RESUMEN
1. This in vitro study was designed to determine the potential use of the NK(1) antagonist, SR140333 as an anti-diarrhoeal treatment for food allergy or inflammatory bowel disease. The effect of various immune and neuronal stimuli on human colonic substance P (SP) release and the effect of SR140333 on subsequently stimulated mucosal ion transport was investigated. 2. Submucosal and sensory nerve fibre stimulation using electrical field stimulation (1 ms/7 Hz/7 V) and capsaicin (50 microM) respectively, mast cell activation by anti-IgE (1/250 dilution) and granulocyte stimulation using fMLP (50 microM) each released SP and evoked a secretory response. 3. SP and the NK(1) selective agonist, Sar-SP (0.1 - 1000 nM) stimulated an increase in colonic secretion which was antagonized by SR140333 (pD'(2)=6.7 and 7.25 versus SP and Sar-SP respectively). 4. SR140333, at a concentration that blocked NK(1)-mediated secretion (500 nM), also reduced the secretory response to both alphaIgE and capsaicin. This suggests a pathophysiologic role for NK(1) receptors. 5. Capsaicin evoked SP release was increased in tissue taken from Crohn's disease but not ulcerative colitis patients. The response to SP was however reduced by 70 and 89% respectively. 6. Mast cells and sensory afferents contribute to allergic diarrhoea. Since SR140333 reduced the secretory response to mast cell and afferent stimulation this compound may be particularly useful in reducing the symptoms of food allergy.
Asunto(s)
Antidiarreicos/uso terapéutico , Colon/efectos de los fármacos , Hipersensibilidad a los Alimentos/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Antagonistas del Receptor de Neuroquinina-1 , Piperidinas/farmacología , Piperidinas/uso terapéutico , Quinuclidinas/farmacología , Quinuclidinas/uso terapéutico , Animales , Antidiarreicos/farmacología , Capsaicina/farmacología , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Colon/citología , Colon/metabolismo , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/metabolismo , Enfermedad de Crohn/patología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Hipersensibilidad a los Alimentos/inmunología , Hipersensibilidad a los Alimentos/patología , Cobayas , Humanos , Inmunoglobulina E/inmunología , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Masculino , Mastocitos/efectos de los fármacos , Mastocitos/inmunología , Mastocitos/patología , Neuroquinina A/antagonistas & inhibidores , Neuroquinina A/farmacología , Neuroquinina B/farmacología , Ratas , Receptores de Neuroquinina-1/metabolismo , Especificidad de la Especie , Sustancia P/antagonistas & inhibidores , Sustancia P/farmacología , Taquicininas/agonistas , Taquicininas/metabolismoRESUMEN
The potent neurokinin receptor 1 (NK1) antagonist SR-140333 has previously been shown to reduce castor oil-induced secretion in animal models. The importance of tachykinins in neuroimmune control of secretion and the effect of SR-140333 on key points in this pathway were elucidated in the present study to determine the type of intestinal dysfunction best targeted by this antagonist. Rat colonic secretion and substance P (SP) release were determined in vitro with the use of Ussing chamber and enzyme immunoassay techniques. NK1 receptors played a secretory role as receptor agonists stimulated secretion and SR-140333 antagonized the response to SP response (pK(b) = 9.2). Sensory fiber stimulation released SP and evoked a large secretion that was reduced by 69% in the presence of SR-140333 (10 nM). Likewise, mastocytes also released SP. The subsequent secretory response was reduced by 43% in the presence of SR-140333 (50 nM). SP was also released from granulocytes; however, this did not cause secretion. Functional NK3 receptors were present in the colon as senktide stimulated secretion, an effect that was increased during stress. We conclude that NK3 receptors may play a role in stress-related disorders, whereas NK1 receptors are more important in mast cell/afferent-mediated secretion.
