An outlook on the trigeminovascular mechanisms of action and side effects concerns of some potential neuropeptidergic antimigraine therapies.

Introduction: In addition to serotonin (5-hydroxytryptamine; 5-HT) and other (neuro)mediators, the role of neuropeptides in migraine pathophysiology is relevant. Indeed, while some molecules interfering with calcitonin gene-related peptide (CGRP) transmission have recently been approved for clinical antimigraine use, other neuropeptides with translational use are in the pipeline. Among others, hypothalamic neuropeptides such as pituitary adenylate cyclase-activating peptide (PACAP), oxytocin (OT), and orexins stand out as potential novel targets to treat this neurovascular disorder. Areas covered: Based on the aforementioned findings, the present review: (i) summarizes the current knowledge on the role of the above neuropeptides in the trigeminovascular system, and migraine pathophysiology; and (ii) discusses some issues related with the mechanisms of action and side effects concerns that could be elicited when targeting the CGRPergic, PACAPergic, oxytocinergic and orexinergic systems. Expert opinion: Specific antimigraine pharmacotherapies have evolved from the enhancement of serotonergic 5-HT1B/1D/1F transmission to the use of compounds interacting with neuropeptidergic systems. Canonically, neuropeptides cause an array of complex intracellular mechanisms that, after modifying neuronal and/or vascular transmission, result in antimigraine action and also potential side effects. Furthermore, due to the chemical nature of some molecules targeting the above neuropeptidergic transmission (e.g., monoclonal antibodies, peptides), there are some limiting pharmacokinetics issues.

Intrathecal Oxytocin Improves Spontaneous Behavior and Reduces Mechanical Hypersensitivity in a Rat Model of Postoperative Pain.

The first few days post-surgery, patients experience intense pain, hypersensitivity and consequently tend to have minor locomotor activity to avoid pain. Certainly, injury to peripheral tissues produces pain and increases sensitivity to painful (hyperalgesia) and non-painful (allodynia) stimuli. In this regard, preemptive pharmacological treatments to avoid or diminish pain after surgery are relevant. Recent data suggest that the neuropeptide oxytocin when given at spinal cord level could be a molecule with potential preemptive analgesic effects, but this hypothesis has not been properly tested. Using a validated postoperative pain model (i.e. plantar incision), we evaluated in male Wistar rats the potential preemptive antinociceptive effects of intrathecal oxytocin administration measuring tactile hypersensitivity (across 8 days) and spontaneous motor activity (across 3 days). Hypersensitivity was evaluated using von Frey filaments, whereas spontaneous activity (total distance, vertical activity episodes, and time spent in the center of the box) was assessed in real time using a semiautomated open-field system. Under these conditions, we found that animals pretreated with spinal oxytocin before plantar incision showed a diminution of hypersensitivity and an improvement of spontaneous behavior (particularly total distance and vertical activity episodes). This report provides a basis for addressing the therapeutic relevance of oxytocin as a potential preemptive analgesic molecule.

Effect of local infiltration with oxytocin on hemodynamic response to surgical incision and postoperative pain in patients having open laparoscopic surgery under general anesthesia.

BACKGROUND: Preemptive analgesia encompasses different perioperative interventions that have the final aim of decreasing postoperative pain and improving recovery. Recently, peripheral analgesic effects of oxytocinergic modulation have been suggested. In this regard, we tested the potential analgesic effects of subcutaneous oxytocin (OT) infiltration in patients submitted to laparoscopic cholecystectomy. METHODS: Thirty patients with similar general characteristics and medical physical conditions were evaluated. The patients were assigned by simple random selection to one of three groups: (a) OT group (n = 10), which received preincisional subcutaneous OT (4 µg/4 ml saline) in the surgical sites for trocar placements; (b) Lidocaine group (n = 10), which received subcutaneous lidocaine 1% (4 ml) in the surgical sites; and (c) Control group (n = 10), which did not receive any treatment. Then we measured the effect of those treatments on the hemodynamic variations produced as responses to the surgical incisions and trocar insertions (open port placements using the Hasson technique). Moreover, we assessed the intensity of postoperative pain with the visual analogue scale during recovery and 24 hr after surgery. RESULTS: Hemodynamic parameters were stable in both intervention groups (subcutaneous OT and lidocaine) during the surgical incisions and trocar placements, whereas a most likely sympathetic activation due to trocar insertions (open port placements) was not blunted in the placebo group. Furthermore, postoperative pain was diminished in both OT and lidocaine groups when compared to the control group. CONCLUSIONS: Preincisional subcutaneous OT administration reduced the hemodynamic response produced by the latter. Furthermore, OT also diminished postoperative pain.

