Neuromedin U receptor 2 does not play a role in the development of neuropathic pain following nerve injury in mice.

BACKGROUND: Previous studies have identified neuromedin U receptor 2 (NMUR2) as the subtype mediating the effects of neuromedin U on acute chemo-nociception induced by capsaicin or formalin injection. The aims of this study were to determine whether NMUR2 is required for the development of mechanical hypersensitivity after nerve injury or heat hypersensitivity after inflammation and whether there is a gender difference in the contribution of NMUR2 to nociception. METHODS: Mechanical sensitivity was assessed with von Frey filaments in wild type (WT) and NMUR2-null mice at baseline and following spared tibial nerve (STN) injury. Heat sensitivity was also assessed at baseline and after induction of inflammation with Freund's complete adjuvant (FCA). RESULTS: The response to von Frey filaments at baseline was similar for WT and NMUR2-null mice and for males and females. The response of male NMUR2-null mice was slightly but significantly decreased when exposed to 52 °C but not 58 °C heat stimuli. There was no difference between the stimulus-response curve for WT and NMUR2-null mice 7, 13 and 16 days after nerve injury. Similarly, after FCA-induced inflammation, there was no significant difference in heat hyperalgesia between WT and NMUR2-null mice or male or female mice in responses to temperatures ranging from 44 to 48 °C. CONCLUSIONS: The present data do not support a significant contribution of NMUR2 to the development of hypersensitivity after nerve injury or tissue inflammation, suggesting that pharmacological intervention aimed at the NMUR2 receptor might not be a valuable approach for the treatment of chronic pain.

Cólico renal: bases fisiopatológicas del dolor de origen ureteral

La sensación que se experimenta como consecuencia del cólico renal es uno de los ejemplos de dolor de origen visceral más intenso que se manifiesta mediante episodios de dolor espontáneo y el desarrollo de hiperalgesia referida (incremento en la sensibilidad). Esta revisión, basada en nuestros estudios en animales in vivo, tiene como objeto describir los mecanismos neurofisiológicos del procesamiento central de la información ureteral cuya consecuencia última será la evocación de dolor ureteral. También hemos examinado los cambios que el uréter y el sistema nervioso central experimentan en presencia de cálculos. Existen cambios respecto que el uréter y el sistema nervioso central experimentan en presencia de cálculos. Existen cambios respecto al peristaltismo y a la sensibilización (aumento de la respuesta) tanto en neuronas periféricas como centrales, responsables de procesar la información del uréter. Estos cambio probablemente constituyen el fundamento fisiopatológico del dolor en el cólico renal (AU)

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.

Analgesic activity of a novel use-dependent sodium channel blocker, crobenetine, in mono-arthritic rats.

1. Although sodium channel blockers are effective analgesics in neuropathic pain, their effectiveness in inflammatory pain has been little studied. Sodium channels are substantially up-regulated in inflamed tissue, which suggests they play a role in maintenance of chronic inflammatory pain. We have examined the effects of sodium channel blockers on mobility, joint hyperalgesia and inflammation induced by complete Freund's adjuvant injected in one ankle joint of adult rats. The clinically effective sodium channel blocker, mexiletine, was compared with crobenetine (BIII 890 CL), a new, highly use-dependent sodium channel blocker. 2. Rats were treated for 5 days, starting on the day of induction of arthritis and were tested daily for joint hyperalgesia, hind limb posture and mobility. At post-mortem, joint stiffness and oedema were assessed. Dose response curves were constructed for each test compound (3 - 30 mg kg day(-1)). Control groups were treated with vehicle or with the non-steroidal anti-inflammatory drug, meloxicam (4 mg kg day(-1) i.p.). 3. Both sodium channel blockers produced dose dependent and significant reversal of mechanical joint hyperalgesia and impaired mobility with an ID50 of 15.5+/-1.1 mg kg day(-1) for crobenetine and 18.1+/-1.2 mg kg day(-1) for mexiletine. Neither compound affected the responses of the contralateral non-inflamed joint, nor had any effect on swelling and stiffness of the inflamed joint. 4. We conclude that sodium channel blockers are analgesic and anti-hyperalgesic in this model of arthritis. These data suggest that up regulation of sodium channel expression in primary afferent neurones may play an important role in the pain and hyperalgesia induced by joint inflammation.

