RESUMEN
The starting point for German headache research and clinical education was the engagement of D. Soyka in the 1970s, which enabled the foundation of the German Headache Society (DMKG) on 28 June 1979 and, some years later, the founding congress of the International Headache Society (IHS) in Munich 1982. As a result of these activities, in 1988 the first international classification of headache disorders was published. This classification was one of the major milestones in the development of basic as well as clinical headache research. In the following years, epidemiological studies all over the world showed a 1-year prevalence for headache of approximately 60%, making headaches one of the most frequent medical complaints. Basic research showed an involvement of serotonergic mechanisms in migraine pain and triptans were one of the first drugs designed to influence these mechanisms. Functional brain imaging studies in migraine patients further showed a cyclic modulation of the activity of brainstem areas independent of the current pain state. Various research groups were involved in the clarification of the role of calcitonin gene-related peptide (CGRP) in migraine and cluster headache. A specific development in the German headache scene is the establishment of integrated headache centers and reflects the primarily multimodal treatment approach in Germany which contrasts with the settings in other countries. These successful developments are increasingly being undermined by the fact that the low financial support of headache research, for example, by the German science council is causing a decreasing interest in headache research, with the consequence that the clinical education of students as well as young medical doctors shows increasing deficits. The consequence for the future will be a deficit in the clinical care of the population.
Asunto(s)
Trastornos de Cefalalgia/etiología , Trastornos de Cefalalgia/terapia , Trastornos Migrañosos/etiología , Trastornos Migrañosos/terapia , Investigación Biomédica/educación , Péptido Relacionado con Gen de Calcitonina/fisiología , Terapia Combinada , Comparación Transcultural , Estudios Transversales , Prestación Integrada de Atención de Salud , Educación de Postgrado en Medicina , Predicción , Trastornos de Cefalalgia/clasificación , Trastornos de Cefalalgia/epidemiología , Humanos , Trastornos Migrañosos/clasificación , Trastornos Migrañosos/epidemiología , Sociedades MédicasAsunto(s)
Analgésicos Opioides/efectos adversos , Péptido Relacionado con Gen de Calcitonina/metabolismo , Estreñimiento/inducido químicamente , Estreñimiento/tratamiento farmacológico , Motilidad Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/metabolismo , Tracto Gastrointestinal/fisiología , Morfina/efectos adversos , Motilina/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Somatostatina/metabolismo , Sustancia P/metabolismo , Péptido Intestinal Vasoactivo/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Péptido Relacionado con Gen de Calcitonina/fisiología , Estreñimiento/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Motilina/fisiología , Panax , Somatostatina/fisiología , Sustancia P/fisiología , Resultado del Tratamiento , Péptido Intestinal Vasoactivo/fisiología , Adulto Joven , Zanthoxylum , ZingiberaceaeRESUMEN
Calcitonin gene-related peptide (CGRP) plays a variety of important roles within the nervous system. Increasing CGRP expression could improve the survival of injured neurons and prevent neuronal loss. In this study, we first evaluated in vitro the neuroprotective function of CGRP on mechanically injured cerebellar granule neurons (CGNs) of rats. We then verified this result through exogenous administration of CGRP in a spinal cord transected completely in rats. Finally, we investigated the effect of electro-acupuncture (EA) on CGRP expression following the spinal cord transected completely in rats. We found that EA can improve CGRP expression, and exogenous CGRP may promote the survival of injured neurons, both in vivo and in vitro. Our results suggest that CGRP may be a specific neuropeptide expressed in GV-EA treatment of spinal cord injuries (SCI), and that CGRP may play a neuroprotective role in survival of neurons injured mechanically.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/biosíntesis , Electroacupuntura , Fármacos Neuroprotectores/uso terapéutico , Traumatismos de la Médula Espinal/terapia , Animales , Péptido Relacionado con Gen de Calcitonina/genética , Péptido Relacionado con Gen de Calcitonina/farmacología , Péptido Relacionado con Gen de Calcitonina/fisiología , Péptido Relacionado con Gen de Calcitonina/uso terapéutico , Células Cultivadas/efectos de los fármacos , Cerebelo/citología , Terapia Combinada , Cordotomía , Implantes de Medicamentos , Femenino , Regulación de la Expresión Génica , Lidocaína/farmacología , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Nocicepción/fisiología , Células del Asta Posterior/metabolismo , Ratas , Ratas Sprague-Dawley , Regeneración , Rizotomía , Médula Espinal/fisiología , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/metabolismo , Regulación hacia ArribaRESUMEN
