RESUMEN
In the present study, we describe the antinociceptive effect of filicene, a triterpene isolated from Adiantum cuneatum (Adiantaceae) leaves, in several models of pain in mice. When evaluated against acetic acid-induced abdominal constrictions, filicene (10, 30 and 60 mg/kg, i.p.) produced dose-related inhibition of the number of constrictions, being several times more potent [ID(50)=9.17 (6.27-13.18) mg/kg] than acetaminophen [ID(50)=18.8 (15.7-22.6) mg/kg], diclofenac [ID(50)=12.1(9.40-15.6) mg/kg] and acetylsalicylic acid [ID(50)=24.0(13.1-43.8) mg/kg] in the same doses as those used for the standard drugs. Filicene also produced dose-related inhibition of the pain caused by capsaicin and glutamate, with mean ID(50) values of 11.7 (8.51-16.0) mg/kg and <10 mg/kg, respectively. Its antinociceptive action was significantly reversed by atropine, haloperidol, GABA(A) and GABA(B) antagonists (bicuculline and phaclofen, respectively), but was not affected by L-arginine-nitric oxide, serotonin, adrenergic and the opioid systems. Together, these results indicate that the mechanisms involved in its action are not completely understood, but seem to involve interaction with the cholinergic, dopaminergic, glutamatergic, GABAergic and tachykinergic systems.
Asunto(s)
Adiantum/química , Analgésicos/aislamiento & purificación , Analgésicos/farmacología , Triterpenos/aislamiento & purificación , Triterpenos/farmacología , Ácido Acético/toxicidad , Analgésicos/administración & dosificación , Analgésicos/química , Animales , Capsaicina/toxicidad , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ácido Glutámico/toxicidad , Masculino , Ratones , Estructura Molecular , Dolor/tratamiento farmacológico , Dolor/fisiopatología , Fitoterapia , Plantas Medicinales/química , Receptores Colinérgicos/efectos de los fármacos , Receptores Colinérgicos/fisiología , Receptores Dopaminérgicos/efectos de los fármacos , Receptores Dopaminérgicos/fisiología , Receptores de GABA/efectos de los fármacos , Receptores de GABA/fisiología , Receptores de Neurotransmisores/efectos de los fármacos , Receptores de Neurotransmisores/fisiología , Receptores de Taquicininas/efectos de los fármacos , Receptores de Taquicininas/fisiología , Triterpenos/administración & dosificación , Triterpenos/químicaRESUMEN
It is known that the muscularis mucosae and mucosa are not pharmacologically homogeneous throughout the rat colon. The aim of this study was to simultaneously characterize all three neurokinin (NK) receptors in the muscularis mucosae and mucosa along the length of the rat colon. Strips of proximal, mid, and distal colonic muscularis mucosae were prepared for isometric recording or sheets of muscle-free mucosa were mounted in Ussing chambers for measurement of short-circuit current. In both muscularis mucosae and mucosa the greatest responses to substance P were found in the proximal region. Use of selective agonists revealed the presence of all three NK receptors in both structures, however, selective antagonism suggests that only NK2 receptors in the muscularis mucosae and NK1 receptors in the mucosa are physiologically relevant. In conclusion, substance P-induced responses in the rat colon are region-specific and not mediated by a single NK receptor subtype common to both structures.
