Severe CNS angiostrongyliasis in a young marine: a case report and literature review.

Angiostrongylus cantonensis is the most common cause of eosinophilic meningitis worldwide. Infection typically occurs through ingestion of undercooked molluscs or vegetables contaminated by infective larvae. Endemic regions were previously limited to southeast Asia and the Pacific basin; however, this parasite is seeing an alarming increase in global distribution with reported cases in more than 30 countries, including several states in the USA. Although infection typically results in meningitis, a broad spectrum of CNS involvement and severity is emerging as diagnostic methods (such as real-time PCR) continue to improve diagnosis. In this Grand Round, we report a case of a 20-year-old active duty US marine serving in Okinawa, Japan, afflicted with severe CNS angiostrongyliasis marked by radiculomyelitis with quadriparesis, hyperaesthesia, and urinary retention. We present this case to highlight that no clear guidelines exist for the treatment of severe CNS angiostrongyliasis and provide our consensus recommendation that treatment algorithms include use of dual corticosteroids plus anthelmintics when radicular symptoms are present. In this Grand Round we review the clinical features, epidemiology, advances to diagnostic techniques, and available data on current treatment options for CNS angiostrongyliasis. This diagnosis should be highly considered in the differential diagnosis of a patient presenting with meningeal symptoms, paraesthesia or hyperaesthesia, and CSF eosinophilia so that treatment can be started early, which is particularly important in children, because of their increased risk of severe disease and mortality. We recommend combined therapy with albendazole and prednisolone, with consideration for increased steroid dosing in severe cases.

Sensitive scalp is associated with excessive sebum and perturbed microbiome.

BACKGROUND: Sensitive scalp, one of the most frequent complaints among sensitive skin syndrome, has been described as abnormal and unpleasant sensory reactions of the scalp to environmental stimulus. However, the symptoms are usually objective and hard to diagnose. OBJECTIVE: This study aimed to reveal the biophysical properties and etiology of sensitive scalp. METHODS: Sixty-two healthy female subjects were enrolled and divided into nonsensitive scalp (NS) and sensitive scalp (SS) groups according to questionnaires. Noninvasive instruments were used to measure biophysical properties. Ultra-performance liquid chromatography-tandem mass spectrometry and gas chromatography mass spectrometry were introduced to quantify skin lipids profiles, and 16S rRNA sequencing was used to detect the composition of bacteria. RESULTS: Sensitive scalp showed elevated pH level, more irritated skin, and more fluorescence of porphyrins. Increased sebum production was found in SS group at occiput, among which free fatty acids, cholesteryl ester, and squalene were significantly in higher amount compared with NS. SS also had significantly higher percentage of Propionibacterium, and lower bacterial diversity. CONCLUSIONS: Taken together, sensitive scalp showed disrupted barrier function, abnormal sebum amount and composition, as well as perturbed microbiome, which might be the direct cause. Products targeting these features could be helpful for the treatment of sensitive scalp.

Bilaterally Reduced Intraepidermal Nerve Fiber Density in Unilateral CRPS-I.

Objective: Findings regarding small nerve fiber damage in complex regional pain syndrome type I (CRPS-I) are not uniform, and studies have not included a matched healthy control group. The aim was to assess intraepidermal nerve fiber density (IENFD) in relation to thermal sensitivity of the same skin areas in CRPS-I patients and a gender- and age-matched healthy control group. Methods: IENFD was investigated in skin biopsies from the CRPS-affected and contralateral limbs of eight CRPS-I patients and from an equivalent site in eight gender- and age-matched healthy controls (HCs). Thermal thresholds (cold/warm detection, cold- and heat-pain detection) were assessed on the affected limb, the matching contralateral limb, and on the equivalent limbs of HCs, and participants rated the intensity of cold/heat and pain to static thermal stimuli (5 °C and 40 °C). Results: IENFD was significantly lower in both the affected and contralateral limbs of CRPS-I patients than HCs, but IENFD did not differ between the affected and contralateral limbs of patients. The heat pain threshold was lower in the affected CRPS-I limb than in HCs, but all other thermal thresholds were similar in both groups. CRPS-I patients rated the cold stimulus as colder and more painful in the affected limb, and the warm stimulus as hotter, bilaterally, than the HCs. Conclusions: CRPS-I may be associated with bilateral small fiber damage, and perhaps small fiber neuropathy and bilateral disturbances in thermo-sensory perception. These disturbances could stem from a systemic response to injury or might increase the risk of developing CRPS-I after physical trauma.

