RESUMEN
While functional imaging and deep brain stimulation studies point to a pivotal role of the hypothalamus in the pathophysiology of migraine and trigeminal autonomic cephalalgias, the circuitry and the mechanisms underlying the modulation of medullary trigeminovascular (Sp5C) neurons have not been fully identified. We investigated the existence of a direct anatomo-functional relationship between hypothalamic excitability disturbances and modifications of the activities of Sp5C neurons in the rat. Anterograde and retrograde neuronal anatomical tracing, intrahypothalamic microinjections, extracellular single-unit recordings of Sp5C neurons, and behavioral trials were used in this study. We found that neurons of the paraventricular nucleus of the hypothalamus (PVN) send descending projections to the superior salivatory nucleus, a region that gives rise to parasympathetic outflow to cephalic and ocular/nasal structures. PVN cells project also to laminae I and outer II of the Sp5C. Microinjections of the GABAA agonist muscimol into PVN inhibit both basal and meningeal-evoked activities of Sp5C neurons. Such inhibitions were reduced in acutely restrained stressed rats. GABAA antagonist gabazine infusions into the PVN facilitate meningeal-evoked responses of Sp5C neurons. PVN injections of the neuropeptide pituitary adenylate cyclase activating peptide (PACAP38) enhance Sp5C basal activities, whereas the antagonist PACAP6-38 depresses all types of Sp5C activities. 5-HT1B/D receptor agonist naratriptan infusion confined to the PVN depresses both basal and meningeal-evoked Sp5C activities. Our findings suggest that paraventricular hypothalamic neurons directly control both spontaneous and evoked activities of Sp5C neurons and could act either as modulators or triggers of migraine and/or trigeminal autonomic cephalalgias by integrating nociceptive, autonomic, and stress processing mechanisms.
Asunto(s)
Potenciales de Acción/fisiología , Neuronas/fisiología , Núcleo Hipotalámico Paraventricular/fisiología , Núcleos del Trigémino/citología , Núcleos del Trigémino/fisiología , Animales , Biotina/análogos & derivados , Corticosterona/metabolismo , Dextranos , Modelos Animales de Enfermedad , Antagonistas del GABA , Agonistas de Receptores de GABA-A/farmacología , Masculino , Muscimol/farmacología , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Núcleo Hipotalámico Paraventricular/citología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Estimulación Física/efectos adversos , Piperidinas/farmacología , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/farmacología , Piridazinas/farmacología , Ratas , Ratas Sprague-Dawley , Agonistas de Receptores de Serotonina/farmacología , Estilbamidinas , Estrés Psicológico/metabolismo , Triptaminas/farmacologíaRESUMEN
UNLABELLED: Several lines of evidence indicate that brain-derived neurotrophic factor (BDNF) plays a key role as a central pronociceptive modulator of pain, acting through postsynaptic TrkB receptors that trigger intracellular signaling cascades leading to central sensitization. The overall aim of this study was to investigate to what extent BDNF could participate in the generation and maintenance of trigeminal neuropathic pain. The results showed that acute intracisternal administration of nanogram doses of BDNF in naïve mice elicited long-lasting, dose-related, cold allodynic responses to topical application of acetone onto vibrissal pad skin. The systemic administration of cyclotraxin-B (CTX-B), a new TrkB receptor antagonist, or propentofylline, an inhibitor of glial activation, was able to either prevent or reverse the effects of intracisternal BDNF on cold nociception. In addition, the blockade of TrkB receptor by CTX-B inhibited the mechanisms that either initiate or maintain cold allodynia in the ipsilateral vibrissal pad skin after unilateral constriction of the infraorbital nerve. These observations raise the possibility that BDNF is capable on its own of conveying many features of the signaling mechanisms that underlie central sensitization caused by nerve constriction. PERSPECTIVE: Although further studies are necessary to examine in detail the mechanisms underlying the strong anti-allodynic action of CTX-B, this compound may represent an interesting lead for the development of novel therapeutic strategies aimed at preventing and/or suppressing central sensitization associated with neuropathic pain.
