A role for extracellular signal-regulated kinases 1 and 2 in the maintenance of persistent mechanical hyperalgesia in ovariectomized mice.

Mitogen-activated protein kinases (MAPKs) are important signaling factors in many cellular processes including cell proliferation and survival during development and synaptic plasticity induced by acute nociception in the adult. There is extensive evidence for the involvement of members of the MAPK family, the extracellular signal-regulated kinases 1 and 2 (ERKs 1/2), in the development of acute inflammatory somatic and visceral pain, but their role in the maintenance of chronic pain states is unknown. We have previously shown that ovariectomy of adult mice (OVX) generates a persistent and estrogen-dependent abdominal hyperalgesic state that lasts for several months and is not related to a persistent nociceptive afferent input. Here we have used OVX mice to study a possible role of ERK 1/2 in the spinal processing of this form of chronic abdominal hyperalgesia. Eight weeks after OVX the mice showed a robust abdominal hyperalgesia and a significant increase in the activation of ERK1/2 in the lumbosacral spinal cord. This enhanced activation was not seen in control and sham-operated mice or in regions of the cord other than lumbosacral in OVX mice. Also, the increased activation of ERK 1/2 observed in OVX mice matched the time course of the hyperalgesic state as no activation was observed at week 1 after OVX when the hyperalgesic state had not yet developed. Administration of slow-release pellets containing 17ß-estradiol at week 5 post OVX reversed both the development of the hyperalgesia and the enhanced activation of ERK 1/2, suggesting that this activation, like the hyperalgesic state, was estrogen-dependent. Intrathecal injections of the ERK 1/2 inhibitor U0126 successfully rescued the mice from the abdominal hyperalgesia for up to 24 h after the injection and also reversed the enhanced expression of ERK 1/2. Our study shows, for the first time, activation of ERK 1/2 in the spinal cord matching the time course of an estrogen-dependent chronic hyperalgesic state.

Cannabinoid CB1 receptors are expressed in the mouse urinary bladder and their activation modulates afferent bladder activity.

Pharmacological studies have indirectly shown the possible presence of cannabinoid receptors in the urinary bladder and their potential role in reducing bladder inflammatory pain. However, the localization of cannabinoid receptors in the urinary bladder remains unknown and there are no published data on the effects of cannabinoids on the sensory system of the bladder. The present study was performed to evaluate the expression of the cannabinoid CB(1) receptors in the mouse urinary bladder and to assess their co-localization with the purinergic P2X(3) receptor, a major player in the transduction of sensory events in the bladder. Also, the effect of intravesical administration of a cannabinoid agonist on the electrical activity of bladder afferent fibers was studied. The expression of mRNA coding for CB(1) receptor was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR). Immunofluorescence experiments were performed to study CB(1) and P2X(3) protein expression in the bladder. The electrical activity of bladder afferent fibers was recorded using an ex vivo bladder-nerve preparation. Mechanical stimulation of the bladder was performed by a controlled slow inflation with an external pump. A bolus of a cannabinoid agonist (AZ12646915) was administered intravesically prior to a second inflation. Afferent activity was measured before and after administration of the cannabinoid compound or its vehicle. The effects of CB(1) receptor antagonist (AM251) on the AZ12646915 response were also analyzed. Cannabinoid receptor CB(1) mRNA was detected in the urinary bladder of the mouse. The protein was found in the urothelium, as well as in nerve fibers. CB(1) and P2X(3) receptors were found to be co-expressed in urothelial cells and in some nerve fibers. In addition, intravesical administration of a cannabinoid receptor agonist reduced the mechanically-evoked activity of bladder afferents in the pelvic nerve. This effect was abolished by the previous administration of the CB(1) antagonist AM251. These data demonstrate the presence of cannabinoid CB(1) receptor mRNA and the protein in the mouse urinary bladder. CB(1) and P2X(3) protein co-localization supports the hypothesis of an interaction between the cannabinoid and the purinergic systems in the transduction of sensory information in the urinary bladder. Finally, the reduction of nerve activity induced by cannabinoid-receptor activation implicates CB(1) receptors in the peripheral modulation of bladder afferent information.

The RNA binding and transport proteins staufen and fragile X mental retardation protein are expressed by rat primary afferent neurons and localize to peripheral and central axons.

Neuronal proteins have been traditionally viewed as being derived solely from the soma; however, accumulating evidence indicates that dendritic and axonal sites are capable of a more autonomous role in terms of new protein synthesis. Such extra-somal translation allows for more rapid, on-demand regulation of neuronal structure and function than would otherwise be possible. While mechanisms of dendritic RNA transport have been elucidated, it remains unclear how RNA is trafficked into the axon for this purpose. Primary afferent neurons of the dorsal root (DRG) and trigeminal (TG) ganglia have among the longest axons in the neuraxis and such axonal protein synthesis would be advantageous, given the greater time involved for protein trafficking to occur via axonal transport. Therefore, we hypothesized that these primary sensory neurons might express proteins involved in RNA transport. Rat DRG and TG neurons expressed staufen (stau) 1 and 2 (detected at the mRNA level) and stau2 and fragile x mental retardation protein (FMRP; detected at the protein level). Stau2 mRNA was also detected in human TG neurons. Stau2 and FMRP protein were localized to the sciatic nerve and dorsal roots by immunohistochemistry and to dorsal roots by Western blot. Stau2 and FMRP immunoreactivities colocalized with transient receptor potential channel type 1 immunoreactivity in sensory axons of the sciatic nerve and dorsal root, suggesting that these proteins are being transported into the peripheral and central terminals of nociceptive sensory axons. Based on these findings, we propose that stau2 and FMRP proteins are attractive candidates to subserve RNA transport in sensory neurons, linking somal transcriptional events to axonal translation.

