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Chronic pain is one of the main symptoms of spinal disorders such as spinal canal stenosis. A major cause of this pain is related to compression of the spinal cord, and chronic pain can develop at the level of the compressed spinal segment. However, in many patients chronic pain arises in an area that does not correspond to the compressed segment, and the underlying mechanism involved remains unknown. This was investigated in the present study using a mouse model of spinal cord compression in which mechanical pain of the hindpaws develops after compression of the first lumbar segment (L1) of the spinal cord. Compression induced the activation of astrocytes in the L1 spinal dorsal horn (SDH)-but not the L4 SDH that corresponds to the hindpaws-and activated signal transducer and activator of transcription 3 (STAT3). Suppressing reactive astrocytes by expressing a dominant negative form of STAT3 (dnSTAT3) in the compressed SDH prevented mechanical pain. Expression of interleukin (IL)-6 was also upregulated in the compressed SDH, and it was inhibited by astrocytic expression of dnSTAT3. Intrathecal administration of a neutralizing anti-IL-6 antibody reversed the compression-induced mechanical pain. These results suggest that astrocytic STAT3 and IL-6 in the compressed SDH are involved in remote mechanical pain observed in the lower extremity, and may provide a target for treating chronic pain associated with spinal cord compression such as spinal canal stenosis.
Learn More >Cholesterol plays vital roles in many central physiological and pathological processes. As a key component in the cell membrane, cholesterol can regulate a variety of ion channels, including ligand-gated ion channels (LGICs). However, relatively little is known about the molecular detail and in vivo consequence of cholesterol-LGIC interaction. Here, we reveal that membrane cholesterol depletion significantly inhibits the potentiating effects of dehydroxylcannabidiol (DH-CBD) on glycine-activated currents (I) in HEK 293T cells expressing α1/α3 glycine receptors (GlyRs). Simvastatin considerably decreases cholesterol levels and DH-CBD-induced potentiation of I in the spinal cord of mice. Simvastatin also significantly decreases DH-CBD analgesia in acute and chronic pain of mice. The cholesterol levels in the dorsal horn of spinal cord, measured by mass spectrometry imaging, are specifically correlated with cannabinoid potentiation of spinal GlyRs and cannabinoid-induced analgesia. These findings suggest that spinal cholesterol is critical for the efficacy of glycinergic cannabinoid-induced analgesia.
Learn More >The IMPACT study focuses on chronic low back pain (CLBP) and depression symptoms, a prevalent and complex problem that represents a challenge for health professionals. Acceptance and Commitment Therapy (ACT) and Brief Behavioural Activation Treatment for Depression (BATD) are effective treatments for patients with persistent pain and depression, respectively. The objectives of this 12 month, multicentre, randomised, controlled trial (RCT) are (i) to examine the efficacy and cost-utility of adding a group-based form of ACT or BATD to treatment-as-usual (TAU) for patients with CLBP and moderate to severe levels of depressive symptoms; (ii) identify pre-post differences in levels of some physiological variables and (iii) analyse the role of polymorphisms in the gene, psychological process measures and physiological variables as mediators or moderators of long-term clinical changes.
Learn More >Toothache is a common painful consequence of damage to the teeth, particularly when coupled to infection. Clinical restoration of tooth integrity, sometimes involving physical and chemical sterilization of the tooth with nerve fiber ablation (i.e., endodontic therapy), generally alleviates pain and allows long-lasting dental function. These observations raise questions regarding the biological role of tooth-innervating fibers. Here, we determined the transcriptomic diversity of the sensory neurons that can be retrogradely labeled from mouse molar teeth. Our results demonstrate that individual molars are each targeted by a dedicated population of about 50 specialized trigeminal neurons. Transcriptomic profiling identifies the majority of these as expressing markers of fast-conducting neurons, with about two-thirds containing nociceptive markers. Our data provide a new view of dental innervation, extending previous reports that used candidate gene approaches. Importantly, almost all retrogradely labeled neurons, including nociceptors, express the recently characterized mechanosensor Piezo2, an ion channel that endows cells with sensitivity to gentle touch. Intriguingly, about a quarter of the labeled neurons do not appear to be nociceptors, perhaps insinuating a role for them in discriminative touch. We hypothesize that dental neurons are capable of providing mechanosensitive information to drive rapid behavioral responses and protect teeth from damage. Damage to the teeth and exposure of the large population of molar nociceptors may trigger prolonged or abnormal activation driving toothache. Future studies examining the responses of these transcriptomically defined classes of neurons will help define their significance in oral sensation.