Asunto(s)
Analgésicos/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hiperalgesia/metabolismo , Neuralgia/metabolismo , Péptidos Cíclicos/farmacología , Receptor trkB/antagonistas & inhibidores , Xantinas/farmacología , Animales , Factor Neurotrófico Derivado del Encéfalo/farmacología , Sensibilización del Sistema Nervioso Central/efectos de los fármacos , Sensibilización del Sistema Nervioso Central/fisiología , Frío , Modelos Animales de Enfermedad , Hiperalgesia/prevención & control , Masculino , Ratones , Neuralgia/prevención & control , Neuroglía/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Neuralgia del Trigémino/metabolismoRESUMEN
Alterations in cortical excitability are implicated in the pathophysiology of migraine. However, the relationship between cortical spreading depression (CSD) and headache has not been fully elucidated. We aimed to identify the corticofugal networks that directly influence meningeal nociception in the brainstem trigeminocervical complex (Sp5C) of the rat. Cortical areas projecting to the brainstem were first identified by retrograde tracing from Sp5C areas that receive direct meningeal inputs. Anterograde tracers were then injected into these cortical areas to determine the precise pattern of descending axonal terminal fields in the Sp5C. Descending cortical projections to brainstem areas innervated by the ophthalmic branch of the trigeminal nerve originate contralaterally from insular (Ins) and primary somatosensory (S1) cortices and terminate in laminae I-II and III-V of the Sp5C, respectively. In another set of experiments, electrophysiological recordings were simultaneously performed in Ins, S1 or primary visual cortex (V1), and Sp5C neurons. KCl was microinjected into such cortical areas to test the effects of CSD on meningeal nociception. CSD initiated in Ins and S1 induced facilitation and inhibition of meningeal-evoked responses, respectively. CSD triggered in V1 affects differently Ins and S1 cortices, enhancing or inhibiting meningeal-evoked responses of Sp5C, without affecting cutaneous-evoked nociceptive responses. Our data suggest that "top-down" influences from lateralized areas within Ins and S1 selectively affect interoceptive (meningeal) over exteroceptive (cutaneous) nociceptive inputs onto Sp5C. Such corticofugal influences could contribute to the development of migraine pain in terms of both topographic localization and pain tuning during an attack.
Asunto(s)
Corteza Cerebral/fisiopatología , Meninges/fisiopatología , Trastornos Migrañosos/fisiopatología , Red Nerviosa/fisiopatología , Dolor/fisiopatología , Núcleos del Trigémino/fisiopatología , Animales , Biotina , Depresión de Propagación Cortical/fisiología , Estimulación Eléctrica , Inmunohistoquímica , Masculino , Microinyecciones , Trastornos Migrañosos/complicaciones , Neuronas/fisiología , Dolor/etiología , Cloruro de Potasio/administración & dosificación , Cloruro de Potasio/farmacología , Ratas , Ratas Sprague-Dawley , Piel/inervación , Corteza Somatosensorial/fisiopatología , Corteza Visual/fisiopatologíaRESUMEN
Human and experimental studies indicate that molecular genetic changes in GABA(A) receptors may underlie the expression of spike-and-waves discharges (SWDs) occurring during absence seizures. However, the full spectrum of the genetic defects underlying these seizures has only been partially elucidated, the expression and functional profiles of putative abnormal protein(s) within the thalamocortical network are undefined, and the pathophysiological mechanism(s) by which these proteins would lead to absence paroxysms are poorly understood. Here we investigated GABA(A) inhibitory postsynaptic currents (IPSCs) in key thalamocortical areas, i.e., the somatosensory cortex, ventrobasal thalamus (VB) and nucleus reticularis thalami (NRT), in preseizure genetic absence epilepsy rats from Strasbourg (GAERS), a well-established genetic model of typical absence seizures that shows no additional neurological abnormalities, and compared their properties to age-matched non-epileptic controls (NECs). Miniature GABA(A) IPSCs of VB and cortical layers II/III neurons were similar in GAERS and NEC, whereas in GAERS NRT neurons they had 25% larger amplitude, 40% faster decay. In addition, baclofen was significantly less effective in decreasing the frequency of NRT mIPSCs in GAERS than in NEC, whereas no difference was observed for cortical and VB mIPSCS between the two strains. Paired-pulse depression was 45% smaller in GAERS NRT, but not in VB, and was insensitive to GABA(B) antagonists. These results point to subtle, nucleus-specific, GABA(A) receptor abnormalities underlying SWDs of typical absence seizures rather than a full block of these receptors across the whole thalamocortical network, and their occurrence prior to seizure onset suggests that they might be of epileptogenic significance.