Glial pannexin1 contributes to tactile hypersensitivity in a mouse model of orofacial pain.

Drug studies in animal models have implicated pannexin1 (Panx1) in various types of pain, including trigeminal hypersensitivity, neuropathic pain and migraine. However, the tested drugs have limited specificity and efficacy so that direct evidence for Panx1 contribution to pain has been lacking. We here show that tactile hypersensitivity is markedly attenuated by deletion of Panx1 in a mouse model of chronic orofacial pain; in this model, trigeminal ganglion Panx1 expression and function are markedly enhanced. Targeted deletion of Panx1 in GFAP-positive glia or in neurons revealed distinct effects. Panx1 deletion in GFAP-positive glia cells prevented hypersensitivity completely, whereas deletion of neuronal Panx1 reduced baseline sensitivity and the duration of hypersensitivity. In trigeminal ganglia with genetically encoded Ca2+ indicator in GFAP-positive glia or in neurons, both cell populations were found to be hyperactive and hyper-responsive to ATP. These novel findings reveal unique roles for GFAP-positive glial and neuronal Panx1 and describe new chronic pain targets for cell-type specific intervention in this often intractable disease.

TrkB.T1 contributes to neuropathic pain after spinal cord injury through regulation of cell cycle pathways.

Spinal cord injury (SCI) frequently causes severe, persistent central neuropathic pain that responds poorly to conventional pain treatments. Brain-derived neurotrophic factor (BDNF) signaling appears to contribute to central sensitization and nocifensive behaviors in certain animal models of chronic pain through effects mediated in part by the alternatively spliced truncated isoform of the BDNF receptor tropomyosin-related kinase B.T1 (trkB.T1). Mechanisms linking trkB.T1 to SCI-induced chronic central pain are unknown. Here, we examined the role of trkB.T1 in central neuropathic pain after spinal cord contusion. Genetic deletion of trkB.T1 in mice significantly reduced post-SCI mechanical hyperesthesia, locomotor dysfunction, lesion volumes, and white matter loss. Whole genome analysis, confirmed at the protein level, revealed that cell cycle genes were upregulated in trkB.T1(+/+) but not trkB.T1(-/-) spinal cord after SCI. TGFß-induced reactive astrocytes from WT mice showed increased cell cycle protein expression that was significantly reduced in astrocytes from trkB.T1(-/-) mice that express neither full-length trkB nor trkB.T1. Administration of CR8, which selectively inhibits cyclin-dependent kinases, reduced hyperesthesia, locomotor deficits, and dorsal horn (SDH) glial changes after SCI, similar to trkB.T1 deletion, without altering trkB.T1 protein expression. In trkB.T1(-/-) mice, CR8 had no effect. These data indicate that trkB.T1 contributes to the pathobiology of SCI and SCI pain through modulation of cell cycle pathways and suggest new therapeutic targets.

Cell cycle activation contributes to increased neuronal activity in the posterior thalamic nucleus and associated chronic hyperesthesia after rat spinal cord contusion.

