RESUMEN
Cannabinoids have been shown to modulate central autonomic regulation and baroreflex control of blood pressure. Both CB1 and CB2 cannabinoid receptors have been described in the nucleus tractus solitarius (NTS), which receives direct afferent projections of cardiovascular reflexes. In the present study we evaluated the effects of WIN 55212-2 (WIN), a cannabinoid agonist, on fast neurotransmission in the NTS. We recorded spontaneous post-synaptic currents using the whole-cell configuration in NTS cells in brainstem slices from young rats (25-30 days old). Application of 5 microM WIN inhibited the frequency of both glutamatergic and GABAergic sPSCs, without affecting their amplitudes. Effects of WIN were not blocked by application of the CB1 antagonist AM251, the CB2 antagonist AM630 or the vanniloid receptor TRPV1 antagonist AMG9810, suggesting that the effect of WIN is via a non-CB1 non-CB2 receptor. Neither the CB1/CB2 agonist HU210 nor the CB1 agonist ACPA affected the frequency of sPSCs. We conclude WIN inhibits the neurotransmission in the NTS of young rats via a receptor distinct from CB1 or CB2.
Asunto(s)
Benzoxazinas/farmacología , Cannabinoides/farmacología , Morfolinas/farmacología , Naftalenos/farmacología , Inhibición Neural/efectos de los fármacos , Receptores de Cannabinoides/metabolismo , Núcleo Solitario/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Animales , Agonistas de Receptores de Cannabinoides , Antagonistas de Receptores de Cannabinoides , Moduladores de Receptores de Cannabinoides/farmacología , Ácido Glutámico/metabolismo , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Potenciales Postsinápticos Inhibidores/fisiología , Masculino , Inhibición Neural/fisiología , Técnicas de Cultivo de Órganos , Técnicas de Placa-Clamp , Ratas , Ratas Wistar , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/antagonistas & inhibidores , Receptor Cannabinoide CB2/metabolismo , Núcleo Solitario/metabolismo , Transmisión Sináptica/fisiología , Aferentes Viscerales/efectos de los fármacos , Aferentes Viscerales/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Hypertonic NaCl intake is produced by serotonin receptor antagonism in the lateral parabrachial nucleus (LPBN) of dehydrated rats or in rats pretreated with a mineralocorticoid, for example deoxycorticosterone (DOCA), that receive an intracerebroventricular injection (icv) of angiotensin II (ang II). The objective of the present work was to find out whether these two mechanisms are also involved with isotonic NaCl intake. Serotonin receptor blockade by methysergide in the LPBN (4 microg/0.2 microl bilaterally) had no effect on 0.15 M NaCl (methysergide: 19.3+/-5.2 ml/60 min; vehicle: 19.3+/-4.2 ml/60 min; n=7) or water (methysergide: 3.4+/-1.4 ml/60 min; vehicle 2.2+/-0.6 ml/60 min) intake induced by systemic diuretic furosemide combined with low dose of captopril (Furo/Cap). Methysergide treatment 4 days later in the same animals produced the expected enhancement in the 0.3 M NaCl intake induced by Furo/Cap (methysergide: 16.6+/-3.5 ml/60 min; vehicle: 6.6+/-1.5 ml/60 min). Similar result was obtained when another group was tested first with 0.3 M NaCl and later with 0.15 M NaCl. Isotonic NaCl intake induced by icv ang II was however enhanced by prior DOCA treatment. A de novo hypertonic NaCl intake was produced in another group by the same combined treatment. The results suggest that a facilitatory mechanism like the mineralocorticoid/ang II synergy may enhance NaCl solution intake at different levels of tonicity, while the action of an inhibitory mechanism, like the LPBN serotonergic system, is restricted to the ingestion at hypertonic levels.
