeptídeos/administração & dosagem , Oligopeptídeos/antagonistas & inibidores , Oligopeptídeos/uso terapêutico , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/antagonistas & inibidores , Índice de Gravidade de DoençaRESUMO
SSAO/VAP-1 is not only involved in the metabolism of biogenic and xenobiotic primary amines and in the production of metabolites with cytotoxic effects or certain physiological actions, but also plays a role, for example, as an adhesion molecule, in leukocyte trafficking, in regulating glucose uptake and in adipocyte homeostasis. Interest in the enzyme has been stimulated by the findings that the activities of the SSAOs are altered (mostly increased) in various human disorders, including diabetes, congestive heart failure, liver cirrhosis, Alzheimer's disease and several inflammatory diseases, although the underlying causes are often unknown. On the basis of their insulin-mimicking effect, SSAO substrates are possibly capable of ameliorating metabolic changes in diabetes, while SSAO inhibitors (somewhat of a contradiction) are of potential benefit in preventing diabetes complications, atherosclerosis and oxidative stress contributing to several disorders or modulating inflammation, and hence may be of substantial therapeutic value. Great efforts have been made to develop novel compounds which may lead to future drugs useful in therapy, based on their effects on SSAO/VAP-1, and some of the results relating to novel substrates and inhibitors are surveyed in the present review.
Assuntos
Amina Oxidase (contendo Cobre)/antagonistas & inibidores , Amina Oxidase (contendo Cobre)/química , Monoaminoxidase/química , Semicarbazidas/química , Doença de Alzheimer/tratamento farmacológico , Amina Oxidase (contendo Cobre)/metabolismo , Aminas/química , Animais , Sangue/metabolismo , Bovinos , Moléculas de Adesão Celular/metabolismo , Diabetes Mellitus/tratamento farmacológico , Humanos , Concentração Inibidora 50 , Plasma/metabolismo , Ratos , Especificidade por SubstratoRESUMO
The maintenance of gastric mucosal function and integrity highly depends on the status of microcirculation. Vasoactive agents--prostaglandins, nitric oxide and sensory neuropeptides (e.g. calcitonin gene-related peptide)--play a crucial role in mucosal defensive processes. Beside the local release of vasoactive mediators the central nervous system is also involved in regulation of gastric functions. Cerebral lesions, stimulation of different brain areas can result in gastric mucosal injury. Noxious challenge of gastric mucosa alters the sodium currents in gastric sensory neurons and induces cfos mRNA expression in nucleus tractus solitarii and area postrema. Vagal nerve has long been established to play a permissive role in the development of gastric lesions. However, several lines of evidences suggest its physiological relevance in the enhancement of gastric mucosal resistance. It was concluded that gastroprotection can be induced by low level of central vagal stimulation and the consequent release of prostaglandins, nitric oxide, and calcitonin gene-related peptide. Prostaglandins, nitric oxide and sensory neuropeptides play a role also in ulcer healing by stimulating the formation of growth factors, the epithelial proliferation and angiogenesis. Both systemic and local administration of growth factors accelerated the ulcer healing. Local, single injection of plasmid-DNA encoding vascular endothelial growth factor (VEGF) was shown to stimulate the ulcer healing in the rat. The transient, local expression of VEGF in ulcerated tissue might be a new therapeutic strategy in the treatment of gastric ulcer disease.