Spinal cord injury (SCI) causes not only sensorimotor and cognitive deficits, but frequently also severe chronic pain that is difficult to treat (SCI pain). We previously showed that hyperesthesia, as well as spontaneous pain induced by electrolytic lesions in the rat spinothalamic tract, is associated with increased spontaneous and sensory-evoked activity in the posterior thalamic nucleus (PO). We have also demonstrated that rodent impact SCI increases cell cycle activation (CCA) in the injury region and that post-traumatic treatment with cyclin dependent kinase inhibitors reduces lesion volume and motor dysfunction. Here we examined whether CCA contributes to neuronal hyperexcitability of PO and hyperpathia after rat contusion SCI, as well as to microglial and astroglial activation (gliopathy) that has been implicated in delayed SCI pain. Trauma caused enhanced pain sensitivity, which developed weeks after injury and was correlated with increased PO neuronal activity. Increased CCA was found at the thoracic spinal lesion site, the lumbar dorsal horn, and the PO. Increased microglial activation and cysteine-cysteine chemokine ligand 21 expression was also observed in the PO after SCI. In vitro, neurons co-cultured with activated microglia showed up-regulation of cyclin D1 and cysteine-cysteine chemokine ligand 21 expression. In vivo, post-injury treatment with a selective cyclin dependent kinase inhibitor (CR8) significantly reduced cell cycle protein induction, microglial activation, and neuronal activity in the PO nucleus, as well as limiting chronic SCI-induced hyperpathia. These results suggest a mechanistic role for CCA in the development of SCI pain, through effects mediated in part by the PO nucleus. Moreover, cell cycle modulation may provide an effective therapeutic strategy to improve reduce both hyperpathia and motor dysfunction after SCI.

Resident glial cell activation in response to perispinal inflammation leads to acute changes in nociceptive sensitivity: implications for the generation of neuropathic pain.

Injury or disease affecting the spinal cord is often accompanied by abnormal, chronic pain. Recent estimates suggest that approximately 60% of patients with multiple sclerosis are affected by significant changes in pain sensitivity or experience ongoing neuropathic pain of unknown etiology. Chronic pain is also a significant concern after direct spinal cord trauma. Inflammatory events and the changes in astrocyte and microglia reactivity at the spinal level in response to injury or disease are now recognized as important processes that can initiate pain hypersensitivity. Changes in the structural integrity or permeability of the blood-brain barrier/blood-spinal cord barrier (BBB/BSCB) can facilitate the inflammatory events that result in these abnormal pain states. It remains unclear, however, whether chronic pain in these disorders is dependent on the influx of peripheral leukocytes or whether changes in the reactivity of resident glial cells within the central nervous system alone are sufficient. To address this question, we generated a model of perispinal inflammation that resulted in significant changes in the reactivity of resident astrocytes and microglia within the spinal cord but maintained the integrity of the BSCB. A number of similar changes at the behavioural and cellular level occur in this model that mimic the responses seen in animal models of multiple sclerosis or spinal cord injury (SCI). However, these changes are short lived and resolve over the course of a 2-week observation period. Our findings suggest that the chronicity of pain after injury or disease in the nervous system is dependent on the integrity of the BBB/BSCB.

Visceral hypersensitivity in symptomatic diverticular disease and the role of neuropeptides and low grade inflammation.

BACKGROUND: Recurrent abdominal pain is reported by a third of patients with diverticulosis, particularly those with previous episodes of acute diverticulitis. The current understanding of the etiology of this pain is poor. Our aim was to assess visceral sensitivity in patients with diverticular disease and its association with markers of previous inflammation and neuropeptides. METHODS: Patients with asymptomatic and symptomatic diverticular disease underwent a flexible sigmoidoscopy and biopsy followed 5-10 days later by visceral sensitivity testing with barostat-mediated rectal distension. Inflammation was assessed by staining of serotonin (5HT) and CD3 positive cells. mRNA levels of tumor necrosis factor alpha (TNF α) and interleukin-6 (IL-6) were quantitated using RT-PCR. Neuropeptide expression was assessed from percentage area staining with substance P (SP) and mRNA levels of the neurokinin 1 & 2 receptors (NK1 & NK2), and galanin 1 receptor (GALR1). KEY RESULTS: Thirteen asymptomatic and 12 symptomatic patients were recruited. The symptomatic patients had a lower first reported threshold to pain (28.4 mmHg i.q.r 25.0-36.0) than the asymptomatic patients (47 mmHg i.q.r 36.0-52.5, P < 0.001). Symptomatic patients had a higher median overall pain rating for the stimuli than the asymptomatic patients (P < 0.02). Symptomatic patients had greater median relative expression of NK1 and TNF alpha mRNA compared with asymptomatic patients. There was a significant correlation between barostat VAS pain scores and NK 1 expression (Figure 4, r(2) 0.54, P < 0.02). CONCLUSIONS & INFERENCES: Patients with symptomatic diverticular disease exhibit visceral hypersensitivity, and this may be mediated by ongoing low grade inflammation and upregulation of tachykinins.