Asunto(s)
Colon/inmunología , Colon/metabolismo , Mastocitos/inmunología , Antagonistas del Receptor de Neuroquinina-1 , Piperidinas/farmacología , Quinuclidinas/farmacología , Receptores de Neuroquinina-1/metabolismo , Sustancia P/análogos & derivados , Animales , Benzamidas/farmacología , Capsaicina/farmacología , Colon/citología , Enfermedades Funcionales del Colon/tratamiento farmacológico , Enfermedades Funcionales del Colon/inmunología , Estimulación Eléctrica , Masculino , Neuroquinina A/farmacología , Fragmentos de Péptidos/farmacología , Ratas , Ratas Endogámicas , Receptores de Neuroquinina-2/antagonistas & inhibidores , Receptores de Neuroquinina-2/metabolismo , Receptores de Neuroquinina-3/metabolismo , Estrés Fisiológico/inmunología , Estrés Fisiológico/metabolismo , Sustancia P/farmacologíaRESUMEN
Existing models used to study the mechanism of action and antagonism of tachykinergic effects on intestinal contraction and secretion suffer from technical problems and have not been fully characterized using specific tachykinin antagonists. Contraction of ileal segments by substance P, colonic circular muscle by beta-alanine-neurokinin A, and longitudinal muscle by senktide were used as models for neurokinin-induced contraction in the guinea-pig. Guinea-pig colonic epithelial tissue was stimulated by substance P and senktide to assess NK1- and NK3-mediated secretion. Using these models the potency of therapeutically useful compounds was determined. NK1 and NK2 activation directly contracted smooth muscle, while NK1-mediated secretion was nerve-mediated. NK3 stimulation of contraction and secretion was neurally mediated, involving cholinergic nerves and 5-HT release. NK1-mediated contraction and secretion were antagonized by SR140333 (pD'2 = 9.29 and pKb = 8.53); NK2-mediated contraction was antagonised by SR48968 (pD'2 = 8.35) and NK3-mediated contraction and secretion were antagonized by SB223412 (pKb = 8.97 and 8.79). The mixed antagonist MDL103392 blocked NK1- and NK2-mediated contraction with pKb values of 7.92 and 6.71 respectively and NK1-mediated secretion with a pKb value of 6.57. This data characterizes existing tachykinin antagonists, and should orientate the development of improved compounds as therapies for intestinal disease.
Asunto(s)
Benzamidas/farmacología , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Piperidinas/farmacología , Quinuclidinas/farmacología , Sustancia P/análogos & derivados , Taquicininas/antagonistas & inhibidores , Animales , Cobayas , Mucosa Intestinal/metabolismo , Intestinos/efectos de los fármacos , Masculino , Modelos Biológicos , Músculo Liso/metabolismo , Sustancia P/farmacología , Taquicininas/metabolismoRESUMEN
UNLABELLED: Antinociception can be produced at the spinal level by activation of opioidergic, noradrenergic, and serotonergic systems. We tested the antinociceptive effects of combined activation of all three systems. Antinociception was assessed in the rat tail-flick test, and drugs were administered via an intrathecal catheter. Morphine, the norepinephrine uptake inhibitor desipramine, and serotonin produced antinociception of their own. The combination of subthreshold doses of morphine 1 microg and of desipramine 3 microg produced pronounced antinociception that was antagonized by yohimbine. The combination of subthreshold morphine with serotonin 50 microg or desipramine with serotonin caused only small antinociceptive effects. When morphine combined with desipramine was decreased to a subthreshold dose, we observed pronounced antinociception when a subthreshold dose of serotonin was added. A complex interaction can be supposed by results obtained with antagonists. The activation of all three neurotransmitter systems with small doses of agonists may represent an effective principle for pain control at the spinal level. IMPLICATIONS: Pain sensations are modulated at the spinal level by opioids, noradrenergic drugs, and serotonin. Using a rat model, we showed that the concurrent use of drugs from each of these classes produces good pain control at doses that should avoid the side effects associated with larger doses of each individual drug.
