RESUMO
An extract of cannabis (5 and 15 mg/kg expressed as delta 9-THC) orally administered to rats caused an elevation of the nociceptive threshold (tail-flick latency and vocalization tests). Naloxone and naltrexone (blockers of mu-type opiate receptors) as well as MR 1452 (blocker of kappa opiate receptors) did not prevent the antinociceptive effect of cannabis when used at the dose of 2 mg/kg SC; only a high dose (10 mg/kg SC) of these narcotic antagonists partially blocked cannabis antinociception. ICI 154, 129, an antagonist of delta-type opiate receptors, failed to prevent the cannabis-induced rise in nociceptive threshold when used at a dose of 2 mg/kg SC but produced a significant effect at 10 mg/kg SC. While the role of opiate receptors does not seem fundamental to cannabis antinociception, the clear-cut effectiveness shown by 6-hydroxydopamine (a neurotoxin which causes a degeneration of catecholamine-containing terminals) in reducing cannabis antinociception is indicative of a participation of catecholamines in the phenomenon.
Assuntos
Analgésicos/farmacologia , Cannabis , Animais , Benzomorfanos/farmacologia , Relação Dose-Resposta a Droga , Encefalina Leucina/análogos & derivados , Encefalina Leucina/farmacologia , Haplorrinos , Hidroxidopaminas/farmacologia , Masculino , Camundongos , Naloxona/farmacologia , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Oxidopamina , Extratos Vegetais/farmacologia , Ratos , Ratos EndogâmicosRESUMO
Prodynorphin-derived peptides were tested for their effects on body temperature after intracerebroventricular administration to unrestrained male rats. Dynorphin A (Dyn A) (5 and 10 nmol) and Dynorphin A-(1-32) (Dyn A-(1-32) (2.5 and 5 nmol) lowered body temperature with a maximum approximately 30 min after administration. Dyn B (up to 50 nmol) did not induce hypothermia. Lower doses of all peptides did not alter body temperature. The hypothermic effect was significantly, but not completely prevented by MR1452 (30 nmol), a preferential antagonist of the kappa receptor, administered intracerebroventricularly. Naloxone, a mu receptor antagonist, naltrexone, its long acting analog up to doses of 100 nmol, as well as MR1453, the (+)-enantiomer of kappa antagonist MR1452 with no opioid binding properties, did not prevent the hypothermic effect. Moreover, episodic barrel rolling and bizarre postures elicited by Dyn A and Dyn A-(1-32) were reduced in rats pretreated i.c.v. with MR1452 (30 nmol), but not with naloxone (up to 100 nmol). Interestingly, des-Tyr-Dynorphin A (Dyn A-(2-17)), a fragment with virtually no opioid binding potential, was 4 times less potent that Dyn A in inducing hypothermia. These findings are consistent with the hypothesis that prodynorphin-derived peptides effects are not exclusively opioids in nature.
Assuntos
Dinorfinas/análogos & derivados , Dinorfinas/farmacologia , Endorfinas/farmacologia , Hipotermia/induzido quimicamente , Fragmentos de Peptídeos/farmacologia , Receptores Opioides/metabolismo , Animais , Benzomorfanos/farmacologia , Temperatura Corporal , Endorfinas/antagonistas & inibidores , Cinética , Masculino , Atividade Motora/efeitos dos fármacos , Naloxona/farmacologia , Naltrexona/farmacologia , Ratos , Ratos EndogâmicosRESUMO
The opioid peptide dynorphin1-32 (DYN1-32, 25 nmol) intrathecally administered causes, in the rat, an elevation of nociceptive threshold of longer duration than that of DYN A, as ascertained by vocalization test. Comparative findings obtained with tail flick test allow to differentiate antinociception from motor dysfunction. The breakdown of DYN A at spinal level is very rapid. The electrical stimulation of the tail associated to a restraint condition of the rat produces a significant increase of immunoreactive DYN in cervical, thoracic and lumbar segments of spinal cord, therefore indicating a correlative, if not causal, relationship between the spinal dynorphinergic system and aversive stimuli.