Compressive myelopathy associated with ectasia of the vertebral and spinal arteries in a dog.

A 4-year-old dog was presented for acute, progressive tetraparesis and cervical hyperesthesia. Symmetrical tubular structures coursing along the lateroventral aspects of the spinal cord at the fourth and fifth cervical vertebrae were identified in magnetic resonance images. At necropsy, vertebral arteries and their spinal branches were severely ectatic bilaterally, and the cervical spinal cord was compressed. Histologically, the ectatic branches of the vertebral and ventral spinal arteries were surrounded by fibrosis with scant mononuclear cell infiltrates and hemorrhage. Spinal branches of the vertebral arteries had focally severe reduction in the tunica media. A thrombus was in an arterial branch. Smaller vessels in adjacent tissue had fibrinoid degeneration. Axonal degeneration was detected in the affected spinal cord and nerve roots. The segmental degenerative radiculomyelopathy in this dog was attributed to anomalous ectasia of the vertebral and ventral spinal arteries.

Hallux interfalándico patológico e incidencia de los distintos grados de onicocriptosis / Pathologic interphalangeal hallux and the incidence of the different stafes of onycochryptosis

El objetivo de este estudio es demostrar la correlación existente entre la patología de Onicocriptosis y la presencia de Hallux interfalángico patológico. Algunos conceptos claves que debemos manejar son el de Hallux Abductus interfalángico del primer dedo y Onicocriptosis, cuya etiología es muy variada. La muestra del estudio está formada por un total de 312 pies pertenecientes a 156 sujetos, de los cuales son 189 mujeres y 123 hombres. El tipo de estudio diseñado es un estudio transversal, analítico, observacional y de caso y control. Los resultados del valor medio de HIF del grupo de estudio son de 17,39“. El valor medio de HIF del grupo control es de 13, 47“. Nuestros resultados muestran que en el grupo de estudio el 73,71% presentan valores de HIF por encima del valor de 13,47“. El valor de HIF no influye en el mayor o menor grado de afectación de onicocriptosis. La mayoría de los pacientes, casi el 60% presentan onicocriptosis de grade 1. Y la mayoría de los casos presentan afectación de los bordes tibial y peroneal. La afectación es mayor en mujeres que en hombres siendo de más del doble para la afectación del borde tibial y peroneal. Como conclusiones de este estudio podemos extraer que existe un alto grado de correlación entre la presencia de HIF patológico y Onicocriptosis. Los pacientes con onicocriptosis tienen un ángulo interfalángico significativamente superior a aquellos que no lo padecen. Los grados de Onicocriptosis más frecuentes son los estadios 1° y 2°. E1 valor medio del H.I.F de este estudio es de 13,47“. No existen resullados significativos para la variables edad y sexo de la muestra. El valor dc HIF no influye en el mayor 0 menor grado de afectación de onicocriptosis (AU)

The aim of this study is to prove the possible relation between onycochryptosis and the pathologic interphalangeal Hallux. Some of the key concepts that we must take into account are interphalangeal Hallux Abductus of the first toe and onycochryptosis, whose etiology is very wide. The sample of this study is 312 feet belonging to 156 subjects, of which 189 are women and 123 men. We conducted a transverse, analytical, observational, case-control study. The mean value of the PIH of the study group is 17,39“ whereas, the mean of the control group is 13, 47". Our results show that in the study group, 73,71% present a PIH value higher than 13,47”. PIH value does not influence the major or minor degree of affectation of onycochryptosis. Most of the patients, almost 60% present onycochryptosis of stage 1. And the majority of the cases present affectation of the tibial and peroneal edges. The affectation is higher in women than men, being more than twice the affectation of the tibial and peroneal edge. As conclusions, we can state that there is a high degree of correlation between the presence of PIH and onycochryptosis. Patients with onycochryptosis have an interphalangeal angle significantly superior to those who do not suffer this condition. The most frequent degrees of onycochryptosis are stage 1 and 2. The mean value of the PIH of this study is 13,47“. We could not find significant results related to age and sex. PIH Value does not influence the major or minor degree of affectation (AU)

Comparison of three strains of diabetic rats with respect to the rate at which retinopathy and tactile allodynia develop.

