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It is unclear whether a diagnosis of chronic pain is associated with an increase or decrease in the placebo response. The aim of this study was to use an experimental placebo conditioning paradigm to test if expectancy for pain relief impacts on acute pain perception in individuals with a chronic pain diagnosis of osteoarthritis (OA) or fibromyalgia (FM), compared to healthy individuals (HI). An inert cream was applied to the dominant forearm of participants (60 OA, 79 FM and 98 HI), randomly assigned to either a placebo or control group. In both groups an inactive cream was applied to the dominant forearm. The placebo group was told this may or may not be a local anaesthetic cream, while the control group was told the cream was inactive. Laser pain was delivered, and numerical pain intensity ratings collected before, during and after cream application, along with expectation of pain relief and anxiety. The procedure was repeated two weeks later to assess reproducibility. There was a significant reduction in pain in the placebo group, independent of clinical diagnosis. Diagnostic groups (OA,FM,HI) did not differ in their magnitude of placebo analgesia or expectancy of pain relief. The results were similar in the repeat session. The results demonstrate that individuals with chronic pain respond to experimental placebo analgesia in a similar and reproducible manner as healthy individuals, despite higher levels of psychological co-morbidity. This has implications for utilising placebo analgesia in the treatment of chronic pain.
Learn More >Next generation transcriptomics in combination with imaging-based approaches have emerged as powerful tools for the characterization of dorsal root ganglion (DRG) neuronal subpopulations. The mouse DRG has been well-characterized by many independently conducted studies with convergent findings, but few studies have directly compared expression of population markers between mouse and human. This is important because of our increasing reliance on the mouse as a preclinical model for translational studies. While calcitonin gene-related peptide (CGRP) and P2X purinergic ion channel type 3 receptor (P2X3R) have been used to define peptidergic and non-peptidergic nociceptor subpopulations, respectively, in mouse DRG, these populations may be different in other species. To directly test this, as well as a host of other markers, we used multiplex RNAscope in-situ hybridization to elucidate the distribution of a multitude of unique and classic neuronal mRNAs in peptidergic (CGRP expressing) and non-peptidergic (P2X3R expressing) nociceptor subpopulations in mouse and human DRG. We found a large overlapping CGRP and P2X3R neuronal subpopulation in human, lumbar DRG that was not present in mouse. We also found differential expression in a variety of mRNAs for TRP-channels, cholinergic receptors, potassium channels, sodium channels, other markers/targets. These data offer insights into the spatial and functional organization of neuronal cell subpopulations in the rodent and human DRG and support the idea that sensory system organizational principles are likely different between both species.
Learn More >Pain-related disability is a multi-faceted construct that refers to the impact of pain on an individual's capacity to fulfill their self-defined and social roles. This research examined the relationship between clinical, psychological and pain sensitivity factors and pain-related disability among adults with chronic temporomandibular disorder (TMD). We analyzed data from a cross-sectional community-based sample of 1088 men and women with chronic TMD. We first constructed and tested a measure of pain-related disability (i.e., pain impact) including a variable assessing presenteeism, created measurement models of jaw limitation, psychological unease (negative affect, somatic symptoms, catastrophizing), and experimental pain sensitivity (e.g., pressure pain threshold, thermal tolerance and mechanical pressure pain threshold). Subsequently, latent variables were combined in a structural equation model. Participants (n=1088) were 18-44 years old (mean 29.2, SD+7.8) whose chronic TMD had persisted, on average, for 6.9 years (SD+6.4). A model of pain related disability, jaw limitation, and psychological unease was created and refined with exploratory model revisions to account for correlation among variables. Estimation of the final model indicated excellent fit with the data (RMSEA=0.048, RMSEA 90% confidence interval (CI) 0.043, 0.053, CFI=0.956, SRMR=0.040). Jaw functional limitation and psychological unease was strongly related to pain-related disability. Experimental pain sensitivity was removed from our model due to weak direct effect and the burden of performing experimental pain sensitivity testing in a clinical setting. The final model explained 78% of the variance in pain-related disability.