Asunto(s)
Epilepsia Tipo Ausencia/genética , Epilepsia Tipo Ausencia/fisiopatología , Núcleos Talámicos Intralaminares/fisiopatología , Corteza Somatosensorial/fisiopatología , Sinapsis/fisiología , Transmisión Sináptica/genética , Transmisión Sináptica/fisiología , Núcleos Talámicos Ventrales/fisiopatología , Ácido gamma-Aminobutírico/fisiología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Animales , Baclofeno/farmacología , Potenciales Postsinápticos Excitadores/fisiología , Agonistas del GABA/farmacología , Antagonistas del GABA/farmacología , Antagonistas de Receptores de GABA-A , Inmunohistoquímica , Técnicas In Vitro , Potenciales de la Membrana/fisiología , Compuestos Organofosforados/farmacología , Ácidos Fosfínicos/farmacología , Propanolaminas/farmacología , Ratas , Receptores de GABA-A/genética , Receptores de GABA-A/fisiología , Sinapsis/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacosRESUMEN
Only a few methods permit researchers to study selected regions of the central and peripheral nervous systems with a spatial and time resolution sufficient to image the function of neural structures. Usually, these methods cannot analyse deep-brain regions and a high-resolution method, which could repeatedly probe dynamic processes in any region of the central and peripheral nervous systems, is much needed. Here, we show that fibred fluorescence microscopy-which uses a small-diameter fibre-optic probe to provide real-time images-has the spatial resolution to image various neural structures in the living animal, the consistency needed for a sequential, quantitative evaluation of axonal degeneration/regeneration of a peripheral nerve, and the sensitivity to detect calcium transients on a sub-second timescale. These unique features should prove useful in many physiological studies requiring the in situ functional imaging of tissues in a living animal.
Asunto(s)
Encéfalo/metabolismo , Tecnología de Fibra Óptica/métodos , Microscopía Fluorescente/métodos , Tejido Nervioso/fisiología , Animales , Encéfalo/anatomía & histología , Estimulación Eléctrica , Epitelio/fisiología , Hipocampo/anatomía & histología , Ratones , Ratones Transgénicos , Tejido Nervioso/anatomía & histología , Tejido Nervioso/metabolismo , RegeneraciónRESUMEN
This study investigates, in the anesthetized rat, the dendritic extent of parabrachial (PB) neurons whose nociceptive response to noxious stimuli has been previously recorded with an extracellular micropipette. The PB neurons were then injected with biocytin through the recording micropipette, via a juxtacellular technique. The dendritic arborization of individual PB neurons was carefully compared with the projections of medullary (trigeminal) and spinal lamina I neurons. The latter projections were labeled in separate animals that received injections of Phaseolus vulgaris-leucoagglutinin restricted to the superficial layers of spinal or medullary dorsal horn. We report here that: 1) PB neurons excited chiefly by noxious stimulation of the face have their dendritic tree located primarily within the field of lamina I trigeminal projections, i.e., in the caudal portion of PB area, around the external medial and the caudal part of the external lateral subnuclei; and 2) PB neurons excited chiefly by noxious stimulation of the paw or the tail have their dendritic tree located primarily within the field of lamina I spinal projections, i.e., in PB mid-extent, around the borderline between the external lateral and both the lateral crescent and the superior lateral subnuclei. Our results suggest the presence of an extensive excitatory axodendritic link between lamina I projections and PB nociceptive neurons around the lateral crescent and the external medial subnuclei. These findings strengthen the possibility of involvement of a subgroup of PB neurons in nociceptive processes.
