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The intermittent cold stress-induced generalized pain response mimics the pathophysiological and pharmacotherapeutic features reported for fibromyalgia patients, including the presence of chronic generalized pain and female dominance. In addition, the intermittent cold stress-induced generalized pain is abolished in lysophosphatidic acid receptor type-1 knockout mice, as reported in many cases of neuropathic pain models. This study aimed to identify the brain loci involved in the intermittent cold stress generalized pain response and test their dependence on the lysophosphatidic acid receptor type-1. Positron emission tomography analyses using 2-deoxy-2-[ F]fluoro-D-glucose in the presence of a pain stimulus showed that intermittent cold stress causes a significant increase in uptake in the ipsilateral regions, including the salience networking-related anterior cingulate cortex and insular cortex and the cognition-related hippocampus. A significant decrease was observed in the default mode network-related posterior cingulate cortex. Almost these intermittent cold stress-induced changes were abolished in lysophosphatidic acid receptor type-1 knockout mice. There results suggest that the intermittent cold stress-induced generalized pain response is mediated by the lysophosphatidic acid receptor type-1 in specific brain loci related to salience networking and cognition, which may lead to further developments in the treatment of fibromyalgia.
Learn More >Despite the existence of evidence-based psychological interventions for pain management, there are barriers that interfere with treatment engagement. A brief intervention integrated into primary care reduced barriers and showed promising benefits from pre- to post-intervention. However, it is unknown whether a brief intervention can provide long-term effects. The purpose of this study was to examine whether a brief psychological intervention offered benefits in pain severity, pain interference, pain catastrophizing, and depressive symptoms at 1- and 6-month follow-ups.
Learn More >Given the high volume of hysterectomies performed, the contribution of gynecologists to the opioid crisis is potentially significant. Following a hysterectomy, most patients are over-prescribed opioids, are vulnerable to developing new persistent opioid use, and can be the source of misuse, diversion, or accidental exposure. People who misuse opioids are at risk of an overdose related death, which is now one of the leading causes of death in the United States and is rising in other countries. It is the physician's responsibility to reduce opioid use by making impactful practice changes, such as 1) using pre-emptive opioid sparing strategies, 2) optimizing multimodal nonopioid pain management, 3) restricting postoperative opioid prescribing, and 4) educating patients on proper disposal of unused opioids. These changes can be implemented with an enhanced recovery after surgery protocol, shared decision-making, and patient education strategies related to opioids.
Learn More >Polypharmacy is often appropriate for children with life-limiting conditions but is associated with an increase in hospitalisations and inappropriate prescribing, and can affect the quality of life of children and their families as they manage complex medication schedules. Despite this, little is known about polypharmacy in this population.
Learn More >Sigma receptors modulate nociception, offering a potential therapeutic target to treat pain, but relatively little is known regarding the role of sigma-2 receptors (S2R) in nociception. The purpose of this study was to investigate the in vivo analgesic and anti-allodynic activity and liabilities of a novel S2R selective ligand, 1-[4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)butyl]-3-methyl-1,3-dihydro-1,3-benzimidazol-2-one (CM-398). The inhibition of thermal, induced chemical, or inflammatory pain as well as the allodynia resulting from chronic nerve constriction injury (CCI) model of neuropathic pain were assessed in male mice. CM-398 dose-dependently (10-45 mg/kg i.p.) reduced mechanical allodynia in the CCI neuropathic pain model, equivalent at the higher dose to the effect of the control analgesic gabapentin (50 mg/kg i.p.). Likewise, pretreatment (i.p.) with CM-398 dose-dependently produced antinociception in the acetic acid writhing test (ED (and 95% C.I.) = 14.7 (10.6-20) mg/kg, i.p.) and the formalin assay (ED (and 95% C.I.) = 0.86 (0.44-1.81) mg/kg, i.p.) but was without effect in the 55 °C warm-water tail-withdrawal assay. A high dose of CM-398 (45 mg/kg, i.p.) exhibited modest locomotor impairment in a rotarod assay and conditioned place aversion, potentially complicating the interpretation of nociceptive testing. However, in an operant pain model resistant to these confounds, mice experiencing CCI and treated with CM-398 demonstrated robust conditioned place preference. Overall, these results demonstrate the S2R selective antagonist CM-398 produces antinociception and anti-allodynia with fewer liabilities than established therapeutics, adding to emerging data suggesting possible mediation of nociception by S2R, and the development of S2R ligands as potential treatments for chronic pain.