Asunto(s)
Inhibidores de Captación Adrenérgica/farmacología , Analgésicos Opioides/farmacología , Desipramina/farmacología , Depuradores de Radicales Libres/farmacología , Morfina/farmacología , Nociceptores/efectos de los fármacos , Serotonina/farmacología , Animales , Interacciones Farmacológicas , Quimioterapia Combinada , Inyecciones Espinales , Masculino , Dimensión del Dolor/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
The metabolic pathway leading to carboxylic acid derivatives of cannabinoids was discovered more than twenty years ago. While these compounds showed no cannabimimetic activity, subsequent work documented several biological responses both in vitro and in vivo for the THC acids. These include inhibition of eicosanoid synthesis, antiedema effects, antagonism to PAF actions, inhibition of leucocyte adhesion and anti nociception. In this report we present data further characterizing the analgesic properties of the title substance which is a potent synthetic member of this group. CT3 was effective in the mouse hot plate assay at 48 degrees C showing an ED-50 of 4.31 (3.37-5.83) mg/kg when administered i.v (10% Cremophor EL in saline). When given by gavage in peanut oil, it resulted in 30-40% MPE (maximum possible effect) at 10 mg/kg with the effect persisting for up to 5 hours. A more potent response was observed in the mouse p-phenylquinone writhing test. When given i.v., it showed an ED-50 of 1.24 (0.84-1.75) mg/kg. However, no activity was found with oral administration either in peanut oil or Cremophor EL. At 10 mg/kg i.v., a 100% inhibition of the writhing response was seen. The mouse formalin antinociception test was also studied in animals that received CT3 (4.64 mg/kg) i.v. using three behavioral parameters for activity. The drug showed decreases in each category when compared with vehicle/formalin treated mice. The formalin effect showed a typical two phase, time related, response in which CT3 caused a 64% reduction in the early phase and a 48% reduction in the late phase in a composite score of nociception. Interestingly, it did not alter motor function in the rota rod procedure at 4.64 mg/kg i.v.
Asunto(s)
Analgésicos/farmacología , Dronabinol/análogos & derivados , Analgésicos/uso terapéutico , Animales , Dronabinol/farmacología , Dronabinol/uso terapéutico , Masculino , Ratones , Dolor/tratamiento farmacológico , Agregación Plaquetaria/efectos de los fármacosRESUMEN
Extracts of the plant Aconitum spec. are used in traditional Chinese medicine predominantly as anti-inflammatory and analgesic agents, the latter allegedly equally potent as morphine but without any habit-forming potential. As the only pharmacologically active compounds, the C19 diterpenoid alkaloid aconitine, and some of its derivatives, have been proven to be antinociceptive in different analgesic assays, but the mode of action is unknown. To elucidate the mode of action, ten aconitine-like derivatives were investigated with respect to their affinity for voltage-dependent Na+ channels, the action on synaptosomal Na+ and Ca2+ homoeostasis and their antinociceptive, arrhythmogenic and acute toxic properties. Since aconitine is known to bind to site II of Na+ channels, we determined the affinity of the aconitine-like derivatives in vitro to synaptosomal membranes by the [3H]-batrachotoxinin-binding assay and their properties on intrasynaptosomal concentrations of free Na+ and Ca2+ ([Na+]i and [Ca2+]i), both the latter determined fluorometrically with SBFI and Fura-2 respectively. Furthermore, the alkaloids' arrhythmogenic potential was investigated in guinea-pig isolated atria and the antinociceptive action on formalin-induced hyperalgesia and the acute toxic action estimated in mice. The results show that the alkaloids could be divided into at least three groups. The first is characterized by a high affinity to the site II of Na+ channels (Ki about 1.2 microM), the ability to enhance [Na+]i and [Ca2+]i (EC50 about 3 microM), a strong arrhythmogenic action that starts at about 30 nM, an antinociceptive effect (ED50 about 0.06 mg/kg) and high acute toxicity (LD50 values about 0.15 mg/kg). To this group belong aconitine, 3-acetylaconitine and hypaconitine. The second group, with lappaconitine as the only member, has an affinity to Na+ channels an order of magnitude lower (Ki = 11.5 microM), less acute toxicity (LD50 about 5 mg/kg), and a two orders of magnitude lower antinociceptive action (ED50 about 2.8 mg/kg) and lower cardiotoxicity (bradycardia observed at 3 microM). Additionally, lappaconitine suppresses the increase in [Ca2+]i of aconitine-stimulated synaptosomes and increases the excitation threshold of left atria, indicating an inhibition of Na+ channels. The other derivatives, i.e. delcorine, desoxydelcorine, karakoline, lappaconidine, lappaconine and lycoctonine, belong to the third group, which has hardly any effects. They have a low affinity to Na+ channels with Ki values in the millimolar range, show no effect on synaptosomal [Na+]i and [Ca2+]i, no arrhythmogenic potential up to 100 microM, no antinociceptive activity and low toxicity with LD50 values greater than 50 mg/kg. For the investigated alkaloids we suggest two different antinociceptive-like modes of action. Aconitine, hypaconitine and 3-acetylaconitine may induce a block of neuronal conduction by a permanent cell depolarisation, whereas lappaconitine might act like local anaesthetics. However, because of the low LD50/ED30 quotients of 2-6, the antinociceptive-like action of the Aconitum alkaloids seems to reflect severe intoxication rather than a specific antinociceptive action. The structure/activity relationship shows that alkaloids that activate or block Na+ channels have a benzoyl ester side chain in the C-14 or C-4 positions respectively, whereas the other compounds lack this group.
