“Damage to the dorsolateral prefrontal

cortex (DLP


“Damage to the dorsolateral prefrontal

cortex (DLPFC) impairs gating of irrelevant sensory Gilteritinib in vitro information at early cortical processing stages. We investigated how transient inhibition of DLPFC impacts early event-related potentials (ERPs) arising from relevant or irrelevant vibrotactile stimuli to the fingertips. Specifically, we hypothesized that suppression of DLPFC using continuous theta burst stimulation (cTBS) would result in reduced attention-based modulation of tactile ERPs generated at early stages of cortical somatosensory processing. Participants received vibrotactile stimulation to the second and fifth digit on the left hand and reported target stimuli on one digit only (as instructed) in one of VX-765 datasheet three groups following: (1) cTBS over DLPFC (40 s; 600 pulses of 3 stimuli at 50 Hz repeated at 5 Hz using 80% of resting motor threshold for abductor pollicis brevis), (2) sham stimulation, or (3) no stimulation. ERP amplitudes for the P50, N70, P100, N140 and long latency positivity (LLP) were quantified for attended and non-attended trials at C4, CP4, and CP3 electrodes. There was no effect of attention on the P50 and N70 however

the P100, N140 and LLP were modulated with attention. The P100 and LLP were significantly more positive during trials where the stimuli were attended to, while the N140 was enhanced for non-attended stimuli. Comparisons between groups revealed a reduction in P100 attention-based modulation for the cTBS group versus sham and no-stimulation groups. While the P100 was clearly reduced for non-attended stimuli relative to attended stimuli in the sham and no-stimulation groups, this effect was attenuated following cTBS. The reduction in attentional modulation of the P100 following cTBS suggests that the DLPFC contributes to filtering irrelevant somatosensory information at early Temsirolimus purchase cortical processing stages. Notably the influence of the DLPFC in attention-based modulation was evident even within digits of the

same hand. The present results support the use of cTBS as an effective means of transiently suppressing DLPFC excitability. (C) 2011 Elsevier Ltd. All rights reserved.”
“Purpose: We investigated the relationship of kidney calculi with plasma free and total testosterone, and androgen receptor up-regulation in the kidneys of men with nephrolithiasis.

Materials and Methods: Male patients with kidney stone and healthy men were included in the study. Blood was collected in a tube containing 2% heparin in the morning. Total and free serum testosterone was measured by enzyme linked immunosorbent assay. All patients underwent percutaneous nephrostolithotomy. At the end of the procedure ultrasound guided puncture biopsy was done to acquire kidney tissue. Normal kidney tissue obtained at autopsy served as the control. Androgen receptor was detected in kidney tissue by immunohistochemistry.

We used this model to test whether the early lytic-cycle gene BHL

We used this model to test whether the early lytic-cycle gene BHLF1, implicated in silencing of the Cp/Wp locus, is required to establish latency I. Upon superinfection with EBV deleted for the BHLF1 locus, however, we have demonstrated that BHLF1 is not essential for this aspect of EBV latency. In the second model, BL cells that maintain Wp-restricted latency, a variant program in which click here Cp is silent but Wp remains active, sustained the latency III program of transcription from the superinfecting-virus genomes, failing to transition to latency I. Importantly, there

was substantial reduction in Wp-mediated protein expression from endogenous EBV genomes, in the absence of Cp reactivation, that could occur independent of a parallel decrease in mRNA. Thus, our data provide evidence of a novel, potentially posttranscriptional mechanism for trans-repression of Wp-dependent gene expression. We suggest that this may ensure against overexpression of

the EBV nuclear antigens (EBNAs) prior to the transcriptional repression of Wp in cis that occurs upon activation of Cp.”
“Variation in drug efficacy and toxicity remains an important clinical concern. Presently, single nucleotide polymorphisms (SNPs) BI 10773 purchase only explain a portion of this problem, even in situations where the pharmacological trait is clearly heritable. The Human CNV Project identified copy number variations (CNVs) across approximately 12% of the human genome, and these CNVs Abiraterone were considered causes of diseases. Although the contribution of CNVs to the pathogenesis of many common diseases is questionable, CNVs play a clear role in drug-related genes by altering drug metabolizing and drug response. In this review, we provide a comprehensive evaluation of the clinical relevance of CNVs to drug efficacy, toxicity, and disease prevalence in world populations, and discuss the implication of using CNVs as a diagnostic tool in clinical intervention.”
“Previous neuropsychological studies demonstrated various deficits of impulse control in pathological gamblers (PGs). However, there are limited data available on response-inhibition