Hypothalamic paraventricular nucleus stimulation enhances c-Fos expression in spinal and supraspinal structures related to pain modulation.

The hypothalamic paraventricular nuclei (PVN) inhibits spinal nociception. Furthermore, projections from the PVN to other structures related to pain modulation exist, but a functional interaction has not yet been fully demonstrated. As an initial approach, we show here that PVN electric stimulation with the same parameters used to induce analgesia in rats enhances c-Fos expression not only in the dorsal horn of the spinal cord but also in the nucleus raphe magnus, locus coeruleus and the periaqueductal gray area. These results suggest that a functional interaction between these structures could occur, possibly to assure a mechanism of endogenous analgesia.

The hormone prolactin is a novel, endogenous trophic factor able to regulate reactive glia and to limit retinal degeneration.

Retinal degeneration is characterized by the progressive destruction of retinal cells, causing the deterioration and eventual loss of vision. We explored whether the hormone prolactin provides trophic support to retinal cells, thus protecting the retina from degenerative pressure. Inducing hyperprolactinemia limited photoreceptor apoptosis, gliosis, and changes in neurotrophin expression, and it preserved the photoresponse in the phototoxicity model of retinal degeneration, in which continuous exposure of rats to bright light leads to retinal cell death and retinal dysfunction. In this model, the expression levels of prolactin receptors in the retina were upregulated. Moreover, retinas from prolactin receptor-deficient mice exhibited photoresponsive dysfunction and gliosis that correlated with decreased levels of retinal bFGF, GDNF, and BDNF. Collectively, these data unveiled prolactin as a retinal trophic factor that may regulate glial-neuronal cell interactions and is a potential therapeutic molecule against retinal degeneration.

Paraventricular hypothalamic regulation of trigeminovascular mechanisms involved in headaches.

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.

Los mecanismos neurofisiológicos del dolor / The neurophysiologic mechanisms of pain

Este trabajo sintetiza algunos de los datos que muestran el desarrollo de una línea de investigación sobre los correlatos entre la acitivdad eléctrica cerebral y la percepción de los estímulos algésicos. Los datos obtenidos, tanto en el hombre como en otras especies, sugieren un mecanismo selectivo en la supresión de las características desagradables del dolor, preservando sus propiedades de identificación y localización. Se describe el fenómeno de habituación al dolor en el hombre y los resultados de un mecanismo tálamo cortical que bloquea las respuestas a la estimulación nociceptiva. De esta forma se plantea una posible alternativa terapéutica en casos de dolor crónico

Cortical facilitatory action on centralis lateralis thalamic activity during the development of carrageenin-produced inflammation