CONTEXT: Calcitonin gene-related peptide (CGRP), substance P and nerve growth factor play an important role in inflammatory pain in various somatic pain models but their role in chronic pancreatitis has not been well studied. OBJECTIVES: The aim of this study was to investigate the effects of intrathecal administration of calcitonin gene-related peptide antagonist and substance P receptor antagonist on pain behavior in a rat model of chronic pancreatitis and to determine whether nerve growth factor drives the up-regulation of expression of these neuropeptides in sensory neurons. METHODS: Pancreatitis was induced by retrograde infusion of trinitobenzene sulfonic acid into the pancreatic duct of adult rats. Three weeks post infusion continuous intrathecal infusion of the calcitonin gene-related peptide antagonist alpha CGRP8-37 or neurokinin-1 receptor antagonist CP-96345 or its inactive enantiomer CP-96344 was administered for seven days. The effects of treatment on pancreatic hyperalgesia were assessed by sensitivity of the abdominal wall to von Frey filament probing as well as by the nocifensive response to electrical stimulation of the pancreas. In a separate experiment chronic pancreatitis was induced and pancreas specific dorsal root ganglion neurons labeled with DiI were assessed for calcitonin gene-related peptide and substance P immunoreactivity. RESULTS: Intrathecal infusion of calcitonin gene-related peptide and neurokinin-1 receptor antagonists significantly attenuated behavioral pain responses in rats with chronic pancreatitis. Further, treatment of chronic pancreatitis rats with nerve growth factor antibody significantly reduced pancreas specific neurons expressing calcitonin gene-related peptide and substance P in thoracic dorsal root ganglion. CONCLUSIONS: Calcitonin gene-related peptide and substance P mediate pancreatic hyperalgesia in chronic pancreatitis and nerve growth factor in turn sustains the up-regulation of these neuropeptides in pancreatic sensory neurons.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/fisiología , Factor de Crecimiento Nervioso/farmacología , Dolor/metabolismo , Pancreatitis Crónica/metabolismo , Sustancia P/fisiología , Animales , Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/farmacología , Compuestos de Bifenilo/uso terapéutico , Péptido Relacionado con Gen de Calcitonina/administración & dosificación , Péptido Relacionado con Gen de Calcitonina/metabolismo , Péptido Relacionado con Gen de Calcitonina/farmacología , Péptido Relacionado con Gen de Calcitonina/uso terapéutico , Evaluación Preclínica de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Inyecciones Espinales , Masculino , Dolor Nociceptivo/metabolismo , Dolor/tratamiento farmacológico , Dolor/etiología , Dimensión del Dolor , Pancreatitis Crónica/complicaciones , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/farmacología , Fragmentos de Péptidos/uso terapéutico , Ratas , Ratas Sprague-Dawley , Sustancia P/metabolismoRESUMEN
Convincing evidence has accumulated of regulation of bone by the central nervous system. The neural connection between brain and bone is mediated centrally by classic neurotransmitters and several neuropeptides, and peripherally by many of the same neurotransmitters and neuropeptides, albeit with actions opposite to their central effects. Pharmacologic blockade of ß2-adrenergic receptors or disruption of the gene encoding them increases bone mass, whereas increased activity of the sympathetic nervous system (SNS) contributes to bone loss. Brainstem serotonergic neurons regulate SNS activity and its modulation by leptin. Physiologic stimulation of osteoblastic nicotinic receptors results in proliferation and deposition of bone, whereas higher levels inhibit osteoblast function. Activation of sensory nerves has a centrally mediated action on bone, albeit poorly understood. The relative importance of, and interactions between autonomic, sensory, and peripheral nervous system actions on bone mass are also not clear in healthy individuals, and less so in pathologic states.
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Osteoporosis/fisiopatología , Acetilcolina/fisiología , Animales , Remodelación Ósea/fisiología , Péptido Relacionado con Gen de Calcitonina/fisiología , Humanos , Hipotálamo/fisiopatología , Leptina/fisiología , Neuropéptidos/fisiología , Norepinefrina/fisiología , Sistema Nervioso Parasimpático/fisiopatología , Disautonomías Primarias/fisiopatología , Accidente Cerebrovascular/fisiopatología , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
AIM OF THE STUDY: Eucommia ulmoides Oliv. leaf is a traditional Chinese medicine that exhibits an anti-diabetic action. This study was designed to investigate whether long-term administration of Eucommia ulmoides Oliv. leaves extract (ELE) ameliorates pre-diabetic state of insulin resistance and abnormal perivascular innervation in the hyperinsulinemic state. MATERIALS AND METHODS: ELE at doses of 500 and 1000mg/kg was administered orally once daily for 4 weeks in fructose-drinking rats (FDRs). Plasma levels of insulin, blood glucose levels, and perivascular innervation were assessed using biochemical and immunohistochemical methods. RESULTS: FDR showed significant increase in plasma levels of insulin, an index for insulin resistance (Homeostasis Model Assessment ratio-HOMA-IR) and systolic blood pressure (SBP), but not blood glucose levels, as compared with control rats. Immunohistochemical study showed significantly greater density of tyrosine hydroxylase (TH)-like immunoreactivity (LI)-containing nerves and significantly lower density of calcitonin gene-related peptide (CGRP)-LI-containing nerves in mesenteric arteries of FDR than those in control. A 4-week treatment with ELE (500 and 1000mg/kg, p.o.) significantly decreased plasma levels of insulin and HOMA-IR without affecting blood glucose levels and significantly lowered SBP in FDR. ELE treatment in FDR resulted in significant increase in CGRP-LI never fiber density and significant decrease in TH-LI never fiber density in mesenteric arteries of FDR. CONCLUSIONS: These results suggest that long-term ELE treatment effectively prevents insulin resistance development and ameliorates abnormal perivascular innervation in FDR.