impairment among PGs. The present study attempted to assess response inhibition in untreated PGs (N=83), in comparison with normal subjects (N=84). Go/no-go and target-detection conditions of a computerized task were used as a measure of response-inhibition ability. A repeated measures analysis of covariance (ANCOVARM) was used with response time, variability of response time, and number of false alarms and misses as dependent measures; group (PG and controls) as the between-subjects measure; condition (target detection or go/no-go) and time slice (first and second in each condition) as repeated measures within-subject factors; and educational level as a covariate. Our results showed that PGs were significantly more impaired in both target detection and go/no-go task performance than controls.

In other cell lines except Karpas 299, CD30 pre-stimulation did n

In other cell lines except Karpas 299, CD30 pre-stimulation did not significantly enhance galectin-1-induced cell death. Galectin-3 transfection of HEK-293 cells resulted in cell surface expression of galectin-3, associated with marked cell aggregation. CD30-targeted therapy in combination with galectin-1 treatment may induce effective killing of ALCL cells but not of HL cells. Laboratory Investigation (2012)

92, 191-199; doi:10.1038/labinvest.2011.151; published online 10 October 2011″
“The potential of diffusion tensor imaging (DTI) to detect spinal cord abnormalities in patients with multiple sclerosis has already been demonstrated. The objective of this study was to apply DTI techniques to multiple sclerosis patients with a recently diagnosed spinal cord lesion, in order to demonstrate a correlation between variations of DTI parameters AZD3965 price and clinical outcome, and to try to identify DTI parameters predictive of outcome.

A prospective single-centre study of patients with spinal cord relapse treated by intravenous steroid therapy was made. Patients were assessed clinically and by conventional this website MRI with DTI sequences at baseline

and at 3 months.

Sixteen patients were recruited. At 3 months, 12 patients were clinically improved. All but one patient had lower fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values than normal subjects in either inflammatory lesions or normal-appearing spinal cord. Patients who improved at 3 months presented a significant reduction in the radial diffusivity (p = 0.05) in lesions during the follow-up period. They also had a significant reduction in the mean ADC (p = 0.002), axial diffusivity (p = 0.02), radial diffusivity (p = 0.02) and a significant increase in FA values (p = 0.02) in normal-appearing

spinal cord. Patients in whom the American Spinal Injury Association sensory score for improved at 3 months showed a significantly higher FA (p = 0.009) and lower radial diffusivity (p = 0.04) in inflammatory lesion at baseline compared to patients with no improvement.

DTI MRI detects more extensive abnormalities than conventional T2 MRI. A less marked decrease in FA value and more marked decreased in radial diffusivity inside the inflammatory lesion were associated with better outcome.”
“Protein sumoylation is an important reversible post-translational modification on proteins, and orchestrates a variety of cellular processes. Recently, computational prediction of sumoylation sites has attracted much attention for its cost-efficiency and power in genomic data mining. In this work, we developed SUMOsp 2.0, an accurate computing program with an improved group-based phosphorylation scoring algorithm. Our analysis demonstrated that SUMOsp 2.0 has greater prediction accuracy than SUMOsp 1.0 and other existing tools, with a sensitivity of 88.17% and a specificity of 92.69% under the medium threshold.

In contrast, a region distal to pact up to 150 by from the point

In contrast, a region distal to pact up to 150 by from the point of cleavage was essential. Scanning substitutions revealed that the pact side of the cleavage site is complex and may contain multiple cis-acting sequence elements in addition to pact. These results should facilitate the identification of transacting factors that bind to these elements and the elucidation of their functions. Such information will be critical for understanding the molecular basis of this complex process.”
“Introduction: There are several instances when it is BI 10773 concentration desirable to control brain concentration of pharmaceuticals, e.g., to modulate the concentration

of anesthetic agents to different desired levels fitting to different needs find more during the course of surgery. This has so far only been possible using indirect estimates of drug concentration such as assuming constant relation between tissue and blood including extrapolations from

animals.