PURPOSE: We compared three rat strains to determine if different strains develop early-stage diabetic retinopathy or sensory neuropathy at different rates. METHODS: Sprague Dawley, Lewis, and Wistar rats were made diabetic with streptozotocin. Diabetic and nondiabetic animals had retinal vascular pathology measured at eight months of diabetes. The number of cells in the retinal ganglion cell layer (GCL), retinal function (using electroretinography [ERG]), and retinal levels of inducible nitric oxide synthase (iNOS), cyclooxygenase2 (COX2), and vascular endothelial growth factor (VEGF) were measured at four months of diabetes. Tactile allodynia was assessed in hind paws at two months of diabetes. RESULTS: Diabetes of eight months' duration resulted in a significant increase in retinal degenerate capillaries and pericyte ghosts in Lewis and Wistar rats, but not in Sprague Dawley rats. A significant loss of cells in the GCL occurred only in diabetic Lewis rats, whereas Wistar and Sprague Dawley rats showed little change. Diabetes-induced iNOS and VEGF were statistically significant in all strains. Cyclooxygenase 2 (COX2) was significantly elevated in the Sprague Dawley and Wistar strains. Lewis rats showed a similar trend, however, the results were not statistically significant. All strains tended to show diabetes-induced impairment of dark-adapted b-wave amplitude, but only Sprague Dawley and Lewis strains had a significant reduction in latency. All strains showed significant tactile allodynia in peripheral nerves. CONCLUSIONS: At the durations studied, Lewis rats showed accelerated loss of both retinal capillaries and ganglion cells in diabetes, whereas diabetic Wistar rats showed degeneration of the capillaries without significant neurodegeneration, and Sprague Dawley rats showed neither lesion. Identification of strains that develop retinal lesions at different rates should be of value in investigating the pathogenesis of retinopathy.

The antinociceptive effect of (-)-linalool in models of chronic inflammatory and neuropathic hypersensitivity in mice.

UNLABELLED: We used multiple pain models to investigate the effects of (-)-linalool, a monoterpene alcohol present in the essential oil of plants, on chronic inflammatory and neuropathic hypersensitivity in adult Swiss mice. Inflammatory or neuropathic hypersensitivity was induced by intraplantar (i.pl.) injection of complete Freund's adjuvant (CFA) or partial sciatic nerve ligation (PSNL), respectively. Twenty-four hours after CFA injection, we used Von Frey filaments and acetone-evoked cooling to evaluate tactile and thermal hypersensitivity, respectively. A single i.p. injection of (-)-linalool (50 or 200 mg/kg) administered 30 minutes before testing reduced CFA-induced mechanical hypersensitivity. Similarly, (-)-linalool reduced acetone-evoked hypersensitivity up to 4 hours after treatment. Compared with vehicle, (-)-linalool produced a marked reduction in CFA-induced paw edema. (-)-Linalool also reduced mechanical hypersensitivity induced by PSNL 7 days after injury. Multiple (-)-linalool treatments given chronically (twice a day for 10 days; 50 mg/kg, i.p.) significantly reduced mechanical hypersensitivity induced by CFA and PSNL. This multidose strategy did not cause tolerance. We also reasoned that (-)-linalool might reduce nociceptive behavior in response to direct administration of inflammatory mediators. Therefore, we injected the cytokines IL-1ß (.1 pg/site) and TNF-α (1 pg/site) intrathecally. (-)-Linalool inhibited the biting response induced by IL-1ß and TNF-α. PERSPECTIVE: The article adds information about antinociceptive properties of (-)-linalool in chronic inflammatory and neuropathic hypersensitivity. It also indicates that (-)-linalool might be potentially interesting in the development of new clinically relevant drugs for the management of persistent pain.

