RESUMEN
Migraine is a common, paroxysmal, highly disabling primary headache disorder. The origin of migraine attacks is enigmatic. Numerous clinical and experimental results suggest that the activation of distinct brainstem nuclei is crucial in its pathogenesis, but the primary cause of this activation is not fully understood. We conclude that the initialization of a migraine attack can be explained as an altered function of the neuronal elements of the brainstem nuclei. In light of our findings and the literature data, we can assume that migraine is a subcortical disorder of a specific brainstem area.
Asunto(s)
Tronco Encefálico/fisiopatología , Trastornos Migrañosos/fisiopatología , Animales , Humanos , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/metabolismo , Vías Nerviosas/fisiopatologíaRESUMEN
Migraine is a common, paroxysmal, highly disabling primary headache disorder with a genetic background. The primary cause and the origin of migraine attacks are enigmatic. Numerous clinical and experimental results suggest that activation of the trigeminal system (TS) is crucial in its pathogenesis, but the primary cause of this activation is not fully understood. Since activation of the peripheral and central arms of the TS might be related to cortical spreading depression and to the activity of distinct brainstem nuclei (e.g. the periaqueductal grey), we conclude that migraine can be explained as an altered function of the neuronal elements of the TS, the brainstem, and the cortex, the centre of this process comprising activation of the TS. In light of our findings and the literature data, therefore, we can assume that migraine is mainly a neuronal disease.
Asunto(s)
Tronco Encefálico/fisiopatología , Corteza Cerebral/fisiopatología , Trastornos Migrañosos/fisiopatología , Red Nerviosa/fisiopatología , Nervio Trigémino/fisiopatología , Animales , Tronco Encefálico/metabolismo , Péptido Relacionado con Gen de Calcitonina/fisiología , Corteza Cerebral/metabolismo , Depresión de Propagación Cortical/fisiología , Ácido Glutámico/fisiología , Humanos , Ácido Quinurénico/metabolismo , Trastornos Migrañosos/metabolismo , Red Nerviosa/metabolismo , Sustancia Gris Periacueductal/metabolismo , Sustancia Gris Periacueductal/fisiopatología , Nervio Trigémino/metabolismo , Núcleos del Trigémino/metabolismo , Núcleos del Trigémino/fisiopatologíaRESUMEN
Migraine can be triggered by systemic administration of the nitric oxide (NO) donor nitroglycerin (NTG) and by abrupt falls in plasma oestradiol. Calmodulin-dependent protein kinase II (CamKII) present in superficial dorsal horns is thought to play a role in sensitization of central nociceptors, a phenomen present in migraineurs. We therefore examined in rats the expression of CamKII in the caudal trigeminal nucleus (TNC) after subcutaneous NTG (10 mg/kg) and its modulation by oestrogen. In male rats and in ovariectomized females, after 4 h NTG increased significantly CamKII expression in the superficial layers of TNC, but not in the upper thoracic spinal cord. NTG had no effect on CamKII expression in oestradiol-treated ovariectomized animals. Thus NTG, i.e. NO, selectively enhances CamKII in the rat TNC and oestradiol blocks this effect. These data may help to understand the mechanisms by which NO triggers migraine attacks and oestrogens influence migraine severity.
Asunto(s)
Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Estradiol/administración & dosificación , Óxido Nítrico/metabolismo , Nitroglicerina/administración & dosificación , Núcleo Espinal del Trigémino/enzimología , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Activación Enzimática/efectos de los fármacos , Femenino , Inyecciones Subcutáneas , Masculino , Ovariectomía , Ratas , Ratas Wistar , Factores Sexuales , Distribución Tisular/efectos de los fármacos , Núcleo Espinal del Trigémino/efectos de los fármacosRESUMEN
Systemic administration of nitroglycerin (NTG), a nitric oxide (NO) donor, in migraineurs triggers after several hours an attack of which the precise mechanisms are unknown. We found previously in rats that nitroglycerin (10 mg/kg s.c.) is able to increase significantly after 4 h the number of neuronal nitric oxide synthase (nNOS)-immunoreactive neurones in the cervical part of trigeminal nucleus caudalis. In the present experiments, we demonstrate that the 5-HT1B/D agonist sumatriptan (0.6 mg/kg s.c.) does not alter this phenomenon when given before NTG. By contrast, pretreatment with lysine acetylsalicylate (50 mg/kg i.m.) attenuates the NTG-induced nNOS expression in the superficial laminae of trigeminal nucleus caudalis. These findings suggest that effect of NTG on nNOS at a high dosage may involve the cycloxygenase pathway and that activation of the peripheral 5-HT1B/D receptors is not able to modify this effect. These data could help to better understand the role of NO in the pathogenesis of headaches and the action of antimigraine drugs.