Learn More >Correct communication between immune cells and peripheral neurons is crucial for the protection of our bodies. Its breakdown is observed in many common, often painful conditions, including arthritis, neuropathies and inflammatory bowel or bladder disease. Here, we have characterised the immune response in a mouse model of neuropathic pain using flow cytometry and cell-type specific RNA sequencing (RNA-seq). We found few striking sex differences, but a very persistent inflammatory response, with increased numbers of monocytes and macrophages up to 3½ months after the initial injury. This raises the question of whether the commonly used categorisation of pain into "inflammatory" and "neuropathic" is one that is mechanistically appropriate. Finally, we collated our data with other published RNA-seq datasets on neurons, macrophages and Schwann cells in naïve and nerve injury states. The result is a practical web-based tool for the transcriptional data-mining of peripheral neuroimmune interactions.
Learn More >Vulvodynia is a chronic pain condition with potential associated factors, including musculoskeletal and psychosocial components.
Learn More >The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network initiated a second observational cohort study-the Symptom Patterns Study (SPS)-to further investigate the underlying pathophysiology of Urologic Chronic Pelvic Pain Syndrome (UCPPS) and to discover factors associated with longitudinal symptom changes and responses to treatments.
Learn More >Although the prevalence of migraine tends to decrease in the fifth to sixth decades of life, there are still a significant number of patients > 65 years of age who experience migraine or have new-onset migraine. Because these older patients are often excluded from clinical trials, there are fewer evidence-based treatment guidelines for them. Migraine treatment in the older population requires careful consideration of changes in medication metabolism and increased medical comorbidities. Furthermore, older patients can present with an atypical migraine phenotype and have a higher rate of secondary headache, which may lead to a delay in diagnosis and subsequent treatment. Classic preventive treatments for migraine, including tricyclic antidepressants, antiepileptic drugs, and beta blockers, often have intolerable side effects. In addition, the presence of coronary artery disease, stroke, and peripheral arterial disease precludes the use of typical rescue medications such as triptans. As such, there has been a dire need for novel acute and preventive treatments for older adults. The purpose of this review is to provide an update on novel acute and preventive treatments for migraine in the older population. The advantages of these therapies include their efficacy, favorable side-effect profile, particularly in patients with atherosclerotic disease, as well as their tolerability.
Learn More >Migraine clinical profile may change with age, making it necessary to verify that migraine treatments are equally safe and effective in older patients. These analyses evaluated the effects of patient age on the pharmacokinetics (PK), efficacy, and safety of galcanezumab for prevention of migraine.
Learn More >The medial prefrontal cortex (mPFC) is a brain region involved in the affective components of pain and undergoes plasticity during the development of chronic pain. Dopamine (DA) is a key neuromodulator in the mesocortical circuit and modulates working memory and aversion. Although DA inputs into the mPFC are known to modulate plasticity, whether and how these inputs affect pain remains incompletely understood. By using optogenetics, we find that phasic activation of DA inputs from the ventral tegmental area (VTA) into the mPFC reduce mechanical hypersensitivity during neuropathic pain states. Mice with neuropathic pain exhibit a preference for contexts paired with photostimulation of DA terminals in the mPFC. Fiber photometry-based calcium imaging reveals that DA increases the activity of mPFC neurons projecting to the ventrolateral periaqueductal gray (vlPAG). Together, our findings indicate an important role of mPFC DA signaling in pain modulation.
Learn More >Peripheral nerve injury induces functional and structural remodeling of neural circuits along the somatosensory pathways, forming the basis for somatotopic reorganization and ectopic sensations, such as referred phantom pain. However, the mechanisms underlying that remodeling remain largely unknown. Whisker sensory nerve injury drives functional remodeling in the somatosensory thalamus: the number of afferent inputs to each thalamic neuron increases from one to many. Here, we report that extrasynaptic γ-aminobutyric acid-type A receptor (GABAR)-mediated tonic inhibition is necessary for that remodeling. Extrasynaptic GABAR currents were potentiated rapidly after nerve injury in advance of remodeling. Pharmacological activation of the thalamic extrasynaptic GABARs in intact mice induced similar remodeling. Notably, conditional deletion of extrasynaptic GABARs in the thalamus rescued both the injury-induced remodeling and the ectopic mechanical hypersensitivity. Together, our results reveal a molecular basis for injury-induced remodeling of neural circuits and may provide a new pharmacological target for referred phantom sensations after peripheral nerve injury.
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