Methods: A system for controlling target tissue concentration (UIPump) was used to regulate whole-brain concentrations of a central benzodiazepine receptor antagonist at therapeutic levels with input from brain kinetics as determined with PET. The system was tested by using pharmacological doses of flumazenil mixed with tracer amounts of [C-11]flumazenil. Flumazenil was used as a model compound for anesthesia. An infusion scheme to produce three different steady-state levels in sequence was designed based on kinetic curves obtained after bolus injection. The subjects (Sprague-Dawley rats, n = 6) were monitored in a microPET scanner during Oxymatrine the whole experiment to verify resulting brain kinetic curves.

Results: A steady-state brain concentration was rapidly achieved corresponding to a whole-brain concentration of 118 +/- 6 ng/ml. As the infusion

rate decreased to lower the exposure by a factor of 2, the brain concentration decreased to 56 +/- 4 ng/ml. A third increased steady-state level of anesthesia corresponding to a whole-brain concentration of 107 +/- 7 ng/ml was rapidly achieved.

Conclusion: The experimental setup with computerized pump infusion and PET supervision enables accurate setting of target tissue drug concentration. (C) 2008 Elsevier Inc. All rights reserved.”
“Human immunodeficiency virus type 1 (HIV-1) particle assembly mediated by the viral structural protein Gag occurs predominantly on the plasma membrane (PM). Although it is known that the matrix (MA) domain of Gag plays a major role in PM localization, molecular mechanisms that determine the location of assembly remain to be elucidated. We observed previously that overexpression of polyphosphoinositide 5-phosphatase IV (5ptaseIV) that depletes PM phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P-2] impairs virus particle production and redirects processed Gag to intracellular compartments.

Consistent with previous reports, alternating, low frequency (1Hz

Consistent with previous reports, alternating, low frequency (1Hz) stimulation of CA1 afferents originating in the contralateral CA3 area and the medial septum resulted in gradually developing, long lasting (>2 h) LTP of field excitatory postsynaptic potentials (fEPSPs) recorded in CA1. Local application of the protein synthesis inhibitor anisomycin in CA1 blocked LFS-induced LTP, as did application of H89, an inhibitor of protein kinase A. Given the apparent overlap in molecular mechanisms mediating

LFS-LTP and “”classic”" high-frequency stimulation (HFS)-induced LTP in CA1, we examined Vistusertib purchase the relation between these forms of LTP by means of occlusion experiments. LFS, delivered to synapses saturated by initial HFS, resulted in a gradually developing LTD, rather than the normally seen LTP. Conversely, initial induction

of LFS-LTP reduced the amount of subsequent HFS-LTP. Together, these experiments reveal a surprising similarity in the molecular mechanisms (dependence on NMDA receptors, protein kinase A, protein synthesis) mediating LTP induced by highly distinct (1 vs. 100 Hz) induction protocols. Importantly, these findings further challenge the “”high-frequency-LTP, low-frequency Ricolinostat manufacturer LTD”" dogma by demonstrating that this dichotomy does not account for all types of plasticity phenomena at central synapses. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.”
“The diversity of human adenoviruses (AdVs) in river waters was studied by single-strand conformational polymorphism (SSCP) analysis. Water samples were collected between 2002 and 2003 from 4 rivers in the Gyeonggi Province, South Korea. Forty-six (79.3%) of the 58 samples Etomidate were positive for AdVs as determined on PCR amplification. Nine different SSCP profiles (profiles A to I) were detected in all the AdVs-positive samples by SSCP analysis, and most of the AdVs-positive samples (38 of 46 samples; 82.6%) showed the SSCP profile D. Nine different sequences were obtained

in the SSCP profiles; sequence alignments and phylogenetic analysis identified 5 different sequences that were closely related to the human AdV type 41, and the 4 different sequences that were closely related to human AdV types 3, 4, 12, and 40. Two AdVs genomic variants were detected (types 3 and 41 in A, types 12 and 41 in B, and 2 genomic variants of type 41 in C) in SSCP profiles A, B, and C, respectively. SSCP analysis could be a useful technique for the identification of genetic variants of AdVs and for studying AdVs diversity in urban rivers. (C) 2010 Elsevier B.V. All rights reserved.”
“There is a growing body of evidence that striosome-matrix dopamine systems are tightly linked with motor and behavioral brain functions and disorders.