Asunto(s)
Puente/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Cloruro de Sodio Dietético/metabolismo , Aferentes Viscerales/metabolismo , Equilibrio Hidroelectrolítico/fisiología , Angiotensina II/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Diuréticos/farmacología , Masculino , Metisergida/farmacología , Puente/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina/efectos de los fármacos , Solución Salina Hipertónica/metabolismo , Solución Salina Hipertónica/farmacología , Serotonina/metabolismo , Cloruro de Sodio Dietético/farmacología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Aferentes Viscerales/efectos de los fármacos , Equilibrio Hidroelectrolítico/efectos de los fármacosRESUMEN
In the present study we evaluated the possible modulatory role of noradrenaline on the neurotransmission of the peripheral chemoreflex afferents in the caudal commissural NTS of awake rats. To reach this goal we performed a dose-response curve to microinjection of increasing dose of noradrenaline into the caudal commissural NTS of awake rats and then the threshold dose, which produces minor changes in the baseline mean arterial pressure, was selected to be used in the chemoreflex experiment. The peripheral chemoreflex was activated with KCN before and after bilateral microinjections of noradrenaline (5 nMol/50 nL, threshold dose) into the NTS. The data show that microinjection of noradrenaline into the caudal NTS produced a significant reduction in the pressor response to the chemoreflex 30 s after the injection when compared to the control response (30+/-6 vs. 49+/-3 mm Hg) but no significant changes in the bradycardic response. The data indicate that noradrenaline in the caudal commissural NTS of awake rats may play an important inhibitory neuromodulatory role on the processing of the pressor/sympathoexcitatory component of the chemoreflex.
Asunto(s)
Presión Sanguínea/fisiología , Células Quimiorreceptoras/fisiología , Inhibición Neural/fisiología , Norepinefrina/metabolismo , Reflejo/fisiología , Núcleo Solitario/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Bradicardia/inducido químicamente , Fenómenos Fisiológicos Cardiovasculares/efectos de los fármacos , Células Quimiorreceptoras/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Masculino , Microinyecciones , Inhibición Neural/efectos de los fármacos , Norepinefrina/farmacología , Sistema Nervioso Parasimpático/efectos de los fármacos , Sistema Nervioso Parasimpático/fisiología , Cianuro de Potasio/farmacología , Ratas , Ratas Wistar , Reflejo/efectos de los fármacos , Núcleo Solitario/efectos de los fármacos , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiología , Vasoconstrictores/metabolismo , Vasoconstrictores/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , Aferentes Viscerales/efectos de los fármacos , Aferentes Viscerales/fisiología , Vigilia/fisiologíaRESUMEN
BACKGROUND & AIMS: Visceral hypersensitivity, a hallmark of irritable bowel syndrome, is generally considered to be mechanosensitive in nature and mediated via spinal afferents. Both stress and inflammation are implicated in visceral hypersensitivity, but the underlying molecular mechanisms of visceral hypersensitivity are unknown. METHODS: Mice were infected with Nippostrongylus brasiliensis (Nb) larvae, exposed to environmental stress and the following separate studies performed 3-4 weeks later. Mesenteric afferent nerve activity was recorded in response to either ramp balloon distention (60 mm Hg), or to an intraluminal perfusion of hydrochloric acid (50 mmol/L), or to octreotide administration (2 micromol/L). Intraperitoneal injection of cholera toxin B-488 identified neurons projecting to the abdominal viscera. Fluorescent neurons in dorsal root and nodose ganglia were isolated using laser-capture microdissection. RNA was hybridized to Affymetrix Mouse whole genome arrays for analysis to evaluate the effects of stress and infection. RESULTS: In mice previously infected with Nb, there was no change in intestinal afferent mechanosensitivity, but there was an increase in chemosensitive responses to intraluminal hydrochloric acid when compared with control animals. Gene expression profiles in vagal but not spinal visceral sensory neurons were significantly altered in stressed Nb-infected mice. Decreased afferent responses to somatostatin receptor 2 stimulation correlated with lower expression of vagal somatostatin receptor 2 in stressed Nb-infected mice, confirming a link between molecular data and functional sequelae. CONCLUSIONS: Alterations in the intestinal brain-gut axis, in chemosensitivity but not mechanosensitivity, and through vagal rather than spinal pathways, are implicated in stress-induced postinflammatory visceral hypersensitivity.