Assuntos
Dinorfinas/fisiologia , Dor/fisiopatologia , Medula Espinal/fisiopatologia , Analgésicos/uso terapêutico , Animais , Dinorfinas/análogos & derivados , Dinorfinas/uso terapêutico , Masculino , Dor/tratamento farmacológico , Ratos , Ratos Endogâmicos , Limiar Sensorial , Transmissão SinápticaRESUMO
Immunoreactive dynorphin A (ir-Dyn A) was detected throughout the human gastrointestinal tract by a validated radioimmunoassay. Moreover, the stability of 125I-Dyn A during extraction procedures was confirmed by high performance liquid chromatography. Levels of ir-Dyn A were higher in the stomach and in the small bowel. In tissue samples separated into the main layers composing the gut wall (muscularis externa, submucosa and mucosa) ir-Dyn A was uniformly distributed. An exception was the colon, where concentrations were higher in the muscular portion. Gel permeation chromatography on samples of mucosa and muscularis externa extracts of ileum and gastric fundus, showed immunoreactive material eluting in several forms of apparently higher molecular weight than Dyn A, while only a minor peak was found to coelute with authentic Dyn A.
Assuntos
Sistema Digestório/análise , Dinorfinas/análise , Dinorfinas/imunologia , Mucosa Gástrica/análise , Humanos , Mucosa Intestinal/análise , Músculo Liso/análise , Especificidade de Órgãos , Radioimunoensaio/métodosRESUMO
The intracerebroventricular (i.c.v.) administration of pertussis toxin (0.5 microgram) to rats significantly reduced the hypothermic and behavioural effects (episodic bizarre postures characterized by limb rigidity and followed by barrel rolling) induced by i.c.v. dynorphin A (10 micrograms). These central effects of dynorphin A thus appear to be initiated at a receptor site that interacts with G proteins substrates sensitive to pertussis toxin. Dynorphin A-induced hypothermia was also significantly reduced by i.c.v. pretreatment with the Ca2+ antagonist, verapamil (10 micrograms), although verapamil per se did not modify the behavioural effects elicited by the peptide.
Assuntos
Comportamento Animal/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Cálcio/fisiologia , Dinorfinas/farmacologia , Proteínas de Ligação ao GTP/fisiologia , Animais , Injeções Intraventriculares , Masculino , Toxina Pertussis , Ratos , Ratos Endogâmicos , Verapamil/administração & dosagem , Verapamil/farmacologia , Fatores de Virulência de Bordetella/farmacologiaRESUMO
Salmon calcitonin injected intrathecally in unanesthetized rats produced long-lasting, dose-dependent elevations of nociceptive threshold as measured in the hot plate test. This antinociceptive action was nonopiate in nature as it was uninfluenced by the narcotic antagonists naloxone and MR 1452; moreover, the peptide was still able to raise the nociceptive threshold in morphine-tolerant rats. It is suggested that the spinal cord may represent one of the sites of action for calcitonin-induced antinociception.
Assuntos
Calcitonina/farmacologia , Nociceptores/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Injeções Espinhais , Masculino , Ratos , Ratos Endogâmicos , Limiar Sensorial , Medula Espinal/efeitos dos fármacosRESUMO
The antagonism of the antinociceptive effects of various kappa-opioid agonists has been studied in the mouse abdominal constriction test. Naloxone produced a much smaller degree of antagonism of U50488H than it did of two other kappa-agonists, U69593 and tifluadom. The kappa-selective antagonist, norbinaltorphimine, also failed to shift the dose-response curve to U50488H in this test, despite producing considerable antagonism of the U50488H effect in the rotarod test and of U69593 in both experimental situations. These results are suggestive of a non-opioid component to the action of U50488H in the abdominal constriction test. At high concentrations, U50488H, but not U69593, also showed non-opioid effects in reducing contractile activity in the field-stimulated isolated guinea-pig ileum, as demonstrated by the profile of antagonism seen with beta-chlornaltrexamine and naloxone. These results suggest that U69593, rather than U50488H, may be the kappa-agonist of choice to use, particularly in in-vivo experiments.