Assuntos
Mucosa Gástrica/efeitos dos fármacos , Terapia Genética , Prostaglandinas/farmacologia , Úlcera Gástrica/terapia , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Fatores de Crescimento Endotelial/genética , Fatores de Crescimento Endotelial/metabolismo , Mucosa Gástrica/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico/farmacologia , Prostaglandinas/genética , Nervo Vago/efeitos dos fármacos , Nervo Vago/metabolismoRESUMO
The role of central nervous system (CNS) in regulation of gastric function has long been known. The dorsal vagal complex (DVC) has an important role in regulation of gastric mucosal integrity; it is involved both in mucosal protection and in ulcer formation. Neuropeptides have been identified in DVC, the origin of these peptides are both intrinsic and extrinsic. Neuropeptides are localized also in the periphery, in afferent neurons. The afferent neurons also have efferent-like function in the gastroinetestinal tract, and neuropeptides released from the peripheral nerve endings of primary afferent neurons can induce gastric mucosal protection. Centrally and /or peripherally injected neuropeptides, such as amylin, adrenomedullin, bombesin, cholecystokinin, neurotensin, opioid peptides, thyreotropin releasing hormone and vasoactive intestinal peptide, influence both the acid secretion and the gastric mucosal lesions induced by different ulcerogens. The centrally induced gastroprotective effect of neuropeptides may be partly due to a vagal dependent increase of gastric mucosal resistance to injury; activation of vagal cholinergic pathway is resulted in stimulation of the release of mucosal prostaglandin and nitric oxide. Furthermore, release of sensory neuropeptides (calcitonin gene-related peptide, tachykinins) from capsaicin sensitive afferent fibers are also involved in the centrally induced gastroprotective effect of neuropeptides.
Assuntos
Mucosa Gástrica/metabolismo , Homeostase , Neuropeptídeos/metabolismo , Adrenomedulina , Amiloide/farmacologia , Animais , Bombesina/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Modelos Animais de Doenças , Ácido Gástrico/metabolismo , Mucosa Gástrica/efeitos dos fármacos , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/metabolismo , Neuropeptídeos/farmacologia , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Peptídeos/farmacologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Taquicininas/fisiologia , Nervo Vago/efeitos dos fármacos , Nervo Vago/fisiologiaRESUMO
The effect of different opioid peptides on acidified ethanol- and indomethacin-induced gastric mucosal lesions was studied following intracerebroventricular (i.c.v.) administration. It was found that both the selective delta opioid receptor agonists--deltorphin II, [D-Ala(2), D-Leu(5)]-enkephalin (DADLE), [D-Pen(2), D-Pen(5)]-enkephalin (DPDPE)-, mu-opioid receptor agonist--[D-Ala(2), Phe(4), GlyT-ol]-enkephalin (DAGO)--as well as beta-endorphin inhibited the mucosal damage induced by both ethanol and indomethacin in pmolar dose range. In contrast, the gastric acid secretion was not influenced by DADLE in the dose of 16 nmol/rat and only a slight reduction (40%) was induced by DAGO in the dose of 1.9 nmol/rat. The protective effect was abolished in both ulcer models by bilateral cervical vagotomy. N(G)-nitro-L-arginine, an inhibitor of NO synthase, reduced the protective action in ethanol-induced, but not in indomethacin-induced gastric damage. The results suggest that activation of supraspinal delta and mu-opioid receptors resulted in inhibition of gastric mucosal lesions elicited by ethanol or indomethacin. The gastroprotective action is independent from the effect of opioids on acid secretion. Vagal nerve is involved in conveying the central action to the periphery. The mechanism of the gastroprotective effect of opioids is different in ethanol- and indomethacin-ulcer models: prostaglandins and nitric oxide are likely to be involved in the protective action of opioid peptides in ethanol-, but not in the indomethacin-ulcer model.