Allodynia in migraine: frequent random association or unavoidable consequence?

Allodynia, the perception of pain induced by a non-painful stimulus, is frequently associated with migraine, especially when chronic, and mainly in the aura subtype. Among migraineurs, allodynia is thought to be caused by the headache and the activation of nociceptors with the development of central sensitization in subjects with an altered regulation of the central nociceptive pathway. The persistence of pain sensation seems to be able to induce central sensitization in the caudal nucleus of the trigeminal nerve by lowering the neuronal pain threshold. Different pathogenetic mechanisms may be involved and genetic, environmental and psychological elements should be considered. The complaint of allodynia is more frequent during the headache attack (acute allodynia) than in-between attacks (interictal allodynia). Acute allodynia is generally referred to the painful region but may diffuse to other areas, cephalic or even extracephalic. Extracephalic allodynia could not be mediated by nucleus caudalis as its neurons do not express whole-body receptive fields. The likely mechanism is thalamic sensitization. This symptom must be carefully assessed because it may be as annoying and limiting in daily activities as pain itself, and because its presence seems to reduce the efficacy of drugs used for migraine attacks. Instrumental measures may be applied, and clinical questionnaires to assess the presence of allodynic symptoms have also been developed and validated. All these aspects will be discussed.

Attenuating phosphorylation of p38 MAPK in the activated microglia: a new mechanism for intrathecal lidocaine reversing tactile allodynia following chronic constriction injury in rats.

Increasing evidences approve the long-term analgesia effects of intrathecal lidocaine in patients with chronic pain and in animal peripheral nerve injury models, but the underlying mechanism remains elusive. Previous evidences suggest that the activation of the p38 MAPK signaling pathway in hyperactive microglia in the dorsal horn of spinal cord involves in nerve injury-induced neuropathic pain. In this study, we demonstrate that attenuating phosphorylation of p38 MAPK in the activated microglia of spinal cord, at least partly, is the mechanism of intrathecal lidocaine reversing established tactile allodynia in chronic constriction injury model of rats. This finding not only provides a new insight into the mechanisms underlying long-term therapeutic effects of lidocaine on neuropathic pain, but also reveals one more specific drug target for analgesia.

A role for G protein-coupled receptor kinase 2 in mechanical allodynia.

Inflammation and nerve injury can both induce mechanical allodynia via mechanisms involving the production of pro-inflammatory cytokines and increased neuronal activity. Many neurotransmitters involved in pain signal via G protein-coupled receptors (GPCRs). GPCR kinase (GRK)2 is a member of the GRK family that regulates agonist-induced desensitization and signalling of GPCRs. Low intracellular GRK2 levels are associated with increased receptor signalling. The aim of this study was to investigate whether mechanical allodynia is associated with decreased spinal cord GRK2 expression and whether reduced GRK2 increases inflammation-induced mechanical allodynia. Mechanical allodynia was induced in rats by chronic constriction injury of the sciatic nerve. After 2 weeks, neuronal GRK2 expression was decreased bilaterally in the superficial layers of the lumbar spinal cord dorsal horn. Moreover, interleukin-1beta significantly reduced GRK2 expression ex vivo in spinal cord slices. To investigate whether reduced GRK2 potentiates inflammation-induced mechanical allodynia, we used GRK2(+/-) animals expressing decreased GRK2. At baseline, the threshold for mechanical stimulation did not differ between GRK2(+/-) and wild-type mice. However, GRK2(+/-) animals were more sensitive to mechanical stimulation than wild-type animals after intraplantar lambda-carrageenan injection. We propose cytokine-induced down-regulation of spinal cord neuronal GRK2 expression as a novel mechanism that contributes to increased neuronal signalling in mechanical allodynia.

Upregulation of substance P in low-threshold myelinated afferents is not required for tactile allodynia in the chronic constriction injury and spinal nerve ligation models.

