Stimulation in the rat fastigial nucleus enhances the responses of neurons in the dorsal column nuclei to innocuous stimuli.

The cerebellum was recently proposed to play a role in cognition and sensation in addition to motor phenomena. We have shown that the cerebellum is involved in the processing of sensory nociceptive information. In this study, the activity of neurons in the dorsal column nuclei (DCN) was tested following stimulation in the rat fastigial nucleus. The results showed an enhancement of the extracellularly recorded responses of DCN neurons to somatic non-noxious stimuli following injection of D,L-homocysteic acid (0.1 M, 1 microl) into the area of the fastigial nucleus. We conclude that the cerebellum influences the processing of non-noxious somatosensory information at the level of the DCN, an important relay and a center for the processing of fine tactile and vibratory information. This observation is not yet supported by clinical data.

Un nuevo modelo de dolor visceral e hiperalgesia referida en el ratón / A new model of visceral pain and referred hyperalgesia in the mouse

La obtención de ratones transgénicos que carecen o expresan en exceso genes relacionados con el dolor se está haciendo cada vez más frecuente. Ahora bien, en los ratones suele utilizarse un único modelo de dolor visceral, la prueba de retorcimiento. Aquí describimos un nuevo modelo, la estimulación química del colon, que hemos desarrollado en el ratón. Ratones de ambos sexos recibieron una inyección intravenosa de 30mg.kg- 1 de Azul de Evans para la posterior determinación de la extravasación plasmática. Para las pruebas de conducta, los ratones se colocaron sobre una rejilla elevada y se les administró 50 µl de suero fisiológico, aceite de mostaza (0,25-2,5 por ciento) o capsaicina (0,03-0,3 por ciento), introduciendo para ello una fina cánula en el colon a través del ano. Las conductas relacionadas con el dolor visceral (lamerse el abdomen, estirarse, contraer el abdomen, etc.) se contabilizaron durante 20 minutos. Antes de la administración intracolónica y 20 minutos después, se determinó la frecuencia de respuestas de retraimiento a la aplicación de filamentos de von Frey al abdomen. El colon se extirpó tras sacrificar a los animales y se midió el contenido de Azul de Evans. La administración de aceite de mostaza y capsaicina provocó conductas de dolor visceral proporcionales a la dosis, hiperalgesia referida (aumento significativo de las respuestas a los filamentos de von Frey) y extravasación plasmática en el colon. Las respuestas máximas de conducta se obtuvieron con capsaicina al 0,1 por ciento y aceite de mostaza al 1 por ciento, respectivamente. Las respuestas de conductas relacionadas con el dolor re mitieron de una manera proporcional a la dosis con morfina (DE50 = 1,9 ñ 1 mg.kg- 1 por vía subcutánea). Nuestra conclusión es que este modelo representa una herramienta útil tanto para establecer el fenotipo de ratones mutantes como para modelos de farmacología clásica, puesto que en el mismo animal puede obtenerse información sobre dolor visceral, hiperalgesia referida e inflamación del colon. (AU)

Vasodilatation in hyperalgesic rat skin evoked by stimulation of afferent A beta-fibers: further evidence for a role of dorsal root reflexes in allodynia.

In areas of secondary hyperalgesia, innocuous mechanical stimuli evoke pain (allodynia). We have proposed that this is produced by a central pre-synaptic interaction whereby A beta-fibers evoke spike activity (dorsal root reflexes) in nociceptive afferents (Pain, 68 (1996) 13). This activity should conduct centrally, evoking allodynia, and peripherally, evoking neurogenic vasodilatation. Here we tested this hypothesis by examining the effects of electrical stimulation of A beta-fibers on cutaneous blood flow before and after producing secondary hyperalgesia in anesthetized rats. Cutaneous blood flow was recorded in the hind paw skin innervated by the sural nerve using a laser Doppler flowmeter. The sural nerve was prepared for electrical stimulation, and the evoked activity was recorded from the sciatic nerve in continuity. Electrical stimulation (1 Hz, 4 x 0.2 ms pulses, 20 s) was applied to the sural nerve at 2T (A beta-fibers only) and 4T and 6T (A beta + A delta-fibers). Flux was recorded at baseline and after capsaicin or mustard oil application outside the sural nerve territory. The effects of intravenous administration of the calcitonin gene-related peptide (CGRP) receptor antagonist, alpha-CGRP(8-37), or of section of the sciatic nerve or of the L4-L6 dorsal roots were examined. Selective activation of the sural nerve A beta-fibers reliably evoked increases in cutaneous blood flow close to areas of chemical irritation or skin damage. A beta-fiber-evoked vasodilatation was abolished by sciatic nerve or dorsal root section and had a spatial arrangement and optimal stimulation pattern suggesting a central synaptic interaction similar to that responsible for dorsal root reflexes. The flux increases were dose-dependently and reversibly inhibited by alpha-CGRP(8-37), indicating that the A beta-fiber-evoked vasodilatation resulted from the antidromic activation of nociceptive cutaneous afferent fibers. These results support our hypothesis by showing activation of nociceptive primary afferents by A beta-fibers in areas of allodynia in a manner consistent with a pre-synaptic interaction evoking dorsal root reflexes.

A new model of visceral pain and referred hyperalgesia in the mouse.

The generation of transgenic mice that lack or overexpress genes relevant to pain is becoming increasing common. However, only one visceral pain model, the writhing test, is widely used in mice. Here we describe a novel model, chemical stimulation of the colon, which we have developed in mice. Mice of either sex were injected i.v. with 30 mg/kg Evan's Blue for subsequent determination of plasma extravasation. For behavioural testing, they were placed on a raised grid and 50 microl of saline, mustard oil (0.25-2.5%) or capsaicin (0.03-0.3%) was administered by inserting a fine cannula into the colon via the anus. Visceral pain-related behaviours (licking abdomen, stretching, contractions of abdomen etc) were counted for 20 min. Before intracolonic administration, and 20 min after, the frequency of withdrawal responses to the application of von Frey probes to the abdomen was tested. The colon was removed post-mortem and the Evan's Blue content measured. Mustard oil and capsaicin administration evoked dose-dependent visceral pain behaviours, referred hyperalgesia (significant increase in responses to von Frey hairs) and colon plasma extravasation. The peak behavioural responses were evoked by 0.1% capsaicin and by 1% mustard oil respectively. The nociceptive behavioural responses were dose-dependently reversed by morphine (ED50 = 1.9 +/- 1 mg/kg s.c.). We conclude that this model represents a useful tool both for phenotyping mutant mice and for classical pharmacology since information on visceral pain, referred hyperalgesia and colon inflammation can all obtained from the same animal.