Assuntos
Encéfalo/fisiologia , Citoproteção/fisiologia , Mucosa Gástrica/fisiologia , Receptores Opioides/fisiologia , Animais , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , D-Penicilina (2,5)-Encefalina/farmacologia , Leucina Encefalina-2-Alanina/farmacologia , Inibidores Enzimáticos/farmacologia , Etanol/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Indometacina/farmacologia , Masculino , Entorpecentes/farmacologia , Nitroarginina/farmacologia , Ratos , Ratos Wistar , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Vagotomia , beta-Endorfina/farmacologiaRESUMO
The aim of the present study was to analyse the role of the central alpha-2 adrenoceptors in the regulation of gastric acid secretion in pylorus ligated rats. It was found that the intracerebroventricularly (icv.) injected presynaptic alpha-2 adrenoceptor agonist clonidine and the alpha-2A adrenoceptor subtype selective stimulant oxymetazoline exerted a dose dependent inhibition on gastric acid secretion. The antisecretory ED(50) values for clonidine and oxymetazoline were 20 and 7.5 nmol/rat icv., respectively. The antisecretory effect of these compounds was antagonised by the presynaptic adrenoceptor antagonist yohimbine (50 nmol/rat icv.) indicating that the action is mediated through central presynaptic alpha-2 adrenoceptors. Moreover, naloxone (50 nmol/rat icv.)--non-selective opioid antagonist--and naltrindole (0.5 nmol/rat icv.)--delta-opioid receptor selective antagonist--also decreased the antisecretory effect of clonidine and oxymetazoline suggesting that the endogenous opioid system is likely to be involved in the central antisecretory action of alpha-2 adrenoceptor stimulants.
Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Endorfinas/fisiologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Clonidina/farmacologia , Injeções Intraventriculares , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Oximetazolina/farmacologia , Ratos , Ratos Wistar , Ioimbina/farmacologiaRESUMO
Neonatal monosodium glutamate treatment reduced immunoreactive beta-endorphin content in the mediobasal hypothalamus by 50% in adult, male Wistar rats as compared to hypertonic saline-treated littermates; there was also a moderate (approx. 25%) reduction in the rostral part of the nucleus of the solitary tract. In sham-treated adults the intracisternally injected alpha-2 adenoceptor stimulant clonidine (0.47 nmol/rat) and the delta opioid receptor type agonist (D-Ala(2), D-Leu(5))-enkephalin (0.8 nmol/rat) reduced acidified ethanol-induced mucosal lesions in the stomach by 84.1 and 77.5%, respectively, whereas the same doses were completely ineffective in rats treated neonatally by monosodium glutamate. The data taken together with the results of previous studies with the same substances in rats with retroarcuate knife cuts suggest that neuronal damage in the nucleus of the solitary tract region rather than in the arcuate nucleus is responsible for the changes seen in the pharmacological responsiveness.
Assuntos
Animais Recém-Nascidos/fisiologia , Tronco Encefálico/fisiologia , Citoproteção/efeitos dos fármacos , Receptores Adrenérgicos alfa/fisiologia , Receptores Opioides delta/fisiologia , Glutamato de Sódio/farmacologia , Estômago/fisiologia , Agonistas alfa-Adrenérgicos/farmacologia , Animais , Tronco Encefálico/efeitos dos fármacos , Clonidina/farmacologia , Leucina Encefalina-2-Alanina/farmacologia , Crescimento/efeitos dos fármacos , Masculino , Neurotransmissores/metabolismo , Pupila/efeitos da radiação , Ratos , Ratos Wistar , beta-Endorfina/antagonistas & inibidores , beta-Endorfina/metabolismoRESUMO
This study evaluated the contribution of supraspinal opioid receptors to gastric mucosal protection in the rat. Intracerebroventricular (i.c.v.) and intracisternal (i.c.) injections of selective delta- [[D-Ala(2),D-Leu(5)]-enkephalin (DADLE), [D-Pen(2),D-Pen(5)]-enkephalin (DPDPE), deltorphin II], selective mu- [[D-Ala(2),Phe(4),Gly(5)-ol]-enkephalin (DAGO)] opioid receptor agonists and beta-endorphin (ligand of both receptor types) produced a dose-dependent inhibition of acidified ethanol-induced gastric mucosal damage. The ED(50) values for beta-endorphin, DAGO, DADLE, deltorphin II, and DPDPE were 3.5, 6.8, 75, 120, and 1100 pmol/rat, respectively, following i.c.v. and 0.8, 9.0, 45, 0.25, and 7 pmol/rat following i.c. injection. The gastroprotective effect of DADLE, deltorphin II, and DPDPE, but not that of DAGO, was inhibited by naltrindole, the selective delta-receptor antagonist. Since the delta(2)-receptor agonist deltorphin II was more potent than the delta(1)-receptor agonist DPDPE, the dominant role of central delta(2)-receptors in gastroprotection might be raised. The site of action for delta-receptor agonists is likely to be the brain stem since the peptides were more potent following i.c. than following i.c.v. administration. The gastroprotective effect was reduced following acute bilateral cervical vagotomy. Moreover, both the nitric-oxide synthase inhibitor N(G)-nitro-L-arginine (3 mg/kg i.v.) and the prostaglandin synthesis inhibitor indomethacin (20 mg/kg p.o.) decreased the protective effect of opioid peptides. The results indicate that 1) activation of supraspinal delta- and mu-opioid receptors induces gastric mucosal protection, 2) integrity of vagal nerve is necessary for the gastroprotective action of opioids, and 3) mucosal nitric oxide and prostaglandins may be involved in the opioid-induced gastroprotection.