Enhancing teacher health literacy in school health promotion: a vision for the new millennium.

While the National Health Education Standards focused interest and attention on student (consumer) health literacy, equal attention should be given to teacher (provider) health literacy. Teacher health literacy may be defined as "the capacity of teachers to obtain, interpret, and understand basic health information and services, with the competence to use such information and services in ways that enhance the learning of health concepts and skills by school students." This paper reviews a traditional model for school health teacher preparation, then presents an alternative, university field-tested model for enhancing health literacy in teacher education. This new model presents an innovative instructional paradigm, the Child and Adolescent Health (CAH) Logic Framework. This training model (vision) illustrates and emphasizes the link between child and adolescent health research and theory, CAH information, and application to health education, public policy, medical care, and health advocacy.

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.

Responses of rat spinal neurons to distension of inflamed colon: role of tachykinin NK2 receptors.

Tachykinin NK2 receptors are implicated in nociception and the control of intestinal motility. Here we examined their involvement in responses of spinal lumbosacral neurons with colon input to distension of normal or inflamed colon in anesthetized rats. The responses of single neurons to colorectal distension (5-80 mmHg), to electrical stimulation of the pelvic nerve (bypassing sensory receptors) and to somatic stimulation were characterized. The effect of cumulative doses of an NK2 receptor antagonist, MEN 11420 (10-1000 microg kg(-1) IV), on responses to these stimuli was tested in control conditions (n=6), or 45 min after intracolonic instillation of acetic acid (n=6). After colonic inflammation, neuronal responses to colorectal distension and pelvic nerve stimulation were significantly greater. MEN 11420 dose-dependently inhibited the enhanced responses to colorectal distension after inflammation (ID50=402+/-14 microg kg(-1)), but had no significant effect on responses to pelvic nerve stimulation or distension of the normal colon, suggesting a peripheral action selective for the inflamed colon. We conclude that MEN 11420 possesses peripheral anti-hyperalgesic effects on neuronal responses to colorectal distension. These results provide a neurophysiological basis for a possible use of tachykinin NK2 receptor antagonists in treating abdominal pain in irritable bowel syndrome patients.

Role of central and peripheral tachykinin NK1 receptors in capsaicin-induced pain and hyperalgesia in mice.

Substance P and its receptor (NK1) are thought to play an important role in pain and hyperalgesia. Here we have further examined this role by comparing the behavioural responses to intradermal capsaicin of mutant mice with a disruption of the NK1 receptor (NK1 KO) and wild-type (WT) mice. We have also evaluated the contribution of peripheral NK1 receptors to capsaicin-evoked behaviour by selective blockade of peripheral NK1 receptors in WT mice using a non-brain penetrant NK1 receptor antagonist. Injection of 6 microg capsaicin into the heel evoked paw licking with the same latency in WT and KO mice, but a significantly longer duration in WT mice. A higher dose (30 microg) evoked a similar duration of licking in both groups. There were no differences in mechanical sensitivity tested with von Frey hairs between WT and KO mice before capsaicin. Both capsaicin doses resulted in pronounced increases in responses to von Frey hairs (hyperalgesia) and novel responses to cotton wisps (allodynia) applied to the digits of the injected paw in WT mice, but no significant changes from baseline in KO mice. Selective blockade of peripheral NK1 receptors in WT mice resulted in a complete inhibition of capsaicin-evoked plasma extravasation, but the mechanical hyperalgesia induced by 30 microg capsaicin intraplantar was still significantly greater than that seen in KO mice. We conclude that the response to intradermal capsaicin is still present but abbreviated in mice lacking NK1 receptors, such that secondary hyperalgesia is not observed even after a high dose. Further, the lack of secondary hyperalgesia in NK1 KO mice is largely due to the loss of central rather than peripheral NK1 receptors. The phenotype of the NK1 KO mice is consistent with a loss of function of mechanically-insensitive nociceptors, and thus we propose that substance P may be expressed by this group of primary sensory neurones and required for their function.