Asunto(s)
Eucommiaceae/química , Fructosa/administración & dosificación , Resistencia a la Insulina , Arterias Mesentéricas/inervación , Hojas de la Planta/química , Animales , Presión Sanguínea/efectos de los fármacos , Péptido Relacionado con Gen de Calcitonina/fisiología , Ingestión de Líquidos , Fructosa/farmacología , Insulina/sangre , Masculino , Ratas , Ratas WistarRESUMEN
OBJECTIVES: Calcitonin gene-related peptide (CGRP) is released from perivascular pancreatic nerves. It effects vasomotion and cytokine liberation in inflammatory processes, including acute pancreatitis (AP). Calcitonin gene-related peptide liberation is stimulated by capsaicin, a substance of red hot chili peppers. Aim of the study was to investigate the influence of exogenous capsaicin on experimental AP. METHODS: Acute pancreatitis was induced in rats by glycodeoxycholic acid and cerulein. Animals were divided into 4 groups: (1) severe AP, (2) severe AP+capsaicin, (3) control without AP, and (4) control+capsaicin. After 24 hours, survival, histology, and CGRP were evaluated (n=6/group). In additional animals, erythrocyte flow and leukocyte activation were evaluated by intravital microscopy 6 hours after AP induction (n=6/group). RESULTS: In the control groups, all animals survived without histological alterations. Mortality in severe AP was 67%. Capsaicin reduced mortality to 16% (P<0.05). Acute pancreatitis animals developed pancreatic inflammation and necrosis, which was significantly less after capsaicin application. Intravital microscopy in severe AP showed reduced erythrocyte velocity and increased leukocyte adhesion, which was nearly normalized by capsaicin (P<0.01). Calcitonin gene-related peptide increased in both capsaicin groups, indicating endogenous CGRP liberation (P<0.01). CONCLUSION: Capsaicin releases endogenous CGRP with improved pancreatic microcirculation and reduced inflammation in experimental AP. This underlines neuropeptide activity in the pathogenesis of AP.
Asunto(s)
Capsaicina/uso terapéutico , Pancreatitis Aguda Necrotizante/tratamiento farmacológico , Amilasas/sangre , Animales , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Péptido Relacionado con Gen de Calcitonina/sangre , Péptido Relacionado con Gen de Calcitonina/fisiología , Adhesión Celular/efectos de los fármacos , Ceruletida/toxicidad , Ácido Glicodesoxicólico/toxicidad , Leucocitos/efectos de los fármacos , Leucocitos/fisiología , Masculino , Pancreatitis Aguda Necrotizante/inducido químicamente , Pancreatitis Aguda Necrotizante/patología , Pancreatitis Aguda Necrotizante/fisiopatología , Ratas , Ratas WistarRESUMEN
We have recently reported the isolation of three new members of the calcitonin (CT) gene-related peptide family of peptides, the CT receptor (CT-R)-stimulating peptides (CRSPs). We now report the sequencing and characterization of ovine/caprine CRSP-1 and caprine CRSP-2. Mature ovine and caprine CRSP-1 are identical and have strong structural homology to CRSP-1s identified to date from other species. As with other CRSP-1s, ovine/caprine CRSP-1 binds to and activates the CT-R but not the CT-like receptor (CL-R) in combination with the receptor activity-modifying proteins (RAMPs). By contrast, caprine CRSP-2 does not activate any of these receptor-RAMP complexes. Intravenous infusions of ovine CRSP-1 to normal conscious sheep induced dose-dependent reduction in plasma total Ca levels (P=0.02) and corrected Ca levels (P=0.017) associated with increases in plasma cAMP (P=0.002). CRSP-1 reduced both plasma amino-terminal pro-C-type natriuretic peptide levels (P=0.006) and plasma renin activity (P=0.028). There were no significant effects observed on hemodynamic or renal indices measured. In conclusion, we have sequenced ovine/caprine CRSP-1 and caprine CRSP-2 precursors. This newly identified CRSP-1 has been shown to share the structural and biological features of CRSP-1s known to date. In vivo studies confirm that ovine CRSP-1 reduces plasma Ca levels in sheep, presumably via a cAMP-mediated mechanism. By contrast, caprine CRSP-2 did not stimulate any combination of CT-R, CL-R, and RAMPs. Accession numbers of cDNA determined in this study are caprine CRSP-1, AB364646; caprine CRSP-2, AB364647; and ovine CRSP-1, AB364648.