Assuntos
Encéfalo/metabolismo , Mucosa Gástrica/fisiologia , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo , Úlcera Gástrica/prevenção & controle , Animais , Encéfalo/efeitos dos fármacos , Capsaicina/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Ala(2)-MePhe(4)-Gly(5)-Encefalina/administração & dosagem , D-Penicilina (2,5)-Encefalina/administração & dosagem , Leucina Encefalina-2-Alanina/administração & dosagem , Encefalinas/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Etanol , Mucosa Gástrica/efeitos dos fármacos , Ácido Clorídrico , Masculino , Antagonistas de Entorpecentes/administração & dosagem , Oligopeptídeos/administração & dosagem , Ratos , Ratos Wistar , Receptores Opioides delta/agonistas , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides mu/agonistas , Úlcera Gástrica/induzido quimicamente , Vagotomia , beta-Endorfina/administração & dosagemRESUMO
Clonidine inhibited the development of gastric mucosal lesions induced by either acidified ethanol or indomethacin. The ED50 values were: 7.1 and 5.2 microg x kg(-1) orally, respectively. The gastroprotective effect was antagonised by the pre-synaptic alpha-2 antagonist yohimbine, the more selective alpha-2 antagonist Ch-38083 and the pre-synaptic alpha-2B antagonist prazosin. Moreover, the non-selective opioid receptor antagonist naloxone, the delta receptor selective naltrindole also reversed the clonidine-induced mucosal protective action. Clonidine was also effective following intracerebroventricular administration with the ED50 of 37 ng/rat against ethanol-induced mucosal damage. Our results suggest that: 1) the gastroprotective effect of clonidine is likely to be mediated by alpha-2B adrenoceptor subtype; 2) there is an interaction between pre-synaptic alpha-2 adrenoceptors and opioid system; and 3) clonidine can induce gastroprotection by central mechanism.