Asunto(s)
Aconitina/análogos & derivados , Analgésicos/farmacología , Diterpenos/farmacología , Hiperalgesia/tratamiento farmacológico , Plantas Medicinales , Aconitina/farmacología , Aconitina/toxicidad , Analgésicos/toxicidad , Animales , Arritmias Cardíacas/inducido químicamente , Batracotoxinas , Calcio/metabolismo , Diterpenos/toxicidad , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/toxicidad , Formaldehído , Cobayas , Atrios Cardíacos/efectos de los fármacos , Hiperalgesia/inducido químicamente , Masculino , Ratones , Sodio/metabolismo , Canales de Sodio/efectos de los fármacos , Relación Estructura-Actividad , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismoRESUMEN
Alkaloids from Aconitum sp., used as analgesics in traditional Chinese medicine, were investigated to elucidate their antinociceptive and toxic properties considering: (1) binding to Na+ channel epitope site 2, (2) alterations in synaptosomal Na+ and Ca2+ concentration ([Na+]i, [Ca2+]i), (3) arrhythmogenic action of isolated atria, (4) antinociceptive and (5) acute toxic action in mice. The study revealed a high affinity group (Ki 1 microM) and a low affinity group (Ki 10 microM) of alkaloids binding to site 2. The compounds of the high affinity group induce an increase in synaptosomal [Na+]i and [Ca2+]i (EC50 3 microM), are antinociceptive (ED50, 25 microg/kg), provoke tachyarrhythmia and are highly toxic (LD50 70 microg/kg), whereas low affinity alkaloids reduce [Ca2+]i, induce bradycardia and are less antinociceptive (ED50 20 mg/kg) and less toxic (LD50 30 mg/kg). These results suggest that the alkaloids can be grouped in Na+ channel activating and blocking compounds, but none of the alkaloids seem to be suitable as analgesics because of the low LD50/ED50 values.
Asunto(s)
Alcaloides/farmacología , Medicamentos Herbarios Chinos/farmacología , Canales de Sodio/efectos de los fármacos , Aconitina/metabolismo , Aconitina/farmacología , Aconitina/toxicidad , Alcaloides/metabolismo , Alcaloides/toxicidad , Animales , Arritmias Cardíacas/inducido químicamente , Calcio/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Corteza Cerebral/ultraestructura , Medicamentos Herbarios Chinos/metabolismo , Medicamentos Herbarios Chinos/toxicidad , Cobayas , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/fisiopatología , Humanos , Activación del Canal Iónico , Dosificación Letal Mediana , Masculino , Ratones , Dimensión del Dolor , Ratas , Ratas Wistar , Sodio/metabolismo , Canales de Sodio/metabolismo , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismoRESUMEN
The involvement of endogenous galanin to antinociception elicited by intrathecally (i.t.) or systemically administered drugs from different chemical and therapeutic classes was investigated using the rat Randall-Selitto or the rat tail-flick test, in the absence or presence of the i.t. administered galanin receptor antagonists galantide and M-35. Antinociception elicited by i.t. tramadol (24 micrograms), DAMGO (1 microgram), clonidine (48 micrograms), desipramine (6 micrograms) or fenfluramine (60 micrograms) was attenuated by i.t. galantide (2 micrograms); the attenuation reached significance at least at one time point. A partial antagonism by i.t. galantide was also observed against the antinociception of i.p. tramadol (10 mg/kg), i.v. clonidine (1 mg/kg), i.p. desipramine (1 mg/kg), or i.p. dipyrone (1000 mg/kg), but antinociception by i.p. fenfluramine (30 mg/kg) was not affected. Using M-35 (2 micrograms i.t.), the antinociception of i.t. tramadol or DAMGO was attenuated, but no inhibition was observed when clonidine, desipramine or fenfluramine were used i.t. If drugs were administered systemically, only antinociception of i.p. fenfluramine but not that of i.p. tramadol, or i.v. clonidine, or i.p. desipramine or i.p dipyrone was attenuated. In the rat tail flick test, co-injection of either 2 micrograms i.t. galantide or M-35 with i.t. tramadol (12 micrograms) almost abolished the antinociceptive effect, whereas the antinociception of systemically administered tramadol (4.6 mg/kg i.p.) was only partially attenuated by i.t. galantide and not affected by i.t. M-35. Binding studies in dorsal spinal cord tissue showed no affinity of galantide or M-35 to spinal mu-, or delta-, or kappa-opioid receptors and none of the other drugs interfered with the spinal galanin binding site. These data give further support of at least a partial galanin link in spinal processes of antinociception.