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/fisiología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Células COS , Péptido Relacionado con Gen de Calcitonina/química , Péptido Relacionado con Gen de Calcitonina/genética , Péptido Relacionado con Gen de Calcitonina/farmacología , Calcio/sangre , Chlorocebus aethiops , AMP Cíclico/metabolismo , ADN Complementario/genética , Cabras , Datos de Secuencia Molecular , Distribución Aleatoria , Receptores de Calcitonina/genética , Receptores de Calcitonina/fisiología , Receptores de Péptidos/genética , Receptores de Péptidos/fisiología , Renina/sangre , Alineación de Secuencia , Ovinos , Transducción de Señal/efectos de los fármacos , PorcinosRESUMEN
Propolis, a honeybee product, contains a variety of biologically active substances. The present study was designed to investigate the effects of propolis on insulin resistance induced by fructose-drinking rats (FDR; type 2 diabetic animal model). Male Wistar rats (6 weeks old) received 15% fructose solution in drinking water for 8 weeks. FDR showed significant increases in plasma levels of insulin, Homeostasis Model Assessment ratio (HOMA-R, an index of insulin resistance), body weight, and systolic blood pressure but not blood glucose levels, when compared with control rats. Brazilian propolis extract (100 and 300 mg/kg, p.o.) treatment for 8 weeks significantly decreased the plasma level of insulin, HOMA-R, and body weight, increased plasma triglyceride levels without affecting blood glucose and total cholesterol levels, and tended to decrease systolic blood pressure. In isolated and perfused mesenteric vascular beds of FDR, propolis treatment resulted in a significant reduction of sympathetic nerve-mediated vasoconstrictor response to periarterial nerve stimulation (PNS; 8 Hz) and tended to increase the calcitonin gene-related peptide (CGRP) nerve-mediated vasodilator response to PNS, compared with those in untreated FDR. However, propolis treatment did not significantly affect norepinephrine-induced vasoconstriction and CGRP-induced vasodilation. These results suggest that propolis could be an effective functional food to prevent the development of insulin resistance.
Asunto(s)
Fructosa/administración & dosificación , Hiperglucemia/prevención & control , Resistencia a la Insulina , Própolis/uso terapéutico , Animales , Presión Sanguínea/efectos de los fármacos , Péptido Relacionado con Gen de Calcitonina/fisiología , Modelos Animales de Enfermedad , Técnicas In Vitro , Insulina/sangre , Masculino , Arterias Mesentéricas/inervación , Própolis/administración & dosificación , Própolis/farmacología , Ratas , Ratas Wistar , Sistema Nervioso Simpático/efectos de los fármacos , Vasoconstricción/efectos de los fármacosRESUMEN
Royal jelly (RJ) is known to have abundant nutritional properties and a variety of biological activities. To investigate the effects of RJ on insulin resistance, 10-week-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a type 2 diabetic model, were treated for 4 weeks with RJ (10, 30, and 300 mg/kg, p.o.). RJ treatment tended to decrease systolic blood pressure and significantly decreased serum levels of insulin and the Homeostasis Model Assessment ratio, an index of insulin resistance. In isolated and perfused mesenteric vascular beds of OLETF rats, RJ treatment resulted in significant reduction of the sympathetic nerve-mediated vasoconstrictor response to periarterial nerve stimulation (PNS) and potentiation of the calcitonin gene-related peptide (CGRP) nerve-mediated vasodilator response to PNS, compared with that in untreated OLETF rats. However, RJ treatment did not significantly affect norepinephrine-induced vasoconstriction and CGRP-induced vasodilation. These results suggest that RJ could be an effective and functional food to prevent the development of insulin resistance.