Learn More >Mutations in the peroxisomal half-transporter ABCD1 cause X-linked adrenoleukodystrophy, resulting in elevated very long-chain fatty acids (VLCFA), progressive neurodegeneration and an associated pain syndrome that is poorly understood. In the nervous system of mice, we found ABCD1 expression to be highest in dorsal root ganglia (DRG), with satellite glial cells (SGCs) displaying higher expression than neurons. We subsequently examined sensory behavior and DRG pathophysiology in mice deficient in ABCD1 compared to wild-type mice. Beginning at 8 months of age, mice developed persistent mechanical allodynia. DRG had a greater number of IB4-positive nociceptive neurons expressing PIEZO2, the mechanosensitive ion channel. Blocking PIEZO2 partially rescued the mechanical allodynia. Beyond affecting neurons, ABCD1 deficiency impacted SGCs, as demonstrated by high levels of VLCFA, increased glial fibrillary acidic protein (GFAP), as well as genes disrupting neuron-SGC connectivity. These findings suggest that lack of the peroxisomal half-transporter ABCD1 leads to PIEZO2-mediated mechanical allodynia as well as SGC dysfunction. Given the known supportive role of SGCs to neurons, this elucidates a novel mechanism underlying pain in X-linked adrenoleukodystrophy.
Learn More >Organismal bilateral symmetry is associated with near-identical halves of the central nervous system, with certain functions displaying specialization through one brain hemisphere. The processing of pain in the brain as well as brain plasticity in the context of painful injuries have garnered much attention in recent decades. Noninvasive brain imaging studies in pain-free human subjects have identified multiple brain regions that are linked to the sensory and affective components of pain. Longlasting adaptations in brains of chronic pain sufferers have likewise been described, suggesting a mechanism for pain chronification. Invasive molecular and biochemical studies in animal models have expanded on these findings, with added emphasis on the role of specific genes and molecules involved. To date, the extent of hemispheric asymmetry in the context of pain is not well-understood. This topical review evaluates the evidence of hemispheric specialization observed in humans and rodent models of pain and compares it to findings where such asymmetry is absent. Our review shows conflicting information regarding the existence of pain-related asymmetry, and if so, the side to which it can be localized. This could be due to the heterogeneity of pain processing pathways, heterogeneity in study parameters, as well as differences in data reporting. With the advent of progressively sophisticated non-invasive tools that can be used in human subjects, in addition to more precise methods to visualize and control specific brain regions or neuronal ensembles in animal models, we predict that the next few decades will witness a better understanding of the supraspinal control and processing of chronic pain, including the role of each of its hemispheres.
Learn More >Phantom limb pain is a rare cause of chronic pain in children but it is associated with extremely refractory pain and disability. The reason for limb amputation is often due to treatment for cancer or trauma and it has a lower incidence compared to adults. The mechanism of why phantom pain exists remains uncertain and may be a result of cortical reorganisation as well as ectopic peripheral input. Treatment is aimed at reducing both symptoms as well as managing pain related disability and functional restoration. Neuromodulatory approaches using deep brain stimulation for phantom limb pain is reserved for only the most refractory cases. The targets for brain stimulation include the thalamic nuclei and motor cortex. Novel targets such as the anterior cingulate cortex remain experimental as cases of serious adverse effects such as seziures have limited their widespread uptake. A multidisciplinary approach is crucial to successful rehabilitation using a biopsychosocial pain management approach.
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