In order to understand the neuronal mechanisms involved in acute and chronic pain, we studied the thalamic and cortical control action, which allows the suppression of the neuronal responses to noxious stimulation. As an experimental pain model we used carrageenin injected in the paw of male Wistar rats. The tonic facilitatory cortical control on centralis lateralis thalamic nuclei (CL) activity is described at different times after carrgeenin-produced inflammation. Simultaneous extracellular unit recordings were carried out at CL and medial prefrontal cortex (PCx) cells in anesthetized male Wistar rats. The PCx control was tested by blocking in a transient and reversible manner, using the cortical spreading depression (CSD). Carrageenin injection (1 percent; 0.2 ml) into the plantar surface of the right hind paw, and the influence of Lidocaine (2 percent; 0.2 ml) applied in the inflamed paw, was tested on unit activity in PCx and CL cells. Thalamic cells recorded in acute and subacute stages (24-72 h aftercarrageenin administration) were activated by tactile, light pressure and joint movement stimulation yielded before the injection. After carrageenin, the thalamic cells displayed spontaneous high frequency burst discharges, also presenting a progressive and significant increase (p < 0.001, ANOVA test) of their spontaneous firing when rate when compared with control cell activity. Lidocaine reduced the enhanced activity induced by carrageenin in thalamic neurones (p < 0.001, Student t test). In PCx neurones were also recorded in acute and subacute stages. Cortical cells from acute and subacute group were activated by nociceptive and non-nociceptives stimulation. In acute stage, cortical cells increased their firing rate after carrageenin and we could not observe modifications upon their firing rate due to Lidocaine. The CSD blocked all cortical activity in acute subacute stages. During the CSDs, overall thalamic activity was suppressed in neurones from acute (91 percent) and subacute (87 percent) stages. The blockage was observed when the propagated weve produced by CSD arrived into the medial prefrontal cortex. the CSD also suppressed the PCx and the CL noxious responses evoked by pressure in the receptive field. This study show the tonic facilitatory control of the PCx upon intralaminar thalamic noxious responses, during acute and subsacute stages of carrageenin produced inflammation. In the literature, it has been proposed that the CL thalamic...

El dolor y los mecanismos de analgesia / Pain and analgesic mechanisms

El Sistema Nervioso Central presenta una compleja especialización estructural y funcional. Entre sus propiedades funcionales destacan los sistemas sensoriales, el control motor, la regulación de la vida vegetativa, la emotividad y los procesos cognoscitivos. La integridad de estas funciones permite al organismo interaccionar con su ambiente, así, las funciones sensoriales tienen como finalidad el ponernos en contacto con el medio externo e interno. El dolor como un proceso sensorial, se integra en una serie de señales nerviosas, con importantes correlatos bio-eléctricos y bio-químicos, que nos advierten sobre un eventual o actual daño a los tejidos del cuerpo. Unas se encargan de captar los estímulos nocivos, otras acarrean las señales nerviosas a estructuras específicas, otras integran estas señales y producen una sensación consciente, otras más interconectan las señales nerviosas sensoriales con las estructuras encargadas de las respuestas motoras, y otras llevan a cabo una función reguladora de la sensación dolorosa, incluyendo a la analgesia. En este trabajo se señalan algunos aspectos generales y básicos de la actividad nerviosa y su relación con los procesos sensoriales, particularmente con el dolor. De esta forma pretendemos que el lector tenga una visión del funcionamientio de los sistemas sensoriales. Con este objetivo presentamos algunos resultados experimentales llevados a cabo pro nuestro grupo de investigación. En ellos se describen algunos correlatos electrofisiológicos implicados en la disminución de las respuestas al dolor de las alteraciones en el tamaño de los campos receptivos periféricos por la activación algógena

Los péptidos opioides en el control del dolor / Opioid peptides in pain control

Este tabajo presenta un descripción breve de las evidencias que señalan el papel de los péptidos opioides en el control del dolor. Se describe el papel inhibidor de la ß-endorfina y de la Met-encefalina en los tejidos periféricos y, se sugiere una acción local en el sitio de la inflamación. Asimismo, se hace referencia a los sistemas endógenos de inhibición del dolor tanto a los segmentarios inherentes a la organización celular de la médula espinal, como a los sistemas descendentes, que tienen su origen en diversos núcleos del tallo cerebral. Las conexiones eferentes de estos sistemas siguen el trayecto del fascículo dorsolateral para terminar en las astas dorsales de la médula espinal, en donde ejercen su acción. Con esta idea, se analiza la participación de la ß-endorfina y los péptidos derivados en la analgesia. También se discute el papel que desempeñan los receptores µ, delta y kappa en el control del dolor y los ligandos endógenos que se unen a estos receptores. Las evidencias sugieren que la analgesia opioide, es el resultado predominante de la activación de los receptores µ, aunque los delta y los kappa pueden potenciar este efecto. Con respecto a los receptores delta y sus ligandos con mayor afinidad, las encefalinas tienen una participación indirecta en la analgesia. En relación a los receptores kappa y sus ligando más afines, las dinorfinas, los datos publicados son controvertidos. Por último, se hace referencia a los efectos paradójicos de la naloxona en el control del dolor, pues a dosis altas, aumentan las respuestas algésicas (hiperalgesia) y las dosis muy bajas producen analgesia