“Following integration, HIV-1 in most cases produces activ


“Following integration, HIV-1 in most cases produces active infection events; however, in some rare instances, latent infection events are established. The latter have major clinical implications, as latent infection allows the virus to persist despite antiretroviral therapy. Both the cellular factors and the viral elements that potentially determine whether HIV-1 establishes active or latent infection events remain largely elusive. We detail here the contribution of different long terminal repeat (LTR) sequences for the learn more establishment of latent HIV-1 infection. Using a panel of full-length replication-competent virus constructs that reflect

naturally occurring differences of HIV-1 subtype-specific LTRs and targeted LTR mutants, we found the primary ability of HIV-1 to establish latent infection in this system to be controlled by a four-nucleotide (nt) AP-1 element just upstream of the NF-kappa B element Caspase Inhibitor VI in the viral promoter. Deletion of this AP-1 site mostly deprived HIV-1 of the ability to establish latent HIV-1 infection. Extension of this site to a 7-nt AP-1 sequence massively promoted latency establishment, suggesting that this promoter region represents

a latency establishment element (LEE). Given that these minimal changes in a transcription factor binding site affect latency establishment to such large extent, our data support the notion that HIV-1 latency is a transcription factor restriction phenomenon.”
“Background. Cognitive rehabilitation has emerged as an effective treatment for addressing cognitive impairments and functional disability in schizophrenia; however, the degree to which changes in various social

and non-social cognitive processes translate into improved functioning during treatment remains unclear. This research sought to identify the neurocognitive and social-cognitive mechanisms of functional improvement during a 2-year trial of cognitive enhancement therapy (CET) for early-course schizophrenia.

Method. Patients in the early course of schizophrenia were randomly assigned to CET (n = 31) or an enriched supportive therapy control SPTBN5 (n = 27) and treated for up to 2 years. A comprehensive neurocognitive assessment battery and the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) were completed annually, along with measures of functioning. Mediator analyses using mixed-effects growth models were conducted to examine the effects of neurocognitive and social-cognitive improvement on functional change.

Results. Improvements over 2 years in neurocognition and the emotion management branch of the MSCEIT were found to be significantly related to improved functional outcome in early-course schizophrenia patients. Neurocognitive improvement, primarily in executive functioning, and social-cognitive change in emotion management also mediated the robust effects of CET on functioning.

However, the ECD and glue injection technique did achieve complet

However, the ECD and glue injection technique did achieve complete occlusion in 1 aneurysm that persisted 1 year later. The histopathological findings in this instance are moderately encouraging. Further investigations of an ECD with N-butyl cyanoacrylate or another LEA are warranted.”
“OBJECTIVE:

Craniopharyngiomas are benign tumors that originate from squamous cell rests of the embryonal hypophyseal-pharyngeal duct located along the pituitary stalk. After their surgical resection, recurrence usually occurs in the region of the original tumor bed. Ectopic recurrence of craniopharyngiomas is extremely check details rare. It usually occurs either along the surgical route, because of direct surgical seeding, or at a distal location in the subarachnoid space, because of seeding along the cerebrospinal fluid pathways. We present 3 examples of ectopic recurrences of craniopharyngiomas.

CLINICAL PRESENTATION: The first patient was a 52-year-old woman with a history of resected suprasellar craniopharyngioma presenting 15 years later with a history of balance problems and new onset of double vision. Her magnetic resonance imaging scan revealed a tumor in the prepontine cistern. The second patient was a 41-year-old man with

a history of a resected suprasellar craniopharyngioma presenting 9 years later www.selleckchem.com/products/Nilotinib.html with headache, dizziness, and disequilibrium. He was noted by his family to have an altered behavior with progressively increasing indifference. His magnetic resonance imaging scan showed a right frontal lesion in the vicinity of the sylvian fissure. The third patient was a 24-year-old man with a history of suprasellar

craniopharyngioma resection, followed by conventional radiotherapy 12 years before his recent presentation with headache, numbness of the right side of his face, and increased drowsiness. His magnetic also resonance imaging scan showed a bilateral cystic cerebellopontine angle lesion.

INTERVENTION: The first patient underwent operation via a petrosal approach with subtotal resection of the tumor and decompression of the brainstem; this patient had an uneventful postoperative course. The tumor in the second patient was surgically resected through a pterional craniotomy, with an uneventful postoperative course. The third patient’s right-sided cerebellopontine angle lesion was microsurgically resected, and the patient was given a single-dose gamma knife for the left-side and residual small right-side tumor. The histological diagnosis of all 3 lesions was craniopharyngioma.