It has been proposed that substance P and calcitonin gene-related peptide (CGRP) are upregulated in low-threshold myelinated primary afferents after certain types of nerve injury, and that release of substance P from these afferents contributes to the resulting tactile allodynia. To test this hypothesis, we looked for neuropeptides in Abeta primary afferent terminals in the ipsilateral gracile nucleus and spinal dorsal horn in three nerve injury models: sciatic nerve transection (SNT), spinal nerve ligation (SNL), and chronic constriction injury (CCI). We also looked for evidence of neurokinin 1 (NK1) receptor internalization in the dorsal horn after electrical stimulation of Abeta afferents. We found no evidence of either substance P or CGRP expression in injured Abeta terminals in the spinal cord in any of the models. Although substance P was not detected in terminals of injured afferents in the gracile nucleus, CGRP was expressed in between 32 and 68% of these terminals, with a significantly higher proportion in the SNL and CCI models, compared with SNT. In addition, we did not detect any Abeta-evoked NK1 receptor internalization in neurons from laminas I, III, or IV of the dorsal horn in the CCI or SNL models. These results do not support the proposal that substance P is present at significant levels in the terminals of injured Abeta primary afferents in neuropathic models. They also suggest that any release of substance P from injured Abeta afferents is unlikely to activate NK1 receptors in the dorsal horn or contribute to neuropathic pain.

The Shetland Islands scrapie monitoring and control programme: analysis of the clinical data collected from 772 scrapie suspects 1985-1997.

There were 574 scrapie positive suspects (histopathological scrapie lesions present) and 198 scrapie negative suspects (histopathological scrapie lesions absent). The greatest number of scrapie cases were recorded in sheep of 2, 3 and 4 years of age which represented 17%, 36% and 23% of the scrapie positive suspects, respectively. The sign sensitivities and specificities for the ten recorded signs were, respectively: pruritus (62%, 42%), ataxia (23%, 74%), hyperaesthesia (32%, 74%), wool loss (25%, 73%), fleece discolouration (29%, 85%), bruxism (23%, 69%), nibbling reflex (17%, 58%), head rubbing (47%, 78%), poll rubbing (25%, 83%). These single signs had poor discriminatory values with likelihood ratios close to one (range 0.89-1.21); combinations of the four signs, pruritus, wool loss, ataxia, hyperaesthesia and emaciation were more discriminatory (range 0.30-4.3). This study covered a time period when bovine spongiform encephalopathy (BSE) might have been introduced into the sheep population on the Shetland Islands via contaminated feed. No temporal changes could be detected in the age structure of the affected animals.

Central representation of muscle pain and mechanical hyperesthesia in the orofacial region: a positron emission tomography study.

Functional neuroimaging studies of the human brain have revealed a network of brain regions involved in the processing of nociceptive information. However, little is known of the cerebral processing of pain originating from muscles. The aim of this study was to investigate the cerebral activation pattern evoked by experimental jaw-muscle pain and its interference by simultaneous mechanical stimuli, which has been shown to evoke hyperesthesia. Ten healthy subjects participated in a PET study and jaw-muscle pain was induced by bolus injections of 5% hypertonic saline into the right masseter muscle. Repeated von Frey hair stimulation (0.5 Hz) of the skin above the masseter muscle was used as the mechanical stimulus. Hypertonic saline injections caused strong muscle pain spreading to adjacent areas. von Frey stimulation was rated as non-painful but produced hyperesthesia during jaw-muscle pain. Jaw-muscle pain was associated with significant increases in regional cerebral blood flow (rCBF) in the dorsal-posterior insula (bilaterally), anterior cingulate and prefrontal cortices, right posterior parietal cortex, brainstem, cavernous sinus and cerebellum. No rCBF changes occurred in primary or secondary somatosensory cortices. In contrast, von Frey stimulation produced a significant rCBF increase in the contralateral SI face representation. Mechanical hyperesthesia was associated with significant rCBF increases in the subgenual cingulate and the ventroposteromedial and dorsomedial thalamus. These results suggest that the cerebral processing of jaw-muscle pain may differ from the processing of cutaneous pain and that mechanical hyperesthesia, which often is encountered in clinical cases, has a unique representation in the brain.

Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency.

BACKGROUND: Faecal urgency and incontinence with rectal hypersensitivity is a distressing, unexplained disorder that is inadequately treated. We aimed to determine whether expression of the heat and capsaicin receptor vanilloid receptor 1 (TRPV1 or VR1) was changed in rectal sensory fibres, and to correlate nerve fibre density with sensory abnormalities. METHODS: We compared full-thickness rectal biopsy samples from nine patients with physiologically characterised rectal hypersensitivity with tissue samples from 12 controls. Sensory thresholds to rectal balloon distension and heating the rectal mucosa were measured before biopsy. We assessed specimens with immunohistochemistry and image analysis using specific antibodies to TRPV1; nerve growth factor (NGF) receptor tyrosine kinase A; glial cell line-derived neurotrophic factor (GDNF); neuropeptides calcitonin gene-related peptide (CGRP) and substance P; the related vanilloid receptor-like protein (VRL) 2; glial markers S-100 and glial fibrillary acid protein (GFAP); and the nerve structural marker peripherin. FINDINGS: In rectal hypersensitivity, nerve fibres immunoreactive to TRPV1 were increased in muscle, submucosal, and mucosal layers: in the mucosal layer, the median% area positive was 0.44 (range 0.30-0.59) in patients who were hypersensitive and 0.11 (0.00-0.21) in controls (p=0.0005). The numbers of peripherin-positive fibres also increased in the mucosal layer (hypersensitive 3.00 [1.80-6.50], controls 1.20 [0.39-2.10]: (p=0.0002). The increase in TRVP1 correlated significantly with the decrease in rectal heat (p=0.03) and the distension (p=0.02) sensory thresholds. The thresholds for heat and distension were also significantly correlated (p=0.0028). Expression of nerve fibres positive for GDNF (p=0.001) and tyrosine kinase A (p=0.002) was also increased, as were cell bodies of the submucosal ganglia immunoreactive to CGRP (p=0.0009). INTERPRETATION: Faecal urgency and rectal hypersensitivity could result from increased numbers of polymodal sensory nerve fibres expressing TRPV1. The triggering factor or factors remain uncertain, but drugs that target nerve terminals that express this receptor, such as topical resiniferatoxin, deserve consideration.

Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity.

Tolerance to the analgesic effects of an opioid occurs after its chronic administration, a pharmacological phenomenon that has been associated with the development of abnormal pain sensitivity such as hyperalgesia. In the present study, we examined the role of spinal glutamate transporters (GTs) in the development of both morphine tolerance and associated thermal hyperalgesia. Chronic morphine administered through either intrathecal boluses or continuous infusion induced a dose-dependent downregulation of GTs (EAAC1 and GLAST) in the rat's superficial spinal cord dorsal horn. This GT downregulation was mediated through opioid receptors because naloxone blocked such GT changes. Morphine-induced GT downregulation reduced the ability to maintain in vivo glutamate homeostasis at the spinal level, because the hyperalgesic response to exogenous glutamate was enhanced, including an increased magnitude and a prolonged time course, in morphine-treated rats with reduced spinal GTs. Moreover, the downregulation of spinal GTs exhibited a temporal correlation with the development of morphine tolerance and thermal hyperalgesia. Consistently, the GT inhibitor l-trans-pyrrolidine-2-4-dicarboxylate (PDC) potentiated, whereas the positive GT regulator riluzole reduced, the development of both morphine tolerance and thermal hyperalgesia. The effects from regulating spinal GT activity by PDC were at least in part mediated through activation of the NMDA receptor (NMDAR), because the noncompetitive NMDAR antagonist MK-801 blocked both morphine tolerance and thermal hyperalgesia that were potentiated by PDC. These results indicate that spinal GTs may contribute to the neural mechanisms of morphine tolerance and associated abnormal pain sensitivity by means of regulating regional glutamate homeostasis.