Asunto(s)
Analgésicos Opioides/farmacología , Analgésicos/farmacología , Encefalinas/farmacología , Nociceptores/efectos de los fármacos , Receptores de la Hormona Gastrointestinal/antagonistas & inhibidores , Médula Espinal/efectos de los fármacos , Tramadol/farmacología , Animales , Clonidina/farmacología , Encefalina Ala(2)-MeFe(4)-Gli(5) , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Galanina , Receptores de la Hormona Gastrointestinal/efectos de los fármacos , Receptores de la Hormona Gastrointestinal/metabolismo , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismoRESUMEN
In rats with adjuvant arthritis we measured the urinary excretion of 2,3-dinor-6-oxo-PGF1 alpha, 7 alpha-hydroxy-5,11-dioxo-tetranor-prosta-1,16- dioic acid (PGE-M) and 2,3-dinor-thromboxane-B2, reflecting total body synthesis of prostacyclin, thromboxane and the E-prostaglandins, respectively. The urinary prostanoid metabolites were assessed by gas chromatography/tandem mass spectrometry using stable isotope internal standards. We found a more than 10-fold increase of urinary 2,3-dinor-6-oxo-PGF1 alpha excretion and a 5-fold higher urinary excretion of PGE-M in adjuvant arthritic rats as compared to non-arthritic control rats (p < 0.001; n = 12, each). There was no significant difference in urinary 2,3-dinor-thromboxane-B2 excretion between arthritic rats and control animals. Our data show a dramatic increase of urinary 2,3-dinor-6-oxo-PGF1 alpha excretion reflecting increased total body prostacyclin synthesis. It can be assumed that prostacyclin plays a role in generalized inflammatory reactions, comparable to that of the E-prostaglandins.
Asunto(s)
Artritis Experimental/metabolismo , Epoprostenol/biosíntesis , 6-Cetoprostaglandina F1 alfa/análogos & derivados , 6-Cetoprostaglandina F1 alfa/metabolismo , 6-Cetoprostaglandina F1 alfa/orina , Animales , Creatinina/orina , Epoprostenol/metabolismo , Cromatografía de Gases y Espectrometría de Masas/métodos , Masculino , Prostaglandinas/metabolismo , Prostaglandinas/orina , Ratas , Ratas Sprague-Dawley , Tromboxano B2/análogos & derivados , Tromboxano B2/metabolismo , Tromboxano B2/orinaRESUMEN
To investigate whether ATP participates in spinal nociceptive transmission, effects of intrathecally applied P2-purinoceptor antagonists and agonists in the tail-flick and the formalin test were studied in rats. In the tail-flick assay, the P2 antagonists suramin (12-120 micrograms), Evans blue (0.1-10 micrograms), Trypan blue (1-30 micrograms) and Reactive blue 2 (1-30 micrograms) but not pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS; 0.03-30 micrograms) caused moderate antinociception up to a doubling of the response latency. In contrast, the P2 agonists alpha,beta-methylene ATP (alpha,beta-mATP, 0.3-30 micrograms) and 2-methylthio-ATP (3-30 micrograms) decreased the tail-flick latency by up to about 50%. When co-injected with alpha,beta-mATP, suramin (120 micrograms) or Evans blue (10 micrograms) prevented the effect of alpha,beta-mATP 3 micrograms but not of alpha,beta-mATP 30 micrograms. In the formalin test, pretreatment with suramin (3-90 micrograms) 60 min prior to testing caused significant antinociception by decreasing the weighted pain intensity score by up to about 80%. alpha,beta-mATP (30 micrograms), applied 30 min prior to testing, was without effect. The results indicate that endogenous ATP, acting through P2-purinoceptors, may contribute to nociceptive information processing in the spinal cord.