Painful stimuli induce in vivo phosphorylation and membrane mobilization of mouse spinal cord NKCC1 co-transporter.

The Na+ --Cl- --K+ isoform 1 (NKCC1) is a co-transporter that increases the intracellular concentration of chloride. NKCC1 plays a critical role in neuronal excitability and it has been recently suggested that it can contribute to hyperalgesic states by modulating the chloride concentration inside nociceptive neurons. In the spinal cord, trafficking of neurotransmitter receptors from the cytosol to the plasma membrane has been demonstrated to contribute to the development of hyperalgesia. However, it is unknown if trafficking of co-transporters can also occur in the nervous system or if it can be induced by painful stimulation. In this study, we have induced referred mechanical hyperalgesia in vivo by intracolonic instillation of capsaicin in mice. Using subcellular fractionation of proteins and cross-linking of membrane proteins we have observed that intracolonic capsaicin induced a 50% increase in NKCC1 in the plasma membrane of lumbosacral spinal cord 90 and 180 min after instillation, in parallel with a similar decrease in the cytosolic fraction. These effects returned to basal levels 6 h after capsaicin treatment. Intracolonic capsaicin also evoked a rapid (10 min) and transient phosphorylation of NKCC1, however, intracolonic saline did not produce significant changes in either NKCC1 trafficking or phosphorylation and none of the treatments induced any alterations of NKCC1 in the thoracic spinal cord. These results suggest that phosphorylation and recruitment of NKCC1 might play a role in referred mechanical hyperalgesia evoked by a painful visceral stimulus. The time course of the effects observed suggests that phosphorylation could contribute to the initial generation of hyperalgesia whereas trafficking could participate in the maintenance of hyperalgesic states observed at longer time points.

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)

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.

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.

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.

[Neurobiology of pain]. / Neurobiología del dolor.

INTRODUCTION AND DEVELOPMENT: An injury to the skin or to an internal organ evokes a discharge in the nociceptive afferents that innervate the damaged area and, as a consequence of the ensuing inflammatory process, sensitizes these nociceptive endings. The activity of sensitized nociceptors evokes two different alterations of pain sensation: 1. A change in the modality of the sensation evoked by low threshold mechanoreceptors, from touch to pain (allodynia) and 2. An increase in the magnitude of the pain sensations evoked by mechanically sensitive nociceptors (hyperalgesia). Allodynia and hyperalgesia show that pain sensation is a dynamic process whose presence and intensity depend on the past history of an affected area and not only on the magnitude of the stimulus. During the initial injury and for the duration of the repair process there will be increased nociceptive activity from the injured region. These afferent barrages cause, in turn, central changes in excitability mediated by positive feedback loops between spinal and supraspinal neurones and by the enhanced synaptic actions of certain neurotransmitters. Among these transmitters, attention has currently focused on the actions of NMDA receptors and neurokinins as putative mediators of the increases in central excitability induced by noxious stimuli. CONCLUSION: The overall mechanism combines the features of the classical 'pain pathway' with the dynamic plastic changes mediated by non-conventional neurotransmitters.

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.

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.

Neurobiología del dolor / Neurobiology of pain

Introducción y desarrollo. Las lesiones de la piel o de los órganos internos producen descargas en las fibras aferentes nociceptivas que inervan la zona dañada y, como consecuencia del proceso inflamatorio subsiguiente, sensibilizan las terminaciones nociceptivas. La actividad de los nociceptores sensibilizados produce dos altera ciones diferentes de la sensibilidad dolorosa: 1. Un cambio en la modalidad de las sensaciones evocadas por la activación de los mecanorreceptores de bajo umbral, que cambia de tacto a dolor (alodinia), y 2. Un aumento en la magnitud de las sensaciones dolorosas evocadas por los nociceptores mecanosensibles (hiperalgesia). La alodinia y la hiperalgesia demuestran la naturaleza dinámica de la sensación dolorosa, cuya presencia e intensidad dependen de la historia inmediata de las zonas afectadas y no sólo de la intensidad del estímulo. Mientras dure la lesión inicial y el proceso de reparación de la misma, existirá una actividad aumentada en los nociceptores que inervan esta zona. Estos aumentos de actividad nerviosa causan a su vez cambios centrales de excitabilidad como consecuencia de lazos de retroalimentación positiva entre la médula espinal y regiones supraespinales y de las acciones celulares de algunos neurotransmisores. Entre los posibles candidatos se han estudiado las acciones de los receptores NMDA y de las neurocininas como mediadores de los aumentos centrales de excitabilidad inducidas por estimulaciones nocivas. Conclusión. En su conjunto, el procesamiento central de la información nociceptiva combina los elementos clásicos de la vía nerviosa del dolor con la plasticidad dinámica característica de las acciones de los neurotransmisores no convencionales (AU)

El dolor neuropático: un problema científico y terapéutico / No disponible

No disponible

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.

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.