Asunto(s)
Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/terapia , Ácidos Grasos/administración & dosificación , Ácidos Grasos/farmacología , Resistencia a la Insulina , Animales , Péptido Relacionado con Gen de Calcitonina/fisiología , Modelos Animales de Enfermedad , Técnicas In Vitro , Insulina/sangre , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/inervación , Ratas , Ratas Long-Evans , Sistema Nervioso Simpático/fisiología , Sístole/efectos de los fármacos , Vasoconstricción/efectos de los fármacosRESUMEN
OBJECTIVE: To probe into the relationship between "Xinshu" (BL 15)-"Jueyinshu" (BL 14) of the Bladder Channel and the heart and the underlying mechanism of electroacupuncture (EA) in resisting acute myocardial ischemia (AMI) in rats. METHODS: A total of 24 male Wistar rats were randomly divided into control, model and EA groups with 8 cases in each group. AMI model was duplicated by intraperitoneal injection of 2% isoproterenol (ISO, 100 mg/kg). EA (pulse duration 300 micros, frequency 2-20 Hz, output voltage 3. 5-5 V) was applied to BL14 and BL15 on the left side for 30 min, twice in a day (with an interval of 12 h). After decapitation, blood samples, myocardial tissue and spinal cord (T1-T6) were collected respectively for detecting serum creatine kinase (CK, with chromatometry) and calcitonin gene-related peptide (CGRP) contents in the plasma, myocardium and the spinal cord (with radioimmunoassay). RESULTS: In comparison with control group, serum CK of both model group and EA group increased significantly (P < 0. 01), and plasma CGRP content of model group lowered lightly; while compared with model group, CK content of EA group decreased obviously (P < 0.05) and plasma CGRP of EA group increased evidently (P < 0.05). No significant differences were found among 3 groups in myocardial CGRP contents and between control group and model group in spinal CGRP contents (P > 0.05). CONCLUSION: EA of "Xinshu" (BL 15)-"Jueyinshu" (BL 14) may suppress isoproterenol-injection induced myocardial injury and plasma CGRP possibly takes part in the protective effect of EA in resisting myocardial ischemia injury.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/fisiología , Electroacupuntura , Isquemia Miocárdica/terapia , Enfermedad Aguda , Animales , Péptido Relacionado con Gen de Calcitonina/análisis , Creatina Quinasa/sangre , Masculino , Miocardio/química , Ratas , Ratas Wistar , Médula Espinal/químicaRESUMEN
Capsaicin-sensitive sensory neurons are nociceptive neurons that release calcitonin gene-related peptide (CGRP) on activation. Since CGRP has potent vasodilatory activity, it has long been considered to be involved in aggravation of inflammation such as tissue hyperemia and edema. However, since ablation of the sensory fibers can result in a marked increase in the severity of inflammation and reperfusion-induced tissue inflammatory responses are enhanced in congenital CGRP-knockout mice, the sensory neurons have been shown to play a role in the maintenance of tissue integrity by regulating local inflammatory responses. We demonstrated in rodents that stimulation of sensory neurons reduces hypertension, stress-induced gastric mucosal injury, reperfusion-induced liver injury, and endotoxin-induced shock responses by attenuating inflammatory responses such as increases in both tissue levels of tumor necrosis factor (TNF) and tissue accumulation of neutrophils. Attenuation of inflammatory responses by sensory neuron activation can be explained mainly by CGRP-induced increase in the endothelial production of prostacyclin (PGI(2)). Since inflammatory responses are critically involved in the development of a wide variety of diseases, pharmacological stimulation of sensory neurons might contribute to treatment of various pathologic conditions. In this review, the authors describe molecular mechanism(s) by which sensory neuron activation inhibits TNF production, thereby attenuating inflammatory responses. Furthermore, the authors discuss some clinically useful therapeutic agents that are capable of activating sensory neurons and raise the possibility that pharmacological stimulation of sensory neurons is the new paradigm for future therapeutic strategies.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/fisiopatología , Neuronas Aferentes/fisiología , Péptido Relacionado con Gen de Calcitonina/genética , Péptido Relacionado con Gen de Calcitonina/fisiología , Capsaicina/uso terapéutico , Endotoxinas , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Calor , Humanos , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/fisiología , Choque Séptico/tratamiento farmacológico , Canales Catiónicos TRPV/fisiología , VasodilatadoresRESUMEN
In addition to its role as a potent vasodilator, calcitonin gene-related peptide (CGRP) is centrally involved in a variety of stress responses, including activation of the hypothalamo-pituitary-adrenocortical axis. It is well known that stress suppresses the activity of the hypothalamic GnRH pulse generator, the central regulator of LH and FSH pulses, resulting in reproductive dysfunction. The aim of this study was to test the hypothesis that CGRP has a critical role in mediating stress-induced suppression of pulsatile LH secretion in the rat. Ovariectomized rats were implanted with intracerebroventricular and iv cannulae. Central administration of CGRP (75 pmol-1.2 nmol) into the lateral cerebral ventricle resulted in a profound, dose-dependent suppression of LH pulses, which was reversed by a CGRP receptor antagonist (CGRP(8-37),1 nmol). Although the site of action of CGRP remains to be established, the induction of c-Fos expression in the preoptic area and hypothalamic paraventricular nucleus might suggest an involvement of these brain regions. Intravenous administration of CGRP did not affect LH pulses. Coadministration (intracerebroventricular) of CGRP (400 pmol) with a CRH antagonist (alpha-helical CRF(9-41), 26 nmol) partly blocked the CGRP-induced suppression of LH pulses. Furthermore, CGRP(8-37) (1 nmol) completely blocked hypoglycemic stress-induced suppression of LH pulses. These results suggest that the suppression of pulsatile LH secretion by central administration of CGRP may be mediated in part by CRH, and that CGRP may play a pivotal role in the normal physiological response of stress-induced suppression of the hypothalamic GnRH pulse generator, and hence the reproductive system.