Asunto(s)
Acetilcolina/farmacología , Colon/efectos de los fármacos , Motilidad Gastrointestinal/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Receptores de Taquicininas/metabolismo , Sustancia P/farmacología , Animales , Colon/patología , Modelos Animales de Enfermedad , Femenino , Motilidad Gastrointestinal/fisiología , Mucosa Intestinal/patología , Masculino , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Neuroquinina-1/efectos de los fármacos , Receptores de Neuroquinina-1/metabolismo , Receptores de Neuroquinina-2/efectos de los fármacos , Receptores de Neuroquinina-2/metabolismo , Receptores de Taquicininas/efectos de los fármacos , Sensibilidad y Especificidad , Técnicas de Cultivo de TejidosRESUMEN
The aim of this work was to verify whether formalin would induce leukocyte recruitment following intraperitoneal (i.p.) injection in rats. Formalin (1.25 - 2.5%) induced cell recruitment, which was concentration- and time-dependent (0 - 24 h). Two peaks of leukocyte recruitment were observed. The first peak (from 2 to 4 h) was characterized by a mixed polymorphonuclear and lymphocyte cell population (representing an increase of 100 - 220% and 55 - 60%, respectively), whereas the second peak was characterized by a marked increase in lymphocytes at 24 h (representing an increase of 230%). Pretreatment of animals with specific antagonists for neurokinin NK(1), NK(2), and NK(3) receptors (SR140333, SR48968, and SR142801 compounds, respectively) reduced the early leukocyte increase (representing a significant reduction of 65%, 51%, and 46%, respectively), whereas only the treatment with NK(2)-specific antagonist reduced the late cell increase induced by formalin injection (amounting to a significant reduction of 48%). These results suggested that substance P, neurokinin A, and neurokinin B release accounted for formalin-induced cell migratory activity. The anti-inflammatory drug dexamethasone also reduced cell recruitment, which was mainly related to a reduction in 79% of the neutrophils at 4 h following 1.25% formalin injection, suggesting also a release of lipid mediators (eicosanoids and/or platelet-activating factor) and/or cytokines/chemokines by the formalin injection.
Asunto(s)
Formaldehído/administración & dosificación , Formaldehído/farmacología , Leucocitos/fisiología , Cavidad Peritoneal/fisiología , Receptores de Taquicininas/antagonistas & inhibidores , Animales , Benzamidas/farmacología , Movimiento Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Inyecciones Intraperitoneales , Leucocitos/citología , Leucocitos/efectos de los fármacos , Modelos Biológicos , Neuroquinina A/metabolismo , Neuroquinina B/metabolismo , Antagonistas del Receptor de Neuroquinina-1 , Lavado Peritoneal , Piperidinas/farmacología , Quinuclidinas/farmacología , Ratas , Ratas Endogámicas , Receptores de Neuroquinina-1/efectos de los fármacos , Receptores de Neuroquinina-2/antagonistas & inhibidores , Receptores de Neuroquinina-2/efectos de los fármacos , Receptores de Neuroquinina-3/antagonistas & inhibidores , Receptores de Neuroquinina-3/efectos de los fármacos , Receptores de Taquicininas/efectos de los fármacos , Sustancia P/metabolismo , Factores de TiempoRESUMEN
In the most severe cases of human envenoming by Tityus serrulatus, pulmonary oedema is a frequent finding and can be the cause of death. We have previously demonstrated a role for neuropeptides acting on tachykinin NK(1) receptors in the development of lung oedema following i.v. injection of T. serrulatus venom (TsV) in experimental animals. The present work was designed to investigate whether capsaicin-sensitive primary afferent neurons were a potential source of NK(1)-acting neuropeptides. To this end, sensory nerves were depleted of neuropeptides by neonatal treatment of rats with capsaicin. The effectiveness of this strategy at depleting sensory nerves was demonstrated by the inhibition of the neuropeptide-dependent response to intraplantar injection of formalin. Pulmonary oedema, as assessed by the levels of extravasation of Evans blue dye in the bronchoalveolar lavage and in the left lung, was markedly inhibited in capsaicin-treated animals. In contrast, capsaicin treatment failed to alter the increase in arterial blood pressure or the lethality following i.v. injection of TsV. Our results demonstrate an important role for capsaicin-sensitive sensory nerves in the cascade of events leading to lung injury following the i.v. administration of TsV.