Asunto(s)
Nociceptores/efectos de los fármacos , Antagonistas Purinérgicos , Médula Espinal/fisiología , Adenosina Trifosfato/análogos & derivados , Adenosina Trifosfato/farmacología , Animales , Conducta Animal/efectos de los fármacos , Formaldehído/farmacología , Inyecciones Espinales , Masculino , Dolor/fisiopatología , Dimensión del Dolor , Agonistas Purinérgicos , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Tionucleótidos/farmacologíaRESUMEN
Galanin, a 29 amino acid peptide, has been reported to possess antinociceptive properties at the spinal site and to potentiate opioid-induced antinociception. Our aim was to investigate whether also endogenous galanin interacts with an exogenously administered opioid, morphine, in the rat spinal cord. This question was investigated by use of the recently developed galanin receptor antagonists galantide [M-15, galanin-(1-13)-substance P-(5-11) amide] and M-35 [galanin-(1-13)-bradykinin-(2-9) amide]. Nociception was assessed in the rat tail-flick test using radiant heat and the rat Randall-Selitto model of inflammatory pain using vocalization as the nociceptive criterion. Intrathecal (i.t.) injections were performed in rats under either anaesthesia. Morphine was administered either i.t. or intraperitoneally (i.p.), and the antagonists were injected i.t. [125I]Galanin binding experiments were performed on crude synaptosomal membranes of the rat spinal cord. In the rat tail-flick test, i.t. injection of 3 micrograms morphine evoked antinociception of about 75% of the maximal possible effect (% MPE). Co-injection of either 2 micrograms galantide or 2 micrograms M-35 with morphine almost completely abolished the antinociceptive effect of morphine. I.p. injection of 2.15 mg/kg morphine elicited about 80% MPE when given 10 min prior to i.t. saline injection. Injection of the antagonists instead of saline antagonised the antinociceptive effect of morphine partially thus showing the spinal proportion of the overall antinociceptive effect. In the rat Randall-Selitto test, 3 micrograms morphine, injected i.t., produced antinociception of almost 100% MPE.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Morfina/antagonistas & inhibidores , Dolor/prevención & control , Péptidos/farmacología , Péptidos/fisiología , Receptores de la Hormona Gastrointestinal/antagonistas & inhibidores , Médula Espinal/efectos de los fármacos , Sustancia P/análogos & derivados , Animales , Sitios de Unión , Bradiquinina/análogos & derivados , Bradiquinina/farmacología , Galanina , Inyecciones Espinales , Masculino , Fragmentos de Péptidos/farmacología , Péptidos/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Galanina , Médula Espinal/metabolismo , Membranas Sinápticas/metabolismoRESUMEN
OBJECTIVES: In rats with adjuvant arthritis measurements were taken of the urinary excretion of nitrate, reflecting endogenous nitric oxide (NO) formation, and cyclic guanosine monophosphate (cGMP). METHODS: Urinary nitrate was determined by gas chromatography, cGMP by radioimmunoassay. RESULTS: A significant (p < 0.001), more than three fold increase of urinary nitrate excretion was found in rats 20 days after induction of adjuvant arthritis compared with non-arthritic rats. There was no significant difference in urinary cGMP excretion between arthritic rats and control animals. CONCLUSION: The data suggest that the dramatic increase of urinary nitrate excretion is due to increase of NO synthesis by the inducible form of NO synthase.