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Péptido Relacionado con Gen de Calcitonina/fisiología , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Hipotálamo/metabolismo , Hormona Luteinizante/metabolismo , Estrés Fisiológico/metabolismo , Animales , Péptido Relacionado con Gen de Calcitonina/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Femenino , Hormona Liberadora de Gonadotropina/metabolismo , Hormona Liberadora de Gonadotropina/farmacología , Hormona Liberadora de Gonadotropina/fisiología , Hipoglucemiantes/farmacología , Insulina/farmacología , Fragmentos de Péptidos/farmacología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas WistarRESUMEN
This study was designed to assess the role of calcitonin gene-related peptide (CGRP) and its receptor in the generation and maintenance of secondary mechanical allodynia and hyperalgesia induced by intradermal injection of capsaicin in rats. Paw withdrawal responses (PWRs) to von Frey hairs with different bending forces applied on the rat paw were tested in this study. CGRP(8-37), a specific antagonist of CGRP 1 receptors, was delivered through a microdialysis fiber inserted across the dorsal horn. Post- and pretreatment paradigms were followed. When CGRP(8-37) was administered 1h after capsaicin injection, the mechanical allodynia and hyperalgesia were partially reversed in a dose-dependent manner. On the other hand, when rats were treated with CGRP(8-37) prior to capsaicin injection, the PWRs to von Frey applications were significantly reduced as compared to control animals. Collectively, these results suggest that CGRP receptors present in the dorsal horn are involved in the generation and maintenance of nociceptive behaviors associated with cutaneous inflammation.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/fisiología , Péptido Relacionado con Gen de Calcitonina/uso terapéutico , Capsaicina/toxicidad , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/fisiopatología , Fragmentos de Péptidos/uso terapéutico , Animales , Péptido Relacionado con Gen de Calcitonina/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Hiperalgesia/inducido químicamente , Inyecciones Intradérmicas , Masculino , Fragmentos de Péptidos/farmacología , Estimulación Física/métodos , Ratas , Ratas Sprague-Dawley , Receptores de Péptido Relacionado con el Gen de Calcitonina/fisiologíaRESUMEN
BACKGROUND: Calcitonin gene-related peptide (CGRP) is extensively localized in the perivascular or periadventitia nerves throughout the body. CGRP is a potent vasodilator and its release is associated with dilation of these blood vessels. The present study investigated the contribution of the CGRP-mediated vasodilation to the insulin-induced vasodilatory response. METHODS: Male Wistar rats were treated with capsaicin (50 mg/kg) at 1-3 days of age to ablate the CGRP-containing neurons. After 8 weeks some animals were made diabetic using streptozotocin. Vehicle-treated animals were used as controls. At 12-13 weeks the animals were fasted, anesthetized with chloralose/urethane and instrumented for recording of cardiovascular dynamics. RESULTS: Body weights and basal, insulin, glucose, mean arterial pressure (MAP), heart rate (HR), and vascular flows were not different in CGRP-deficient rats versus controls. Insulin infusion significantly decreased the MAP in vehicle-treated controls but this response was completely attenuated in CGRP-deficient rats. The decreased response to insulin was associated with a diminished vascular dilatory response in the iliac, renal, and superior mesenteric vessel beds. When insulin was infused in CGRP-deficient diabetic animals there was also a diminished response. Diabetes resulted in an increased renal vascular flow in response to insulin. CONCLUSIONS: From the present studies we conclude that the insulin-mediated vasodilation was due, in part, to the stimulation of perivascular nerves to release CGRP, and the action of CGRP on vascular smooth muscle enhanced directly or indirectly the vasodilatory response to insulin.
