ASICs do not play a role in maintaining hyperalgesia induced by repeated intramuscular acid injections

pre-printRepeated intramuscular acid injections produce long-lasting mechanical hyperalgesia that depends on activation of ASICs. The present study investigated if pH-activated currents in sensory neurons innervating muscle were altered in response to repeated acid injections, and if blockade of ASICs reverses existing hyperalgesia. In muscle sensory neurons, the mean acid-evoked current amplitudes and the biophysical properties of the ASIC-like currents were unchanged following acidic saline injections when compared to neutral pH saline injections or uninjected controls. Moreover, increased mechanical sensitivity of the muscle and paw after the second acid injection was unaffected by local blockade of ASICs (A-317567) in the muscle. As a control, electron microscopic analysis showed that the tibial nerve was undamaged after acid injections. Our previous studies demonstrated that ASICs are important in the development of hyperalgesia to repeated acid injections. However, the current data suggest that ASICs are not involved in maintaining hyperalgesia to repeated intramuscular acid injections

Response to Letter by Dr. Smirmaul Group III/IV muscle afferents contribute to both perception of effort and fatigue

pre-printWe thank Dr. Smirmaul for his interest in our findings, but advise caution not to over-interpret the data to address a question which would have required an entirely different study design. Specifically, the letter to the editor is strongly focused on effort perception, a variable which was, as expected, not considered as a descriptor by the participants when asked to report evoked sensations (Pollak et al., 2014). In fact, given the absence of any sort of muscle contraction or task in our study (i.e. there was no required effort to be rated), an altered effort perception would have been rather unusual

Functional properties of tooth pulp neurons responding to thermal stimulation

ManuscriptThe response properties of tooth pulp neurons that respond to noxious thermal stimulation of the dental pulp have been not well studied. The present study was designed to characterize the response properties of tooth pulp neurons to noxious thermal stimulation of the dental pulp. Experiments were conducted on 25 male ferrets and heat stimulation was applied by a computer-controlled thermode. Only 15% of tooth pulp neurons (n=39) responded to noxious thermal stimulation of tooth. Tooth pulp neurons were found in both the superficial and deep nuclear regions of the subnucleus caudalis (Vc) and in the interface between nucleus caudalis and interpolaris (Vc/Vi). Thirty-seven neurons had cutaneous receptive fields and were classified as either NS (16) or WDR (21) neurons. Repeated heat stimulation of the dental pulp sensitized and increased the number of electrically evoked potentials of tooth pulp neurons. These results provide evidence that both the Vc and Vc/Vi region contain neurons that respond to noxious thermal stimulation of the dental pulp and that these cells may contribute to the sensitization process associated with symptomatic pulpitis

Activation of Src family kinases in spinal microglia contributes to formalin-induced persistent pain state through p38 pathway

pre-printProtein tyrosine phosphorylation has been implicated in normal and pathological functions, such as cell proliferation, migration and differentiation. Recently, some studies have shown that Src family kinases (SFKs) were involved in neurological disorders and neuropathic pain states in which microglial activation plays a role. In the formalin test, we have reported that microglia undergo at least two distinct stages of activation on the basis of signaling events regarding p38 mitogen-activated protein kinases (MAPK). Here, we investigated the involvement of SFKs signaling in formalin pain animal model, and the association with p38 MAPK. Our results showed that SFKs were activated in the spinal microglia beginning 1 day after peripheral formalin injection, lasting for 7 days. Pretreatment with SFK specific inhibitor PP2 could not inhibit formalin induced spontaneous pain behaviors. However, PP2 inhibited formalin injury induced persistent mechanical hyperalgesia, and reversed microglial phospho-p38 expression as well using immunohistostaining and Western blot at day 3 and 7 after injection. Our results suggested that the activation of the Src/p38MAPK signaling cascade in spinal microglia contributed to late stage persistent mechanical hyperalgesia evoked by formalin injection into the paw

Genetics and Gene Expression Involving Stress and Distress Pathways in Fibromyalgia with and without Comorbid Chronic Fatigue Syndrome

In complex multisymptom disorders like fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS) that are defined primarily by subjective symptoms, genetic and gene expression profiles can provide very useful objective information. This paper summarizes research on genes that may be linked to increased susceptibility in developing and maintaining these disorders, and research on resting and stressor-evoked changes in leukocyte gene expression, highlighting physiological pathways linked to stress and distress. These include the adrenergic nervous system, the hypothalamic-pituitary-adrenal axis and serotonergic pathways, and exercise responsive metabolite-detecting ion channels. The findings to date provide some support for both inherited susceptibility and/or physiological dysregulation in all three systems, particularly for catechol-O-methyl transferase (COMT) genes, the glucocorticoid and the related mineralocorticoid receptors (NR3C1, NR3C2), and the purinergic 2X4 (P2X4) ion channel involved as a sensory receptor for muscle pain and fatigue and also in upregulation of spinal microglia in chronic pain models. Methodological concerns for future research, including potential influences of comorbid clinical depression and antidepressants and other medications, on gene expression are also addressed