Assuntos
Analgésicos/farmacologia , Benzenoacetamidas , Pirrolidinas/farmacologia , Receptores Opioides/metabolismo , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida , Animais , Estimulação Elétrica , Cobaias , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos , Contração Muscular/efeitos dos fármacos , Músculo Liso/metabolismo , Equilíbrio Postural/efeitos dos fármacos , Receptores Opioides kappaRESUMO
As a part of wider research project on chiral anti-inflammatory arylacanoic acids, the 3-(o- and m-)-(methyl and methoxy)-phenyl-2-biphenylyl-3-hydroxypropionic acids 3a-d were synthesized and resolved in their optically active erythro and threo stereomers, which were submitted to the carrageenan induced rat paw edema test. With respect to the p-isomers, only the threo p-methoxy substitution enhances the anti-inflammatory activity. Some conclusions on structure-activity relationship are discussed.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Propionatos/síntese química , Animais , Edema/tratamento farmacológico , Isomerismo , Espectroscopia de Ressonância Magnética , Masculino , Conformação Molecular , Propionatos/farmacologia , Ratos , Ratos Endogâmicos , EstereoisomerismoRESUMO
As part of a wider research project on structure-activity relationships of chiral arylalkanoic acids, stereomeric aryl- biphenylyl-hydroxypropionic acids 3a-d have been prepared and their antiinflammatory activity evaluated. Diastereomeric racemic erythro- and threo-acids have been synthesized by reaction of alpha-lithiated biphenylyl-acetic acid salts with the appropriate aldehyde. They were separated, and after attribution of their relative configuration by 1H-NMR analysis, resolved. The antiinflammatory activities of the enantiomeric potassium salts were determined by the carrageenan test.
Assuntos
Anti-Inflamatórios/síntese química , Compostos de Bifenilo/síntese química , Fenilpropionatos/síntese química , Animais , Anti-Inflamatórios/administração & dosagem , Compostos de Bifenilo/administração & dosagem , Carragenina , Edema/induzido quimicamente , Edema/tratamento farmacológico , Injeções Intraperitoneais , Masculino , Fenilpropionatos/administração & dosagem , Ratos , Ratos Endogâmicos , EstereoisomerismoAssuntos
Dinorfinas/análogos & derivados , Sistema Hipotálamo-Hipofisário/fisiologia , Dor/fisiopatologia , Animais , Benzomorfanos/farmacologia , Ciclazocina/análogos & derivados , Ciclazocina/farmacologia , Dinorfinas/farmacologia , Estradiol/farmacologia , Etilcetociclazocina , Feminino , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Ovário/fisiologia , Medição da Dor , Ratos , Ratos Endogâmicos , Relação Estrutura-AtividadeRESUMO
The synthetic opioid met-enkephalin analog [D-Ala2, MePhe4, Met(0)5ol] enkephalin (DAMME) and the opiate morphine injected intraperitoneally to rats at doses of 0.5-2 and 5-20 mg/kg, respectively, showed a protective effect on gastric damage induced by oral administration of necrotizing agents (0.6 N HCl or 0.2 N NaOH solutions, 1 ml/rat). The protection was prevented by naltrexone (10 mg/kg s.c.), an opioid antagonist with long-lasting activity. Histological sections of mucosal samples from animals pretreated with morphine (10 mg/kg i.p.) and DAMME (1 mg/kg i.p.) showed less alteration of the columnar epithelium, with a normal glandular structure, than untreated rats. A mediation of prostaglandins is suggested, since indomethacin (10 mg/kg s.c.) significantly reduced the protective effects of opioids.
Assuntos
D-Ala(2),MePhe(4),Met(0)-ol-encefalina/uso terapêutico , Endorfinas/uso terapêutico , Úlcera Gástrica/prevenção & controle , Animais , Mucosa Gástrica/patologia , Ácido Clorídrico/farmacologia , Masculino , Morfina/farmacologia , Naltrexona/farmacologia , Ratos , Ratos Endogâmicos , Hidróxido de Sódio/farmacologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologiaRESUMO
The optically active stereomers of some 3-(fluoro-, chloro-, bromophenyl)-2-biphenylyl-3-hydroxypropionic acids were prepared and tested for antiinflammatory activity. Surprisingly, the four bromo-isomers were the most active ones, particularly in the threo configuration.
Assuntos
Anti-Inflamatórios não Esteroides , Fenilpropionatos , Anti-Inflamatórios não Esteroides/uso terapêutico , Fenômenos Químicos , Físico-Química , Edema/tratamento farmacológico , Fenilpropionatos/uso terapêutico , EstereoisomerismoRESUMO
Selective radiofrequency and neurotoxic lesions of the serotonergic pathways caused in the rat a significant reduction of ir-dynorphin A and B in the hypothalamus but not at pituitary level. These data confirm that dynorphin-related peptides are regulated independently in these areas.