Asunto(s)
Presión Sanguínea/fisiología , Péptido Relacionado con Gen de Calcitonina/deficiencia , Péptido Relacionado con Gen de Calcitonina/fisiología , Diabetes Mellitus Experimental/fisiopatología , Insulina/uso terapéutico , Animales , Velocidad del Flujo Sanguíneo , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Capsaicina/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Frecuencia Cardíaca , Hipoglucemiantes/uso terapéutico , Masculino , Ratas , Ratas WistarRESUMEN
BACKGROUND: Capsaicin-sensitive nerve fibres protect gastrointestinal mucosa in animal models of mucosal injury by modulation of mucosal blood flow and mucus secretion. The aim of our study was to evaluate the effects of capsaicin-sensitive nerve fibres in rat colonic mucosa on epithelial cell proliferation and transforming growth factor-alpha (TGFalpha) expression, which is important in mucosal defence, protection and repair. METHODS: Male Wistar rats received either a capsaicin enema with or without giving antagonists to calcitonin-gene-related-peptide (CGRP) or substance P (SP) i.v. immediately prior to the capsaicin enemas; a capsaicin enema after sensory desensitization as described previously; or a vehicle enema. In all experiments, animals received 50 mg/kg BrdU i.v. and were killed at 2, 4, 8, 12, 24 and 48 h after the various treatments. Colonic mucosal specimens were evaluated microscopically for mucosal damage, changes in the numbers of inflammatory cells and BrdU-immunoreactive epithelial cell nuclei. In the same specimens, TGFalpha-mRNA and -protein expression were evaluated by RT-PCR and Western blot analysis using standardized procedures. RESULTS: A significant increase in the number of mucosal inflammatory cells and an increase in BrdU-immunoreactive nuclei were detected following mucosal exposure to capsaicin. A 2-fold increase of TGFalpha mRNA and a 10-fold increase of TGFalpha protein expression were obtained 2-12 h after capsaicin enemas. The effects on the invading number of inflammatory cells and on the increase in BrdU immunoreactive epithelial cell nuclei were significantly reduced by both CGRP and SP antagonists and were abolished in rats previously sensory-desensitized. CONCLUSION: Capsaicin-sensitive nerve fibres modulate epithelial cell proliferation and TGFalpha expression in colonic mucosa as well as a migration of inflammatory cells into the colonic mucosa. These effects are mediated by the neurotransmitters CGRP and SP.
Asunto(s)
Capsaicina/farmacología , División Celular/fisiología , Colon/inervación , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Fibras Nerviosas/fisiología , Factor de Crecimiento Transformador alfa/biosíntesis , Animales , Western Blotting , Bromodesoxiuridina/metabolismo , Péptido Relacionado con Gen de Calcitonina/antagonistas & inhibidores , Péptido Relacionado con Gen de Calcitonina/fisiología , Colon/citología , Colon/metabolismo , Desnervación , Células Caliciformes/citología , Células Caliciformes/efectos de los fármacos , Células Caliciformes/patología , Inmunohistoquímica , Inflamación/patología , Mucosa Intestinal/patología , Masculino , Fibras Nerviosas/efectos de los fármacos , Peroxidasa/metabolismo , ARN Mensajero/análisis , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sustancia P/antagonistas & inhibidores , Sustancia P/fisiología , Factor de Crecimiento Transformador alfa/genéticaRESUMEN
Recently we demonstrated that sensory denervation with the neurotoxin capsaicin worsened the inflammation in an acute and chronic model of experimental colitis, which suggests a protective role of sensory nerve fibers during gut inflammation. Because we could demonstrate that sensory neuropeptides like Calcitonin gene-related peptide (CGRP) and substance P (SP) are released from sensory nerve fibers during intestinal inflammation, both are strong candidates as mediators for the protective effect of sensory neurons. In this study we investigate the role of CGRP and SP during experimental colitis in the rat by use of receptor antagonists against CGRP (CGRP 8-37, 1 microg/h continuous subcutaneous infusion), SP (RP67580, a NK-1 receptor antagonist, 3 mg/kg i.p.) and an immunoneutralizing CGRP-antibody. A mild colitis was induced by a rectal enema containing trinitrobenzenesulfonic acid. The severity of inflammation increased markedly after 7 days in the CGRP receptor antagonist and CGRP-antibody group compared with the vehicle group as determined by a macroscopic damage score (10.4 +/- 1.2 and 9.6 +/- 1.6 vs. 6.2 +/- 2.1) by a histologic ulceration score (82 +/- 8% and 73 +/- 6% vs. 42 +/- 23%) and by myeloperoxidase activity (19.2 +/- 6.8 and 18.1 +/- 5.9 vs. 8.6 +/- 5.3 U/mg tissue protein), respectively. Treatment with the specific SP receptor antagonist did not significantly alter the severity of colitis at 7 days compared with the control group. These data suggest that CGRP exerts mucosal protection during chronic experimental colitis.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/fisiología , Colitis Ulcerosa/fisiopatología , Neuronas Aferentes/fisiología , Animales , Anticuerpos Monoclonales , Enfermedad Crónica , Colitis Ulcerosa/patología , Indoles/farmacología , Isoindoles , Masculino , Antagonistas del Receptor de Neuroquinina-1 , Neuronas Aferentes/efectos de los fármacos , Biosíntesis de Proteínas , Ratas , Ratas Wistar , Sustancia P/fisiologíaRESUMEN