Learn More >Background and Aims Higher chronic pain acceptance is associated with lower pain and disability. Clinician beliefs are associated with patients' beliefs. This study therefore aimed to develop the Chronic Pain Acceptance Questionnaire for Clinicians (CPAQ-C) to measure clinicians' beliefs regarding the importance of levels of acceptance in patients with chronic pain, and to examine the questionnaire's psychometric properties. Methods Phase one: the CPAQ-C was adapted from the Chronic Pain Acceptance Questionnaire. Data on 162 completed questionnaires were analysed using Rasch analysis. Phase Two: the cohort completed the Healthcare Providers Pain and Impairment Relationship Scale, and the association (Pearson's correlation co-efficient) between these questionnaires examined to assist CPAQ-C validation. Twenty-four participants completed the CPAQ-C one-week later. Test re-test reliability was examined using intraclass correlation co-efficient (2,1) and standard error of measurement. Phase Three: to examine responsiveness 17 clinicians attending a workshop on Acceptance and Commitment Therapy completed the CPAQ-C before and immediately after the workshop, and six-months later. The Skillings Mack test was used to determine whether CPAQ-C scores differed across different timepoints. Results Rasch analysis supported two subscales: activity engagement and pain willingness. Five poorly functioning items were excluded. There was good correlation between the CPAQ-C and Healthcare Providers Pain and Impairment Relationship Scale (-.54). The CPAQ-C demonstrated good reliability (ICC (2,1): .81; standard error of measurement: 4.76). There was significant improvement in CPAQ-C scores following the workshop (p=<.001). Conclusions The CPAQ-C appears a valid, reliable and responsive measure of clinicians' beliefs regarding the importance of levels of acceptance in patients with chronic pain. Implications Where the CPAQ-C reveals that clinicians have low perceived levels of importance regarding acceptance in patients with chronic pain those clinicians may benefit from specific education, however, this requires further examination.
Learn More >Migraine is diagnosed in 5% of children in the United States by the age of ten. The estimated prevalence for children with migraine is 10%. It has become increasingly important to diagnose children and adolescents with migraine as they are disabling. Children are more likely to miss school and activities due to headaches compared to other children. In addition, poor management and treatment in children and adolescents could potentially lead to an increase in migraine in adults.
Learn More >Hamstring injuries in athletes can lead to significant time away from competition as a result of persistent posterior thigh pain. These cases are often difficult to treat as the state of the tissues alone cannot explain symptoms. In non-athletic populations with persistent pain, disruptions to tactile, proprioceptive, and spatial cortical representations exist, which has led to promising brain-based treatments. Here, we explored whether athletes with persistent posterior thigh pain also display impairments in these cortical representations.
Learn More >TRESK belongs to the K family of potassium channels, also known as background or leak potassium channels due to their biophysical properties and their role regulating membrane potential of cells. Several studies to date have highlighted the role of TRESK in regulating the excitability of specific subtypes of sensory neurons. These findings suggest TRESK could be involved in pain sensitivity. Here, we review the different evidence available that involves the channel in pain and sensory perception, from studies knocking out the channel or overexpressing it to identified mutations that link the channel to migraine pain. In addition, the therapeutic possibilities are discussed, as targeting the channel seems an interesting therapeutic approach to reduce nociceptor activation and to decrease pain.
Learn More >The profound burden of disease associated with musculoskeletal health conditions is well established. Despite the unequivocal disability burden and personal and societal consequences, relative to other non-communicable diseases (NCDs), system-level responses for musculoskeletal conditions that are commensurate with their burden have been lacking nationally and globally. Health policy priorities and responses in the 21st century have evolved significantly from the 20th century, with health systems now challenged by an increasing prevalence and impact of NCDs and an unprecedented rate of global population ageing. Further, health policy priorities are now strongly aligned to the 2030 Sustainable Development Goals. With this background, what are the challenges and opportunities available to influence global health policy to support high-value care for musculoskeletal health conditions and persistent pain? This paper explores these issues by considering the current global health policy landscape, the role of global health networks, and progress and opportunities since the 2000-2010 Bone and Joint Decade for health policy to support improved musculoskeletal health and high-value musculoskeletal health care.
Learn More >Previous frameworks have failed to adequately explain the observed correlation between within-subject variability in pain reporting and analgesic placebo response. These relationships have been observed in both clinical and experimental setups. Within-subject variability of clinical pain scores is traditionally assessed based on daily pain diaries collected during the pre-intervention stage. Experimental variability can be assessed by the Focused Analgesia Selection Test (FAST), which calculates the relationship between noxious stimuli administrated at various intensities and pain reports. The variability, either clinical or experimental, has been shown to predict the placebo response. In explaining the placebo response, Bayesian Brain Hypothesis (BBH) posits that pain perception (posterior), is composed of certainty (precision) of expectations (priors due to belief or conditioning) and incoming sensory information (likelihood), with the bulk of research focused on the precision of priors. Virtually all placebo analgesia research has focused on the priors and their certainty, rather than on the certainty of the likelihood, mainly because it cannot be assessed directly. We propose that the within-subject variability, as encapsulated by the FAST, is a proxy for certainty in (or, precision of) ascending sensory signals, and our results suggest that it could not only be assessed, but also manipulated. If true, our hypothesis will facilitate new lines of research and could potentially promote precision analgesic medicine by use of variability of pain scores as a diagnostic method to identify pain patients who will benefit from specific treatments.
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