Deficits in visceral pain and hyperalgesia of mice with a disruption of the tachykinin NK1 receptor gene.

Studies in mice lacking genes encoding for substance P or its receptor (NK1), or with NK1 antagonists, have shown that this system contributes to nociception, but the data are complex. Here, we have further examined the role of NK1 receptors in pain and hyperalgesia by comparing nociceptive responses to mechanical and chemical stimulation of viscera and the resulting hyperalgesia and inflammation in NK1 knockout (-/-) and wild-type (+/+) mice. We concentrated on visceral nociception because substance P is expressed by a much greater proportion of visceral than cutaneous afferents. NK1 -/- mice showed normal responses to visceral mechanical stimuli, measured as behavioural responses to intraperitoneal acetylcholine or hypertonic saline or reflex responses to colon distension in anaesthetized mice, although -/- mice failed to encode the intensity of noxious colon distensions. In contrast, NK1 -/- mice showed profound deficits in spontaneous behavioural reactions to an acute visceral chemical stimulus (intracolonic capsaicin) and failed to develop referred hyperalgesia or tissue oedema. However, in an identical procedure, intracolonic mustard oil evoked normal spontaneous behaviour, referred hyperalgesia and oedema in -/- mice. The inflammatory effects of capsaicin were abolished by denervation of the extrinsic innervation of the colon in rats, whereas those of mustard oil were unchanged, showing that intracolonic capsaicin evokes neurogenic inflammation, but mustard oil does not. Tests of other neurogenic inflammatory stimuli in NK1 -/- mice revealed impaired behavioural responses to cyclophosphamide cystitis and no acute reflex responses or primary hyperalgesia to intracolonic acetic acid. We conclude that NK1 receptors have an essential role mediating central nociceptive and peripheral inflammatory responses to noxious stimuli that evoke neurogenic inflammation, and modulating responses to noxious mechanical stimuli. We propose that two separate hyperalgesia pathways exist, one of which is NK1 receptor dependent, whereas the other does not require intact substance P/NK1 signalling.

Efectos diferenciales del bloqueo de los receptores de N-metil-D-aspartato en los reflejos nociceptivos somáticos y viscerales / Differential effects of Nmethyl-D-aspartate receptor blockade on nociceptive somatic and visceral reflexes

Los receptores de N-metil-D-aspartato (NMDA) parecen desempeñar una función poco importante en las respuestas nociceptivas provocadas por la estimulación aguda de tejidos somáticos normales, interviniendo, eso sí, en las respuestas hiperalgésicas que aparecen después de una lesión periférica o inflamación. Estudios anteriores de este laboratorio han demostrado la existencia de diferencias importantes en la organización neural de las rutas nociceptivas somáticas y viscerales. En este caso, hemos explorado la función de los re c e p t o res de NMDA en el procesamiento de los estímulos dolorosos viscerales frente a los estímulos dolorosos somáticos. Canulamos cerca de la vejiga el uréter izquierdo de ratas Wistar hembras adultas anestesiadas con fentobarbitona (50 mg.kg- 1 i.p.) La distensión gradual del uréter (30 s, 25-80 mmHg) provocó un aumento de la presión arterial. Esa respuesta fue inhibida de una form a dependiente de la dosis por quetamina y memantina, dos sustancias que bloquean los canales de iones de los receptores de NMDA (DI5 0 = 2,4 ñ 1,6 y 14,5 ñ 1,3 mg.kg- 1, i.v.), así como por Mrz 2/576, un antagonista del sitio de la glicina de Merz (DI5 0 = 0,2 ñ 0,2 mg.kg- 1). Los estímulos graduales provocados por un pellizco (30s, 2-4 N) en la pata trasera provocaron una respuesta similar de la presión, si bien dicha respuesta no se vio afectada por la quetamina (hasta 10 mg.kg- 1). Tampoco Mrz 2/576 influyó en la re spuesta a los pellizcos dolorosos, mientras que la memantina (DI5 0 = 17 ñ 12 mg.kg- 1) sí inhibió la respuesta a ese tipo de estímulo. Sin embargo, en el rango de dosis utilizado, ni la quetamina ni Mrz 2/576 inhibieron la re spuesta de la presión a un estímulo de origen no nociceptivo (oclusión carótida bilateral), mientras que la memantina sí la inhibió. Por tanto, los efectos de la memantina se deban probablemente a una acción cardiovascular inespecífica. Estos resultados demuestran que los antagonistas de los receptores de NMDA inhiben los reflejos nociceptivos provocados en el uréter normal, y sugieren que los receptore s de NMDA están implicados en el procesamiento de los estímulos nociceptivos agudos en las vísceras. Hemos concluido que la estimulación aguda del tejido visceral normal provoca intensas respuestas por activación de mecanismos neurales mediados por los re c e p t o res de NMDA. No obstante, en las rutas somáticas estos mecanismos se activan sólo ante un estímulo periférico de mayor intensidad, como el producido por una lesión o inflamación. 1999 Asociación Internacional para el Estudio del Dolor (AU)