Asunto(s)
Artritis Experimental/orina , Nitratos/orina , Animales , Cromatografía de Gases/métodos , Creatinina/orina , GMP Cíclico/orina , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
The house musk shrew Suncus murinus recently has been introduced for the study of emesis. We investigated the emetic effects of the opioids morphine (0.1-21.5 mg/kg i.p.) and loperamide (0.01-10 mg/kg i.p.) and found a complete lack of emetogenic potential. Nicotine, however, dose dependently induced vomiting in the Suncus with an ED50 of 8.8 mg/kg s.c. and a 100% incidence at 20 mg/kg. This drug-induced vomiting was reduced by morphine or loperamide: ED50 values obtained were 1.2 mg/kg i.p. for morphine and 0.7 mg/kg i.p. for loperamide. Naloxone (2 mg/kg s.c.) antagonised the inhibitory effect of morphine (2 mg/kg i.p.) or loperamide (10 mg/kg i.p.). Serotonin (20 mg/kg s.c.) had less reliable emetogenic potency than nicotine in the Suncus with incidences between 50 and 100%. However, the serotonin-induced vomiting was abolished by morphine and loperamide and this inhibition was antagonised by naloxone. These results suggest that systemically administered opioids are pure antiemetics in Suncus murinus in contrast to other animal models and man. Naloxone antagonism indicates that this antiemetic effect is mediated by opioid receptors.
Asunto(s)
Loperamida/uso terapéutico , Morfina/uso terapéutico , Nicotina/toxicidad , Vómitos/inducido químicamente , Vómitos/prevención & control , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Loperamida/antagonistas & inhibidores , Masculino , Naloxona/farmacología , Nicotina/antagonistas & inhibidores , Serotonina/toxicidad , Antagonistas de la Serotonina/farmacología , MusarañasRESUMEN
The explanation for the co-existence of opioid and nonopioid components of tramadol-induced antinociception appears to be related to the different, but complementary and interactive, pharmacologies of its enantiomers. The (+) enantiomer had Ki values of only 1.33, 62.4 and 54.0 microM at mu, delta and kappa receptors, respectively. The (-) enantiomer had even lower affinity at the mu and delta sites (Ki = 24.8, 213 and 53.5 microM, respectively. The (+) enantiomer was the most potent inhibitor of serotonin uptake (Ki = 0.53 microM) and the (-) enantiomer was the most potent inhibitor of norepinephrine uptake (Ki = 0.43 microM). Basal serotonin release was preferentially enhanced by the (+) enantiomer and stimulation-evoked norepinephrine release was preferentially enhanced by the (-) enantiomer. The (+) and (-) enantiomers each independently produced centrally mediated antinociception in the acetylcholine-induced abdominal constriction test (ED50 = 14.1 and 35.0 micrograms i.t., respectively). Racemic tramadol was significantly more potent (P < .05) than the theoretical additive effect of the enantiomers (antinociceptive synergy). Synergy was also demonstrated (P < .1) in the mouse 55 degrees C hot-plate test (i.p. route) and (P < .05) the rat Randall-Selitto yeast-induced inflammatory nociception model (i.v. and i.p. routes). Critically, the enantiomers interacted less than synergistically in two side-effects of inhibition of colonic propulsive motility and impairment of rotarod performance. The racemate and the (+) enantiomer were active in a chronic (arthritic) inflammatory pain model. Taken together, these findings provide a rational explanation for the coexistence of dual components to tramadol-induced antinociception and might form the basis for understanding its clinical profile.
Asunto(s)
Analgésicos/química , Tramadol/administración & dosificación , Acetilcolina/farmacología , Animales , Artritis/tratamiento farmacológico , Sinergismo Farmacológico , Masculino , Ratones , Ratones Endogámicos , Inhibidores de la Captación de Neurotransmisores , Norepinefrina/metabolismo , Umbral del Dolor/efectos de los fármacos , Receptores Opioides/metabolismo , Serotonina/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Tramadol/química , Tramadol/metabolismoRESUMEN
Conclusive evidence of particular aetiologic factors in human inflammatory bowel diseases (IBDs) has not been obtained. However, there is information to suggest that immunologic mechanisms are involved in the pathogenesis and perpetuation of both ulcerative colitis and Crohn's disease. A TNBS-induced enteritis was developed by immunisation and local challenge of rats with TNBS. This animal model mimicked several features of human Crohn's disease. Because of the immunoglobulin component in human Crohn's disease, investigation of the TNBS-induced immunological response in the animal model was performed. A specific ELISA was developed to assess the humoral part of the TNBS sensitisation in the rat. Investigation of sera obtained from sensitized animals 11 weeks after the start of TNBS immunisation procedure revealed a clear IgG-specific immune response against TNBS. Immunoglobulin subtypes were differentiated by goat anti-rat antibodies and results indicate a specific IgG2 subtype response.