Assuntos
Antiulcerosos/farmacologia , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Receptores Opioides/efeitos dos fármacos , Úlcera Gástrica/prevenção & controle , Agonistas alfa-Adrenérgicos/administração & dosagem , Agonistas alfa-Adrenérgicos/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Anti-Inflamatórios não Esteroides , Clonidina/administração & dosagem , Clonidina/antagonistas & inibidores , Clonidina/farmacologia , Etanol , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Indometacina , Injeções Intraventriculares , Injeções Espinhais , Masculino , Antagonistas de Entorpecentes/farmacologia , Ratos , Ratos Wistar , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologiaRESUMO
Clonidine injected intracerebroventricularly (i.c.v.) (0.47 nmol/rat) exerted gastric mucosal protective effect against acidified ethanol. Evidence was obtained that the gastroprotective effect of clonidine was blocked by i.c.v. injected alpha(2)-adrenoceptor antagonists yohimbine (non-subtype selective antagonist), prazosin and 2-[2-(4-(O-methoxyphenyl)piperazin-1-yl)ethyl]-4,4-dimethyl-1,3-(2 H, 4H)-isoquinolindione (ARC-239) (representative alpha(2B/2C)-adrenoceptor blocking agents) and opioid receptor antagonists naloxone (a non-selective, moderately mu-opioid receptor preferring antagonist), naltrindole and naltriben delta-opioid receptor antagonists). The centrally injected naltrindole (0.5 nmol/rat) antagonised also the gastroprotective effect of clonidine --but not that of the delta-agonist [D-Ala(2), D-Leu(5)]enkephalin--administered peripherally. The results suggest that central alpha(2B/2C)-adrenoceptor subtypes and opioid--particularly delta--receptors are likely to be involved in the gastric mucosal protective effect of clonidine.
Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Encéfalo/fisiologia , Clonidina/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/fisiologia , Animais , Leucina Encefalina-2-Alanina/farmacologia , Injeções Intraventriculares , Masculino , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa 2/classificaçãoRESUMO
The possibility that the endogenous opioid system could be involved in the central nervous system (CNS)-mediated gastroprotective effect of clonidine was investigated. Intracerebroventricularly (i.c.v.) injected clonidine (470 pmol/rat) inhibited the gastric mucosal lesions induced by (orally administered) acidified ethanol in a significant manner in the rat. The gastroprotective effect of the centrally administered clonidine was antagonised by i.c.v. or intracisternally (i.c.) administered presynaptic alpha-2 adrenoceptor antagonist, yohimbine; the non-selective opioid receptor antagonist, naloxone; and the delta opioid receptor antagonist naltrindole. These results suggest that an interaction between central alpha-2 adrenoceptors and endogenous opioid systems is involved in mediating the mucosal protective effect. beta-endorphin antiserum (i.c.) also antagonised the gastroprotection induced by intracerebroventricularly injected clonidine indicating that beta-endorphin release is likely to be a key factor in the gastroprotective effect of clonidine. Furthermore, the i.c.v. or i.c. injection of beta-endorphin produced a potent gastroprotection in the picomolar range. The mucosal protective effect of clonidine was abolished after vagotomy indicating that the central effect may be conveyed to the periphery by vagal efferents. Since atropine (1 mg/kg i.v.) failed to modify, but hexamethonium (10 mg/kg i.v.) antagonised the gastroprotective effect of clonidine, it would appear that in the periphery nicotinic, but not muscarinic, cholinergic receptors are likely to be involved in the mucosal protective effect of clonidine. In conclusion, clonidine (i.c.v.) induces gastroprotective action by releasing an endogenous opioid substance - most likely beta-endorphin - in the rat. The clonidine-induced central gastroprotection requires the integrity of vagal pathway; cholinergic nicotinic - but not muscarinic - receptors might mediate the effect in the periphery.
Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Clonidina/farmacologia , Mucosa Gástrica/efeitos dos fármacos , beta-Endorfina/metabolismo , Agonistas alfa-Adrenérgicos/administração & dosagem , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Clonidina/administração & dosagem , Etanol , Mucosa Gástrica/patologia , Injeções Intraventriculares , Masculino , Antagonistas de Entorpecentes/farmacologia , Úlcera Péptica/induzido quimicamente , Úlcera Péptica/patologia , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Transdução de SinaisRESUMO
The effect of delta opioid agonists - [D-Ala2, D-Leu5]-enkephalin (DADLE), [D-Pen2, D-Pen5]-enkephalin (DPDPE) and deltorphin II - on acidified ethanol induced gastric mucosal lesions was studied in the rat compared with that of morphine. It was found that DADLE, DPDPE, deltorphin II and morphine exerted a dose-dependent inhibition on the mucosal lesions injected subcutaneously, their ID50 values were 0.037, 1.8, 3.5 and 0.35 micromoles/kg, respectively. Naltrindole (10 mg/kg sc.), the selective delta opioid receptor antagonist, inhibited the gastroprotective effect of DADLE, DPDPE and deltorphin II, but it failed to antagonise the effect of morphine. Our results suggest that 1. delta receptors are involved in opioid-mediated gastroprotection, 2. ethanol-induced gastric mucosal damage in the rat may be a quick, simple in vivo model for screening opioid delta receptor agonists and antagonists in the periphery.