The aim of this study was to investigate whether decreased sensory innervation induced by capsaicin treatment or axotomy of the inferior alveolar nerve has an effect upon dentine formation in the rat first molar. Dentine formation was visualized by intravital injection of Procion brilliant Red H8BS and denervation was verified immunohistochemically for the neuropeptides calcitonin gene-related peptide (CGRP) and substance P. The observation times were 6 weeks for the capsaicin-treated group and 11 days for the axotomized group. Capsaicin injections caused a consistent reduction in numbers of CGRP- and substance P-immunoreactive fibres in the pulps and a somewhat smaller reduction in the periodontal tissues. Unilateral axotomy of the inferior alveolar nerve induced an almost complete loss of immunoreactive fibres in the pulp and in the mesial gingiva of the first molar. Dentine formation at the mesial pulp horn and at the central pulp floor was significantly reduced in both groups compared to controls. The results suggest that sensory neuropeptides such as CGRP and substance P may play a part in dentine formation.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/análisis , Capsaicina/farmacología , Pulpa Dental/inervación , Dentinogénesis/fisiología , Nervio Mandibular/fisiología , Fibras Nerviosas/fisiología , Sustancia P/análisis , Animales , Péptido Relacionado con Gen de Calcitonina/fisiología , Colorantes , Dentina/inervación , Dentina/ultraestructura , Dentinogénesis/efectos de los fármacos , Femenino , Encía/inervación , Inmunohistoquímica , Nervio Mandibular/cirugía , Diente Molar , Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/metabolismo , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/fisiología , Periodoncio/inervación , Ratas , Ratas Sprague-Dawley , Sustancia P/fisiología , TriazinasRESUMEN
To study the interaction between human recombinant interleukin-1 alpha and the nervous system, substance P-, neurokinin A-, calcitonin gene-related peptide-, and neuropeptide Y-like immunoreactivity in the cerebrospinal fluid, plasma, and temporomandibular joint (TMJ) perfusates of rats during acute experimental monarthritis were examined. The right TMJs of the experimental rats were injected with 0.01 mL of human recombinant interleukin-1 alpha. The right TMJs of control rats were injected with 0.01 mL of saline. Cerebrospinal fluid, plasma, and perfusates from the right TMJs were obtained at 2, 6, and 24 hours following injection, and neuropeptide-like immunoreactivity was analyzed by specific radioimmunoassays. Values of neuropeptide-like immunoreactivity for the experimental rats were compared with those of the control rats. In the experimental group, substance P-, neurokinin A-, and calcitonin gene-related peptide-like immunoreactivities were increased in cerebrospinal fluid compared to those of the control group. In plasma, no changes in neuropeptide-like immunoreactivities rose significantly in the TMJ perfusates. Most pronounced changes in neuropeptide Y-like immunoreactivity occurred intra-articularly in the TMJ perfusates. The results indicate that the contribution of the nervous system to human recombinant interleukin-1 alpha-induced monarthritis is most pronounced in the affected joint.
Asunto(s)
Artritis/inmunología , Interleucina-1/farmacología , Neuroinmunomodulación/fisiología , Neuropéptidos/fisiología , Trastornos de la Articulación Temporomandibular/inmunología , Animales , Artritis/inducido químicamente , Artritis/metabolismo , Péptido Relacionado con Gen de Calcitonina/análisis , Péptido Relacionado con Gen de Calcitonina/fisiología , Humanos , Masculino , Neuroinmunomodulación/efectos de los fármacos , Neuroquinina A/análisis , Neuroquinina A/fisiología , Neuropéptido Y/análisis , Neuropéptido Y/fisiología , Neuropéptidos/análisis , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/farmacología , Sustancia P/análisis , Sustancia P/fisiología , Líquido Sinovial/química , Articulación Temporomandibular/efectos de los fármacos , Articulación Temporomandibular/inmunología , Trastornos de la Articulación Temporomandibular/inducido químicamente , Trastornos de la Articulación Temporomandibular/metabolismoRESUMEN
Alterations in calcium metabolism and calcium-regulating hormones have been described in essential hypertension. However, the mechanisms that mediate these responses are unknown. In previous studies, using the genetically spontaneously hypertensive rat and the mineralocorticoid-salt (DOC-salt) hypertensive rat model, we and others have observed that oral calcium supplementation attenuates the associated increase in peripheral vascular resistance and consequently lowers blood pressure (BP). When hypertensive patients (n = 8, diastolic BP 90-95 mmHg (1 mmHg = 133.3 Pa)) were given daily oral calcium supplementation (1.4 g elemental calcium), both systolic and diastolic BP were decreased (5-10 mmHg, p < 0.01). The only biochemical variables significantly changed were serum ionized calcium and intact parathyroid hormone (PTH, 1-84) (p < 0.05); furthermore, the levels of calcitonin gene related peptide (CGRP), measured by both radioimmunoassay and radioreceptor assay, showed a marked 75% increase (p < 0.001). The antihypertensive effects of Ca2+ and the increased levels of CGRP in the circulation returned to baseline levels immediately following cessation of calcium supplementation, suggesting that the effects of calcium on BP and CGRP are specific. On the basis of these observations were proposed that the antihypertensive effect of dietary calcium supplementation, at least in part, is mediated through CGRP.