Responses of rat spinal neurones to natural and electrical stimulation of colonic afferents: effect of inflammation.

Single unit electrical activity has been recorded from 107 neurones excited by electrical stimulation of the pelvic nerve in or around lamina X of the L6-S1 spinal cord in anaesthetised rats. Responses to colorectal distension (CRD; 30 s, 5-80 mmHg) and to somatic electrical and mechanical stimulation were characterised. Of 107 neurones excited by pelvic nerve stimulation, 58 (54%) were affected by CRD: 46 neurones were excited (39 with a sustained response and 7 with an on-off response) and 12 neurones were inhibited. The vast majority of the neurones affected by CRD (54/58) had nociceptive somatic receptive fields. Neurones excited by CRD showed graded stimulus response functions in the noxious range (20-80 mmHg), except for two neurones which only encoded stimulus intensity below 20 mmHg. Neurones inhibited by CRD had significantly larger somatic receptive fields, and more superficial recording sites than those excited by CRD. A group of 12 neurones with sustained excitatory responses to CRD were characterised before and 45 min after intracolonic instillation of 1 ml 0.6% acetic acid. Colon inflammation provoked a significant increase in responses to CRD and to pelvic nerve stimulation (n=12), but no significant change in responses to pinch of their somatic receptive field (n=10). We conclude that of these neurones, the population with excitatory sustained responses to CRD are those likely responsible for processing information leading to acute pain sensations from the colon, and also show central sensitisation after colon inflammation, suggesting they play an important role in development of colonic hyperalgesia.

Allodynia and hyperalgesia evoked by sciatic mononeuropathy in NKI receptor knockout mice.

We have examined the participation of NK1 receptors in neuropathic pain by comparing behavioural responses after partial sciatic nerve ligation in wild-type (WT) and NK1 receptor knockout (KO) mice. Mechanical responses were tested with von Frey hairs, and cooling responses with acetone. WT and KO mice showed similar reactions before surgery. Nerve-ligated WT and KO mice showed equivalent spontaneous pain-related behaviour. Mechanical (mean threshold 20 +/- vs 9 +/- 1 mN) and cold allodynia (61 +/- vs 14 +/- 2 behaviours evoked by acetone) were significantly greater than in sham animals, but similar in WT and KO mice. We conclude that NK1 receptors are not essential for mechanical and cold allodynia evoked by partial nerve ligation.

Wind-up of spinal cord neurones and pain sensation: much ado about something?

Wind-up is a frequency-dependent increase in the excitability of spinal cord neurones, evoked by electrical stimulation of afferent C-fibres. Although it has been studied over the past thirty years, there are still uncertainties about its physiological meaning. Glutamate (NMDA) and tachykinin NK1 receptors are required to generate wind-up and therefore a positive modulation between these two receptor types has been suggested by some authors. However, most drugs capable of reducing the excitability of spinal cord neurones, including opioids and NSAIDs, can also reduce or even abolish wind-up. Thus, other theories involving synaptic efficacy, potassium channels, calcium channels, etc. have also been proposed for the generation of this phenomenon. Whatever the mechanisms involved in its generation, wind-up has been interpreted as a system for the amplification in the spinal cord of the nociceptive message that arrives from peripheral nociceptors connected to C-fibres. This probably reflects the physiological system activated in the spinal cord after an intense or persistent barrage of afferent nociceptive impulses. On the other hand, wind-up, central sensitisation and hyperalgesia are not the same phenomena, although they may share common properties. Wind-up can be an important tool to study the processing of nociceptive information in the spinal cord, and the central effects of drugs that modulate the nociceptive system. This paper reviews the physiological and pharmacological data on wind-up of spinal cord neurones, and the perceptual correlates of wind-up in human subjects, in the context of its possible relation to the triggering of hyperalgesic states, and also the multiple factors which contribute to the generation of wind-up.