Asunto(s)
Aspirina/análogos & derivados , Aspirina/farmacología , Lisina/análogos & derivados , Lisina/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/biosíntesis , Nitroglicerina/farmacología , Sumatriptán/farmacología , Núcleo Espinal del Trigémino/efectos de los fármacos , Núcleo Espinal del Trigémino/enzimología , Animales , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Masculino , Óxido Nítrico Sintasa de Tipo I , Nitroglicerina/antagonistas & inhibidores , Ratas , Ratas WistarRESUMEN
Systemic administration of nitroglycerin, a nitric oxide donor, triggers in migraine patients a delayed attack of unknown mechanism. After puberty migraine is more prevalent in women. Attacks can be triggered by abrupt falls in plasma estrogen levels, which accounts in part for sexual dimorphism, but lacks an established neurobiological explanation. We studied the effect of nitroglycerin on the innervated area of calcitonin gene-related peptide (CGRP) and serotonin-immunoreactive afferents to the superficial laminae of the spinal portion of trigeminal nucleus caudalis, and its modulation by estrogen. In male rats, nitroglycerin produced after 4 h a significant decrease of the area innervated by CGRP-immunoreactive afferents and an increase of that covered by serotonin-immunoreactive fibres. These effects were not observed in the superficial laminae of thoracic dorsal horns. The effect of nitroglycerin was similar in ovariectomized females. In estradiol-treated ovariectomized females the area in the spinal portion of trigeminal nucleus caudalis laminae I-II covered by CGRP-immunoreactive fibres was lower and that of serotonin-immunoreactive fibres was higher than in males and for both transmitters not significantly changed after nitroglycerin. The bouton size of CGRP profiles was smaller in estradiol-treated ovariectomized females, whereas after nitroglycerin it decreased significantly but only in males and ovariectomized females. Nitroglycerin, i.e. nitric oxide, is thus able to differentially influence afferent fibres in the superficial laminae of rat spinal trigeminal nucleus caudalis. Estradiol modulates the basal expression of these transmitters and blocks the nitroglycerin effect. These data may contribute to understanding the mechanisms by which estrogens influence migraine severity and the triggering of attacks by nitric oxide.
Asunto(s)
Vías Aferentes/metabolismo , Péptido Relacionado con Gen de Calcitonina/metabolismo , Estradiol/deficiencia , Trastornos Migrañosos/metabolismo , Óxido Nítrico/metabolismo , Serotonina/metabolismo , Núcleo Caudal del Trigémino/metabolismo , Vías Aferentes/citología , Vías Aferentes/efectos de los fármacos , Animales , Tamaño de la Célula/efectos de los fármacos , Tamaño de la Célula/fisiología , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/fisiología , Interacciones Farmacológicas/fisiología , Estradiol/genética , Femenino , Inmunohistoquímica , Masculino , Trastornos Migrañosos/inducido químicamente , Trastornos Migrañosos/fisiopatología , Nitroglicerina/farmacología , Ovariectomía , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/metabolismo , Terminales Presinápticos/ultraestructura , Ratas , Ratas Wistar , Caracteres Sexuales , Núcleo Caudal del Trigémino/citología , Núcleo Caudal del Trigémino/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiologíaRESUMEN
Systemic administration of nitroglycerin, a nitric oxide donor, triggers in migraineurs a delayed attack of unknown mechanisms. Subcutaneous nitroglycerin (10 mg/kg) produced a significant increase of nitric oxide synthase (NOS)- and c-fos-immunoreactive neurons in the cervical part of trigeminal nucleus caudalis in rats after 4 h. This effect was not observed in the thoracic dorsal horn. Similar increase of NOS and c-fos was obtained in the brain stem after a somatic nociceptive stimulus, i.e. on the side of the formalin injection in the lip. Nitric oxide is thus able to increase NOS availability in second order nociceptive trigeminal neurons, which may be relevant for central sensitization and the understanding of its effect in migraine.