Asunto(s)
Dendritas/ultraestructura , Vías Nerviosas/anatomía & histología , Nociceptores/fisiología , Puente/anatomía & histología , Animales , Dendritas/fisiología , Masculino , Bulbo Raquídeo/anatomía & histología , Bulbo Raquídeo/fisiología , Dolor/fisiopatología , Puente/fisiología , Células del Asta Posterior/anatomía & histología , Células del Asta Posterior/fisiología , Ratas , Ratas Sprague-Dawley , Médula Espinal/anatomía & histología , Médula Espinal/fisiología , Núcleos del Trigémino/anatomía & histología , Núcleos del Trigémino/fisiologíaRESUMEN
We have recently described a population of neurons in the lateral part of the ventromedial thalamus (VMl), that respond exclusively to noxious cutaneous stimuli, regardless of which part of the body is stimulated. The purpose of the present study was to investigate the convergence of cutaneous, muscular and visceral noxious inputs onto single, VMl neurons in anesthetized rats. VMl neurons were characterized by their responses to Adelta- and C-fiber activation as well as noxious heat applied to the hindpaw. We investigated whether they responded also to colorectal distensions. In an additional series of experiments, we tested the effects of colorectal, intraperitoneal, intramuscular and subcutaneous applications of the chemical irritant mustard oil (MO). The present study shows that a population of neurons located within the thalamic VMl nucleus, carries nociceptive somatosensory signals from the entire body. All these neurons responded to noxious cutaneous and intramuscular stimuli but not to levels of distension that could be considered innocuous or noxious, of the intact and inflammed colon and rectum. Although colorectal distension did not elicit VMl responses, convergence of visceral as well as muscle and cutaneous nociceptors was demonstrated by the increases in ongoing (background) discharges following intracolonic MO. A distinct effect is seen after MO injection into the lumen of the colon: an increase in ongoing activity for 15min but still a lack of effect of colorectal distension. Moreover, following inflammation induced by subcutaneous injections of MO VMl neurons developed responses to both thermal and mechanical innocuous skin stimulation, reminiscent of allodynia phenomena. It is suggested that the VMl contributes to attentional aspects of nociceptive processing and/or to the integration of widespread noxious events in terms of the appropriate potential motor responses.
Asunto(s)
Vías Aferentes/fisiología , Músculos/fisiología , Neuronas/fisiología , Piel , Núcleos Talámicos Ventrales/fisiología , Vísceras/fisiología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Vías de Administración de Medicamentos/veterinaria , Estimulación Eléctrica , Masculino , Morfina/farmacología , Músculos/inervación , Planta de la Mostaza , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Narcóticos/farmacología , Dolor/fisiopatología , Estimulación Física , Extractos Vegetales/farmacología , Aceites de Plantas , Ratas , Ratas Sprague-Dawley , Piel/inervación , Estimulación Química , Núcleos Talámicos Ventrales/anatomía & histología , Núcleos Talámicos Ventrales/efectos de los fármacos , Vísceras/inervaciónRESUMEN
The lateral part of the ventromedial thalamus (VM l) relays nociceptive inputs from the whole body surface to the dorsolateral frontal cortex. The aim of the present study was to investigate the effects of systemic morphine on nociceptive activity evoked in VM l neurones either by thermal (48 degrees C) or by supramaximal percutaneous electrical stimuli. The noxious thermal evoked responses were depressed by 10.8 +/- 10.1%, 48.3 +/- 23.0% and 67.3 +/- 10.1%, 5 min after i.v. injections of 1.0, 1.73 and 3.0 mg/kg of morphine, respectively. Moreover, strong depressive effects on the Adelta- and C-fibre responses were already present 5 min after the injection. The responses were significantly reduced by 7.2 +/- 5.9%, 32.5 +/ 11.1% and 37.2 +/- 11.8% for Adelta fibres after i.v. injections of 1.0, 1.73 and 3.0 mg/kg of morphine, respectively. The corresponding values for C-fibre evoked responses were 16.3 +/- 16.2%, 57.0 +/- 12.0% and 69.0 +/- 8.2%. The dose of morphine that reduced VM l neuronal nociceptive responses by 50% (1.73 mg/kg) was around 3.5 times lower than that necessary to inhibit the responses of its spinal or medullary relays under similar experimental conditions. These results, added to the data of the literature, suggest that supraspinal effects of morphine are primarily mediated at the thalamic level. It is tempting to speculate that morphine-induced reductions of attentional or psychomotor responses related to pain may be mediated by its action on VM l.