Time-course of spinal sensitization following carrageenan-induced inflammation in the young rat: a comparative electrophysiological and behavioural study in vitro and in vivo.

Inflammation of peripheral tissues evokes spontaneous pain and an increased responsiveness to external stimuli known as hyperalgesia, produced by both peripheral and central changes. The central component is initiated by a sustained afferent barrage produced by sensitized peripheral nociceptors, but it is unclear to which extent ongoing nociceptive input is required to maintain these central changes. Here, we have used an isolated preparation of the spinal cord in vitro obtained from eight- to 12-day-old rats to examine spinal plasticity in the absence of naturally occurring afferent inputs. Spinal reflex responses in preparations obtained from naive rats were compared with those from animals with carrageenan-induced inflammation of one hindpaw of 3 h, 6 h and 20 h duration prior to the extraction of the cord. Measurements of thermal (heat) and mechanical hyperalgesia in awake animals were also made at the same time-points. At 6 h post-carrageenan, there was a significant increase in the wind-up evoked by trains of high-intensity (C-fibre) stimuli, and at 20 h increased responses to both trains and single high-intensity stimuli, and a novel wind-up to low-intensity (Abeta-fibre) trains were observed. In contrast, maximal behavioural hyperalgesia was observed by 3 h post-carrageenan, and thermal hyperalgesia had resolved by 20 h, although mechanical hyperalgesia remained. These results show that the induction of spinal plasticity independent of peripheral input is a progressive process with a slow time-course, since significant hyperreflexia in the isolated spinal preparation appears 6 h after inflammation and develops further within 20 h. We conclude that during the first 3 h following inflammation, hyperalgesia is the result of peripheral sensitization and of central mechanisms that depend on an ongoing peripheral input and thus changes were not observed in the isolated spinal cord.

Visceral pain.

Visceral pain is the most common form of pain produced by disease and one of the most frequent reasons why patients seek medical attention. Yet much of what we know about the mechanisms of pain derives from experimental studies of somatic not visceral nociception. The conventional view is that visceral pain is simply a variant of somatic pain, a view based on the belief that a single neurological mechanism is responsible for all pain. However, the more we learn about the mechanisms of somatic and visceral pain, the more we realise that although these two processes have much in common, they also have important differences. Although visceral pain is an important part of the normal sensory repertoire of all human beings and a prominent symptom of many clinical conditions, not much clinical research has been done in this field and there are few clinical scientists with expertise in the management of visceral pain. Instead, visceral pain is usually treated by a range of specialists who take quite different approaches to the management of this type of pain. Thus, the management of visceral pain is frequently unsatisfactory. In this review, we consider visceral pain as a separate form of pain and examine its distinct sensory properties from a clinical perspective. We describe recent research findings that may change the way we think about visceral pain and, more importantly, may help develop new procedures for its management.

Antinociceptive activity of metamizol in rats with experimental ureteric calculosis: central and peripheral components.

OBJECTIVE AND DESIGN: To study the antinociceptive effects of metamizol in a rat model of ureteric calculosis. SUBJECTS: Adult female Wistar rats (n = 40). TREATMENT: Metamizol was given i.p. 50-100 mg/kg, 3 times daily for 4 days for behavioural testing, and 25-100 mg/kg i.v. whilst recording peristalsis or dorsal horn neurons. METHODS: An artificial stone was induced in one ureter. In 3 separate groups of stone-implanted rats, behaviour was recorded continuously on video tape, ureteric peristalsis or the electrical activity of single nociceptive dorsal horn neurons with ureteric input was recorded under anaesthesia. Data were compared with analysis of variance. RESULTS: Metamizol inhibited the behavioural visceral crises, the abnormal ureteric peristalsis and the activity of nociceptive dorsal horn neurons. CONCLUSIONS: Metamizol has central antinociceptive effects on the pain produced by a ureteric stone, and an additional spasmolytic effect on the hyperperistalsis produced by the stone.