CONCLUSION: Although ectopic recurrence of a craniopharyngioma is very rare, it should always be considered in the differential diagnosis of what appears to be a new tumor in a patient with a history of previously resected craniopharyngiomas. Long-term follow-up of patients with resected craniopharyngioma is very important.

Thus, our data provides a method to increase the

Thus, our data provides a method to increase the C59 wnt survival of stem cells being employed in transplantation within CNS and hence increase the success rate of cell-based therapies in damaged area of brain and spinal cord. (C) 2011 Elsevier Ireland Ltd. All rights reserved.”
“The usefulness of combined anti-HCV and 24 mini-pool HCV RNA screening strategy was re-evaluated after a six-year continuous routine use in a clinical virology laboratory, at which more than half of newly diagnosed hepatitis C patients are intravenous

drug users. Pools of 24 samples were prepared from 20,448 anti-HCV negative serum samples and tested using an automated commercial PCR assay with a lower limit of detection of 50 IU/ml. After detection of anti-HCV negative/HCV RNA positive patients, responsible physicians provided follow-up samples. Thirty-eight (0.19%) anti-HCV negative/HCV RNA positive samples from 30 patients (28 intravenous drug users) were detected. Follow-up samples were available for 27/30 patients. Twenty, six and one patient seroconverted in the second, third and fourth available samples, respectively. The interval between AZD1480 chemical structure the first HCV RNA positive and the first available

anti-HCV positive sample was 17-517 days. The costs of detecting a single anti-HCV negative/HCV RNA positive patient were 1227 Euros. Combined anti-HCV and 24 mini-pool HCV RNA screening is a useful and cost effective strategy, not only in blood-transfusion settings but also in a routine clinical virology laboratory, at which a significant proportion of the tested population belongs to a high-risk population. (C) 2010 Elsevier

B.V. All rights reserved.”
“Death and dying are central events in the live of an organism, but neurobiological changes during this Cyclooxygenase (COX) process are still rarely understood. Extracellular levels of serotonin, one of the phylogenetically oldest neurotransmitters, were measured continuously during dying. Serotonin levels increased threefold, while the EEG recorded simultaneously went down to a zero-line of no activity. This could be caused by the neuroprotective activity of brain serotonergic system, which subjectively makes dying easier due to the mood enhancing function of this neurotransmitter. (C) 2011 Elsevier Ireland Ltd. All rights reserved.”
“A novel reverse-transcription, loop-mediated isothermal amplification (RT-LAMP) assay for the detection of bovine ephemeral fever virus (BEFV) was developed and evaluated in this study. The RT-LAMP assay exhibited higher sensitivity when compared with conventional reverse-transcription polymerase chain reaction (RT-PCR) and virus isolation methods. The specificity of the assay was determined by digestion of the RT-LAMP products with restriction enzyme and detection of BEFV serogroup rabies virus (RV).

Five automated 5-h animal exposures were performed that produced

Five automated 5-h animal exposures were performed that produced controlled and consistent

COREXIT EC9500A concentrations (27.1 +/- 2.9 mg/m(3), mean +/- SD).”
“COREXIT EC9500A (COREXIT) was used to disperse crude oil during the 2010 Deepwater Horizon oil spill. While the environmental impact of COREXIT has been examined, the pulmonary effects click here are unknown. Investigations were undertaken to determine whether inhaled COREXIT elicits airway inflammation, alters pulmonary function or airway reactivity, or exerts pharmacological effects. Male rats were exposed to COREXIT (mean 27 mg/m(3), 5 h). Bronchoalveolar lavage was performed on d 1 and 7 postexposure. Lactate dehydrogenase (LDH) and

albumin were measured as indices of lung injury; macrophages, neutrophils, lymphocytes, and eosinophils were quantified to evaluate inflammation; and oxidant production by macrophages and neutrophils was measured. There were no significant effects of COREXIT on LDH, albumin, inflammatory cell levels or oxidant production at either time point. In conscious animals, neither breathing frequency nor specific airway resistance were altered at 1 hr, 1 d and 7 d postexposure. Airway resistance responses to methacholine (MCh) aerosol in anesthetized animals were unaffected at 1 and 7 d postexposure, while dynamic compliance responses were decreased after 1 d but not 7 d. In tracheal strips, in the presence or absence of MCh, low concentrations of COREXIT (0.001% A-1210477 v/v) elicited relaxation; contraction occurred at 0.003-0.1% v/v. In isolated, perfused trachea,