Asunto(s)
Enteritis/inmunología , Inmunoglobulina G/fisiología , Ácido Trinitrobencenosulfónico/inmunología , Animales , Enteritis/inducido químicamente , Enteritis/etiología , Inmunoglobulina G/biosíntesis , Ovalbúmina/inmunología , RatasRESUMEN
Inflammation of the rat distal intestine was induced by intradermal sensitization and subsequent multiple intrajejunal challenge with the hapten 2,4,6-trinitrobenzenesulphonic acid (TNBS) via an implanted catheter. The time course of the inflammatory reaction was followed by determination of the enteritis score and measurement of in vitro eicosanoid formation of homogenates of the gut after 0, 1, 2, 4, 7, 14 and 21 days of local daily challenge with 0.08% TNBS. There was a small initial increase of eicosanoid formation, reached at days 1 and 2, followed by a significant increase in metabolism of arachidonic acid on day 21. Although at day 1 a four-fold increase in inflammation score was reached, no further significant changes were observed during the following 3 weeks. The greatest increase in metabolite formation was observed in prostanoids TxB(2), PGE(2). and PGD(2) and the 5-lipoxygenase product LTC(4), whereas minor changes were found for LTB(4) and other lipoxygenase products such as 12- and 15-HETE. The formation of these metabolites was already inhibited by low-dose 5-aminosalicylic acid (5-ASA), given orally twice daily during the 3 weeks challenge period, while the enteritis score was affected dosedependently.
RESUMEN
EM 405 has analgesic and antitussive effects, probably exerted by noradrenaline uptake inhibition and local anaesthetic actions. It showed anti-inflammatory, which may be due to anti-histaminic and indirect sympathomimetic properties. As oral application of EM 405 did not induce gastrointestinal side effects a possible ulcer preventing action was investigated. EM 405 reduced gastric ulcers induced by ethnology or indomethacin with ED50 values of 45 and 26 mg/kg p.o. Stress-induced ulcer was inhibited with an ED50 of 34 mg/kg. EM 405 reduced basal and stimulated gastric secretion by reducing volume as well as H(+)- and Cl(-)-production. Therefore ulcer prevention by EM 405 may be explained by its inhibitory effects on gastric secretion. The results characterise EM 405 as a novel anti-inflammatory compound with ulcer-protective action.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Ciclohexanos/farmacología , Úlcera Gástrica/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/toxicidad , Ciclohexanos/administración & dosificación , Ciclohexanos/toxicidad , Ciclohexenos , Ácido Gástrico/metabolismo , Masculino , Pentagastrina/farmacología , Ratas , Ratas Sprague-Dawley , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/prevención & control , Estrés FisiológicoRESUMEN
An enteritis, based on a delayed-type hypersensitivity reaction, was induced in TNBS (2,4,4-trinitrobenzenesulphonic acid) sensitized rats by multiple intrajejunal challenge with TNBS via an implanted catheter. This treatment induced chronic inflammation of the distal small intestine characterized by intense hyperaemia, oedema and gut wall thickening as assessed by macroscopic scoring and weighing a defined part of the dissected intestine. Histologically, the inflammatory response included mucosal and submucosal cell infiltration by lymphocytes and histiocytes, transmural granulomatous inflammation with multinucleated cells and activated mesenteric lymph nodes. Ex vivo stimulated release of the inflammatory mediator LTB(4) in the dissected part of the intestine was increased following TNBS treatment. Drug treatment with sulphasalazine or 5-aminosalicylic acid improved the enteritis score and attenuated TNBS induced oedema formation and LTB(4) production. The applicability and relevance of this new model are discussed with respect to drug development and basic research of inflammatory bowel diseases.
RESUMEN
An enteritis, based on a delayed-type hypersensitivity reaction, was induced in TNBS (2,4,4-trinitrobenzenesulfonic acid) sensitized rats by intrajejunal challenge with TNBS. This treatment induced a chronic inflammation of the distal small intestine, characterized by gross hyperaemia and oedema, as assessed by a macroscopic score. Histologically, the inflammatory response included cell infiltration by lymphocytes and histiocytes, a transmural granulomatous inflammation with multinucleated cells and activated mesenteric lymph nodes. Drug treatment with sulfasalazine or 5-aminosalicylic acid improved enteritis score. The applicability and relevance of this new model is discussed in relation to drug development and basic research of inflammatory bowel diseases.