GABAA receptor blockade inhibits A beta fibre evoked wind-up in the arthritic rat.

To clarify the mechanisms of allodynia we have examined whether 'wind-up' of nociceptive withdrawal reflexes (NWR), a phenomenon characteristic of nociceptive C fiber spinal processing, can be mimicked by stimulation of tactile A beta fibers in monoarthritic decerebrate spinal rats. Knee joint monoarthritis was induced by carrageenan/kaolin under halothane anaesthesia 5 h before recordings. In arthritic, but not in control rats, wind-up of NWR of the semitendinosus muscle could be evoked by repeated stimulation of A beta fibres. By contrast, peroneus longus reflexes did not exhibit marked wind-up. Bicuculline (0.03-0.3 mg/kg, i.v.) dose-dependently inhibited this wind-up. Hence, reflex wind-up can be elicited by tactile A beta fibers in arthritis rats through a GABAA dependent mechanism.

Spinal mechanisms underlying persistent pain and referred hyperalgesia in rats with an experimental ureteric stone.

Spinal neurons processing information from the ureter have been characterized in rats 1-4 days after the implantation of an experimental ureteric stone and compared with those of normal rats. The effects of a conditioning noxious stimulation of the ureter in the presence of the hyperalgesia evoked by the calculosis also were examined. Extracellular recordings were performed at the T12-L1 segments of the spinal cord. In rats with calculosis, more neurons expressed a ureter input (53 vs. 42% in normal rats); such cells being more likely to show background activity, at a higher rate than normals (6.6 +/- 1.2 vs. 3.2 +/- 0.9 spikes/s; mean +/- SE) and increasing with the continuing presence of the stone. The threshold pressure for a ureteric response was higher than in normal rats (79 +/- 5 vs. 54 +/- 4 mmHg) but the neurons failed to encode increasing intensities of stimulation. Thirty-five percent of the neurons with exclusively innocuous somatic receptive fields had a ureter input in rats with calculosis, whereas none were seen in normal rats. A noxious ureteric distention applied to neurons with ureter input evoked a complex mixture of increases and decreases in somatic receptive field size and/or somatic input properties markedly different from the generalized increases in excitability seen when such a stimulus was applied to normal animals. We conclude that the presence of a ureteric stone evokes excitability changes of spinal neurons (enhanced background activity, greater number of ureter-driven cells, decreased threshold of convergent somatic receptive fields), which likely account for the referred hyperalgesia seen in rats with calculosis. However, further noxious visceral input occurring in the presence of persistent hyperalgesia produces selective changes that cannot be explained by a generalized excitability increase and suggest that the mechanisms underlying maintenance of hyperalgesia include alteration of both central inhibitory and excitatory systems.

Altered nociception, analgesia and aggression in mice lacking the receptor for substance P.

The peptide neurotransmitter substance P modulates sensitivity to pain by activating the neurokinin-1 (NK-1) receptor, which is expressed by discrete populations of neurons throughout the central nervous system. Substance P is synthesized by small-diameter sensory 'pain' fibres, and release of the peptide into the dorsal horn of the spinal cord following intense peripheral stimulation promotes central hyperexcitability and increased sensitivity to pain. However, despite the availability of specific NK-1 antagonists, the function of substance P in the perception of pain remains unclear. Here we investigate the effect of disrupting the gene encoding the NK-1 receptor in mice. We found that the mutant mice were healthy and fertile, but the characteristic amplification ('wind up') and intensity coding of nociceptive reflexes was absent. Although substance P did not mediate the signalling of acute pain or hyperalgesia, it was essential for the full development of stress-induced analgesia and for an aggressive response to territorial challenge, demonstrating that the peptide plays an unexpected role in the adaptive response to stress.