intraluminally applied COREXIT produced similar effects but at higher concentrations. COREXIT inhibited neurogenic contractile responses of strips to electrical field stimulation. Our findings suggest that COREXIT inhalation did not initiate lung inflammation, but may transiently next increase the difficulty of breathing.”
“These studies characterized cardiovascular responses after an acute inhalation exposure to COREXIT EC9500A, the oil dispersant used in the Deepwater Horizon oil spill. Male Sprague-Dawley rats underwent a single 5-h inhalation exposure to COREXIT EC9500A (average exposure level 27.12 mg/m(3)) or air. On d 1 and 7 following the exposure, rats were implanted with indwelling catheters and changes in heart rate and blood pressure were assessed in response to increasing levels of adrenoreceptor agonists. A separate group of rats was euthanized at the same time points, ventral tail arteries were dissected, and vascular tone along with dose-dependent responses to vasoconstricting and dilating factors were assessed in vitro. Agonist-induced dose-dependent increases in heart rate and blood pressure were greater in COREXIT EC9500A-exposed than in air-exposed rats at 1 d but not 7 d after the exposure.

When the reject button was pressed, participants continued on to

When the reject button was pressed, participants continued on to the next trial, without viewing further. In comparison with rejected stimuli, selected stimuli elicited a larger negative component, with a peak latency of similar to 250 ms. The increase in the negative component was independent of the type of visual stimulus. These results suggest that interest toward content information is reflected in early-stage event-related brain potential responses. NeuroReport 23:331-335 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.”
“Rationale Evidence for an association between phosphatidylinositol-4-phosphate

5-kinase II alpha (PIP5K2A) and schizophrenia CFTRinh-172 was recently obtained and replicated in several samples. PIP5K2A controls the function of

KCNQ NVP-BSK805 chemical structure channels via phosphatidylinositol-4,5-bisphosphate(PIP(2)) synthesis. Interestingly, recent data suggest that KCNQ channels suppress basal activity of dopaminergic neurons and dopaminergic firing. Activation of KCNQ accordingly attenuates the central stimulating effects of dopamine, cocaine, methylphenidate, and phenylcyclidine.

Objective The aim of this study was to explore the functional relevance of PIP5K2A, which might influence schizophrenic behavior.

Materials and methods Here, we study the effects of the neuronal PIP5K2A on KCNQ2, KCNQ5, KCNQ2/KCNQ3, and KCNQ3/KCNQ5 in the Xenopus expression system.

Results We find that wild-type PIP5K2A but not the schizophrenia-associated mutant (N251S)-PIP5K2A activates heteromeric KCNQ2/KCNQ3 and KCNQ3/KCNQ5, the molecular

correlate of neuronal M channels. Homomeric KCNQ2 and KCNQ5 channels were not activated by the kinase indicating that the presence of KCNQ3 in the channel complex is required for the kinase-mediated effects. Acute application of PI(4,5)P(2) and a PIP(2) scavenger indicates that the mutation N251S renders the kinase PIP5K2A inactive.

Conclusions Our results suggest that the schizophrenia-linked mutation of the kinase results in reduced KCNQ channel function and thereby might explain the loss of dopaminergic control PTK6 in schizophrenic patients. Moreover, the addictive potential of dopaminergic drugs often observed in schizophrenic patients might be explained by this mechanism. At least, the insufficiency of (N251S)-PIP5K2A to stimulate neuronal M channels may contribute to the clinical phenotype of schizophrenia.”
“Chronic pain is characterized by enhanced sensory neurotransmission that underlies increased sensitivity to noxious stimuli and the perception of non-noxious stimuli as painful. Evidence from neurophysiological and pharmacological studies demonstrates that ATP produces pain by directly enhancing neuronal excitability via the activation of specific ligand-gated ion channels, the P2X3 and P2X2/3 receptors. In addition, ATP activates CNS glial cells (e.g. microglia) in response to persistent nociceptive stimulation.