Reflection on-line or off-line: the role of learning technologies in encouraging students to reflect

This paper presents case studies that describe the experiences of the two authors in trying to use learning technologies to facilitate reflective thinking in their students. At the University of Leicester, a Web-based biology tutorial called ‘How Now Mad Cow’, which covers the topics of bovine spongiform encephalopathy and a new variant Creutzfeldt–Jakob disease (nvCJD). At the University of Southampton, a web-based hyper-mail discussion list to support teaching on a first year psychosocial science module for occupational therapy and physiotherapy students has been established. In both examples, the tutors had attempted to create a learning environment that would engage students in the learning experience and facilitate reflection by helping them to create meaning from the learning experience and see things in a different way. The evaluation data from both case studies provides some evidence that the learning technologies helped to facilitate reflection for some students. However, the evidence for reflection is not overwhelming and the data provides some evidence that four key factors may have influenced how successful the use of learning technologies were in facilitating reflection. These factors are the way the learning technology is used, the nature of the student groups, the role of the tutor and student preferences for ‘off-line reflection’. These are discussed and ways forward are identified

Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Post exertion malaise is one of the most debilitating aspects of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, yet the neurobiological consequences are largely unexplored. The objective of the study was to determine the neural consequences of acute exercise using functional brain imaging. Fifteen female Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients and 15 healthy female controls completed 30 min of submaximal exercise (70% of peak heart rate) on a cycle ergometer. Symptom assessments (e.g. fatigue, pain, mood) and brain imaging data were collected one week prior to and 24 h following exercise. Functional brain images were obtained during performance of: 1) a fatiguing cognitive task – the Paced Auditory Serial Addition Task, 2) a non-fatiguing cognitive task – simple number recognition, and 3) a non-fatiguing motor task – finger tapping. Symptom and exercise data were analyzed using independent samples t-tests. Cognitive performance data were analyzed using mixed-model analysis of variance with repeated measures. Brain responses to fatiguing and non-fatiguing tasks were analyzed using linear mixed effects with cluster-wise (101-voxels) alpha of 0.05. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients reported large symptom changes compared to controls (effect size ≥0.8, p \u3c 0.05). Patients and controls had similar physiological responses to exercise (p \u3e 0.05). However, patients exercised at significantly lower Watts and reported greater exertion and leg muscle pain (p \u3c 0.05). For cognitive performance, a significant Group by Time interaction (p \u3c 0.05), demonstrated pre- to post-exercise improvements for controls and worsening for patients. Brain responses to finger tapping did not differ between groups at either time point. During number recognition, controls exhibited greater brain activity (p \u3c 0.05) in the posterior cingulate cortex, but only for the pre-exercise scan. For the Paced Serial Auditory Addition Task, there was a significant Group by Time interaction (p \u3c 0.05) with patients exhibiting increased brain activity from pre- to post-exercise compared to controls bilaterally for inferior and superior parietal and cingulate cortices. Changes in brain activity were significantly related to symptoms for patients (p \u3c 0.05). Acute exercise exacerbated symptoms, impaired cognitive performance and affected brain function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients. These converging results, linking symptom exacerbation with brain function, provide objective evidence of the detrimental neurophysiological effects of post-exertion malaise

Development of a computerized 2D rating scale for continuous and simultaneous evaluation of two dimensions of a sensory stimulus

INTRODUCTION One-dimensional rating scales are widely used in research and in the clinic to assess individuals' perceptions of sensory stimuli. Although these scales provide essential knowledge of stimulus perception, their limitation to one dimension hinders our understanding of complex stimuli. METHODS To allow improved investigation of complex stimuli, a two-dimensional scale based on the one-dimensional Gracely Box Scale was developed and tested in healthy participants on a visual and an auditory task (rating changes in brightness and size of circles and rating changes in frequency and sound pressure of sounds, which was compared to ratings on one-dimensional scales). Before performing these tasks, participants were familiarized with the intensity descriptors of the two-dimensional scale by completing two tasks. First, participants sorted the descriptors based on their judgment of the intensity of the descriptors. Second, participants evaluated the intensity of the descriptors by pressing a button for the duration they considered matching the intensity of the descriptors or squeezing a hand grip dynamometer as strong as they considered matching the intensity of the descriptors. RESULTS Results from these tasks confirmed the order of the descriptors as displayed on the original rating scale. Results from the visual and auditory tasks showed that participants were able to rate changes in the physical attributes of visual or auditory stimuli on the two-dimensional scale as accurately as on one-dimensional scales. DISCUSSION These results support the use of a two-dimensional scale to simultaneously report multiple dimensions of complex stimuli