Asunto(s)
Capsaicina/farmacología , Neuronas Aferentes/efectos de los fármacos , Edema Pulmonar/etiología , Venenos de Escorpión/toxicidad , Escorpiones , Animales , Capsaicina/administración & dosificación , Inyecciones Intravenosas , Masculino , Neuronas Aferentes/fisiología , Edema Pulmonar/fisiopatología , Ratas , Ratas Wistar , Receptores de Taquicininas/efectos de los fármacos , Receptores de Taquicininas/fisiología , Venenos de Escorpión/farmacologíaRESUMEN
The intradermal (i.d.) injection of NK1 receptor antagonists GR 82334 and FK 888 (1-50 pmol/paw), in association with formalin, produced graded inhibition of the early but not the late phase of the formalin test. The NK2, SR 48968 and NK3 SR 142801 receptor antagonists (1-50 pmol/paw) were effective in inhibiting both phases of the formalin model. Co-injection of NK1, (FK 888, GR 82334), NK2 (SR 48968) or NK3 (SR 142801) receptor antagonists with capsaicin dose-dependently attenuated capsaicin-induced licking. In addition, all antagonists were more efficacious when compared with response in the formalin test. The antinociception caused by i.d. injection of the NK3 receptor antagonist SR 142801 against both phases of the formalin test, but not that of NK1 and NK2 receptor antagonists, was significantly reversed by intraperitoneal (i.p.) injection of naloxone (5 mg/kg). Intracerebroventricular (i.c.v.) injection of NK1, NK2 or NK3 receptor antagonists (15-500 pmol/site), all produced significant and dose-dependent inhibition of both phases of the formalin and capsaicin tests. With the exception of the response of SR 48968, which was equipotent in both models of nociception, FK 888, GR 82334 and SR 142801 were about 2-25-fold less potent at the ID50 level against the capsaicin-induced pain. The antinociception caused by i.c.v. injection of NK1, NK2 or NK3 receptor antagonists was reversed by i.p. injection of naloxone (5 mg/kg). These results indicate that tachykinin receptor antagonists, acting through NK1, NK2 and NK3 receptors, produce powerful antinociception when injected i.d. or by i.c.v. route against both formalin- and capsaicin-induced licking, being more efficacious against the latter model of nociception. The action of NK3 receptor antagonist given i.d. was mediated through an opioid mechanism sensitive to naloxone. However, when injected i.c.v., the antinociception caused by NK1, NK2 or NK3 receptor antagonists was largely reversed by naloxone when assessed in the formalin test, suggesting a distinct mechanism of action.
Asunto(s)
Capsaicina/farmacología , Formaldehído/farmacología , Dolor/metabolismo , Receptores de Taquicininas/efectos de los fármacos , Receptores de Taquicininas/fisiología , Animales , Conducta Animal/efectos de los fármacos , Capsaicina/administración & dosificación , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Formaldehído/administración & dosificación , Inyecciones Intradérmicas , Inyecciones Intraperitoneales , Inyecciones Intraventriculares , Masculino , Ratones , Dolor/inducido químicamente , Receptores de Taquicininas/antagonistas & inhibidoresRESUMEN
Phoneeutria nigriventer venom induces oedema formation when injected in the rat dorsal skin and such oedema is, in part, dependent on the stimulation of tachykinin NK1 receptors. This study investigated whether Phoneutria nigriventer venom acts directly on tachykinin NK1 receptors, or indirectly to activate sensory neurones which in turn release a tachykinin NK1 receptor agonist. The plasma extravasation induced by Phoneutria nigriventer venom (1-10 microg/site) in neonatally capsaicin (8-methyl N-vanillyl-6-nonenamide)-pretreated rats was substantially attenuated (P < 0.05) but the response to either the tachykinin NK1 receptor agonist GR73632 ((deltaAva[L-Pro9, N-MeLeu10] substance P-(7-11) 30 pmol/site) or bradykinin (0.3-3 nmol/site) was not affected. These results indicate that Phoneutria nigriventer venom stimulates sensory nerves indirectly. The lack of effect of capsaicin-pretreatment on the GR73632 and bradykinin responses indicated that the tachykinin NK1 and bradykinin B2 receptors remained functional. There was no evidence to suggest that Phoneutria nigriventer venom contains a tachykinin NK1 receptor agonist.