Assuntos
Receptores Opioides delta/agonistas , Receptores Opioides delta/fisiologia , Gastropatias/prevenção & controle , Analgésicos/uso terapêutico , Animais , Sítios de Ligação , Relação Dose-Resposta a Droga , D-Penicilina (2,5)-Encefalina , Leucina Encefalina-2-Alanina/uso terapêutico , Encefalinas/uso terapêutico , Etanol/toxicidade , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/ultraestrutura , Íleo/efeitos dos fármacos , Íleo/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos , Morfina/uso terapêutico , Músculo Liso/efeitos dos fármacos , Músculo Liso/ultraestrutura , Oligopeptídeos/uso terapêutico , Ratos , Ratos Wistar , Receptores Opioides mu/fisiologia , Estômago/efeitos dos fármacos , Estômago/ultraestrutura , Gastropatias/induzido quimicamente , Ducto Deferente/efeitos dos fármacos , Ducto Deferente/ultraestruturaRESUMO
The effect of different opioids receptor agonists-morphine, DAGO (mu-agonists), DADLE, DPDPE and deltorphin II (delta-agonists)-on gastric mucosal damage induced by either acidified ethanol or acidified aspirin was studied following subcutaneous (sc) administration of these agonists. The results indicate that both mu and delta receptors are involved in gastroprotection. Morphine, DAGO and DADLE, injected intracerebroventricularly, were also effective in both ulcer models. This suggests that gastric cytoprotection can be induced also be central action, since gastric acid secretion is not involved in the pathomechanism of mucosal damage induced by acidified ethanol. Interaction between the opioids and alpha(2)-adrenoceptors in gastroprotection is suggested by the findings that the gastroprotective effect of clonidine (0.09 mumol/kg orally) was antagonized by opioid antagonists. As both naloxone (1.38 mumol/kg sc) and naltrindole (12 mumol/kg sc) exerted antagonist effects, both mu and delta receptors are likely to be involved in presynaptic alpha(2)-receptor-mediated gastroprotection.
RESUMO
Morphine in a dose of 1 mg/kg s.c. decreased mucosal lesions induced by 100% ethanol or acidified aspirin by 79% and 85%, respectively, in rats. When the animals were pretreated with NG-nitro-L-arginine (40 mg/kg i.v.), the mucosal lesions were aggravated in both tests and the gastroprotective action of morphine decreased to 17% and 20%, respectively. This decrease in morphine protection was antagonized by L-arginine but not by D-arginine in the case of ethanol-induced lesions; however, L-arginine failed to restore the gastroprotective effect of morphine when the mucosal damage was induced by acidified aspirin. The protective action of either prostaglandin E2 (0.1 mg/kg orally) or cysteamine (50 mg/kg orally) was not influenced by NG-nitro-L-arginine (L-NNA). When L-NNA was given simultaneously with either indomethacin (10 mg/kg p.o.) or N-ethyl-maleimide (50 mg/kg s.c.), compounds which also reduced the gastroprotective action of morphine, almost complete inhibition of the gastroprotective action of morphine against 100% ethanol-induced lesions was observed as a result of the addition of the inhibitory activities of the latter substances. These results suggest that: (1) Endogenous nitric oxide is likely to be involved in the gastroprotective action of morphine. (2) The protective action of nitric oxide is independent of both mucosal prostaglandins and sulfhydryls.