Double cortical control acting upon activities of intralaminar thalamic cells

We report the effects exertec by the cortex upon the intralaminar thalamic nuclei, as revealed by blockade of the cortex with spreading depression in awake rats. Extracellular recordings of spontaneuous activity were made simultaneusly at thalamic and cortical sites. The effect of peripheral receptive field stimulation was to decrease activity of intralaminar thalamic cells. Cortical recordings revealed the cortical regions affected by spreading depression. Two type of cells were identified depending on the changes in their sensorial responses during the cortical spreading depression propagation. The first exhibited a tonic facilitating cortical control when the cortical spreading depression was located at a 8.0 to 10.0. The second type exhibited a disappearance of the sensorial responses when cortical spreadinf depression was a located at 4.0 to a 8.0 and also displayed the tonic facilitating control. This indicated that two different identifies cortical regions influenced the thalamic activity

Localization of the microelectrode tip combining a rapid procedure method and marking with pontamine sky blue

Uno de los aspectos más relevantes del registro de la actividad unitaria celular en mamíferos, es la localización precisa de los sitios registrados. El asignar a las neuronas o grupos neuronales una colección definida, muchas veces permite establecer la función que estas estructuras tienen en el SNC. Es por esto que hemos desarrollado un método para identificar las neuromas estudiadas, utilizando micropipetas de vidrio que contienen una solución de azul de pontamina al 4% ne KCL 1M. Al finalizar los registros de actividad neuronal unitaria se hace una inyección iontofeorética, se sacrifican los animales, se fijan y se corta el tejido en microtomo de congelación. Se aplica la técnica de procedimiento rápido para obtener una fotografía de la zona de interés. Este método es fácil y rapido de realizar, y tiene la ventaja de que los mismos cortes del tejido pueden ser usados para procedimientos histológicos posteriores

Relaciones tálamo corticales / Cortical thalamic relations

El objetivo de este trabajo es enfatizar algunas características de las relaciones tálamo-corticales. Una forma de estudiar estas relaciones es detallar su participación en los diferentes sistemas sensoriales, haciendo referencia a las regiones corticales que tienen una estrecha relación con los diferentes núcleos talámicos. Por ejemplo, para los sistemas visual, auditivo y somatosensitivo se señalan las regiones talámicas y corticales correspondientes. Asimismo, se describe un sistema talámico heterosensorial y las zonas corticales con las que se relaciona, ya que forman parte de los objetivos de estudio de nuestro laboratorio. Con la fianlidad de simplificar el tema, se describen algunas propiedades que comparten las estructuras talámicas, como es la citoarquitectura. El funcionamiento talámico se ilustra a partir de un circuito básico, deducido de los hallazgos anatómicos y electrofisiológicos. El estudio de este circuito pretende hacer evidentes las interconexiones que se suceden en el tálamo mismo, con la posibilidad de que a partir de éstas y las llevadas a cabo con la corteza cerebral, se establezca el sustrato anatómico responsable de la actividad rítmica, que puede ser registrada en algunos núcleos talámicos y en regiones corticales. La corteza cerebral se analiza desde el punto de vista anatómico, describiendo las capas que al constituyen y sus diferentes clasificaciones. De la misma forma que para los núcleos talámicos, se ejemplificará el funcionamiento cortical a partir de un circuito básico. Los resultados que ene este trabajo se resumen, particularmente los referentes a los circuito básicos, pretenden resaltar las características que dan origen a la actividad rítmica. Esta actividad rítmica puede ser registrada de manera espontánea y se puede producir tanto por la estimulación de la corteza cerebral como por la talámica. De la misma forma, la estimulación del núcleo caudado produce dicha activida, y a partir de las evidencias experimentales tiene el efecto de suprimir las respuestas sensoriales que se registran a nivel talámico