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Chemotherapy-induced peripheral neuropathy (CIPN) adversely impacts quality of life and a challenge to treat with existing drugs used for neuropathic pain. Losartan, an angiotensin II type 1 receptor (AT1R) antagonist widely used to treat hypertension, has been reported to have analgesic effects in several pain models. In this study, we assessed losartan's analgesic effect on paclitaxel-induced neuropathic pain (PINP) in rats and its mechanism of action in dorsal root ganglion (DRG). Rats received intraperitoneal injections of 2 mg/kg paclitaxel on days 0, 2, 4, and 6 and received single or multiple intraperitoneal injections of losartan potassium dissolved in phosphate-buffered saline at various times. The mechanical thresholds, protein levels of inflammatory cytokines, and cellular location of AT1R and interleukin 1β (IL-1β) in the DRG were assessed with behavioral testing, Western blotting, and immunohistochemistry, respectively. Data were analyzed by two-way repeated-measures analysis of variance for the behavioral test or the Mann-Whitney U test for the Western blot analysis and immunohistochemistry. Single and multiple injections of losartan ameliorated PINP, and losartan delayed the development of PINP. Paclitaxel significantly increased, and losartan subsequently decreased, the expression levels of inflammatory cytokines, including IL-1β and tumor necrosis factor α (TNF-α), in the lumbar DRG. AT1R and IL-1β were expressed in both neurons and satellite cells and losartan decreased the intensity of IL-1β in the DRG. Losartan ameliorates PINP by decreasing inflammatory cytokines including IL-1β and TNF-α in the DRG. Our findings provide a new or add-on therapy for CIPN patients.
Learn More >Fibromyalgia (FM) is a prevalent chronic pain disorder associated with large suffering and substantial societal costs. Pain-related avoidance behaviour and hypervigilance to bodily symptoms are common in FM and contribute in maintaining and exacerbating the disorder. Exposure therapy targeting avoidance behaviours and hypervigilance has shown promise in the treatment of FM. The present study investigated mediators of treatment outcome in exposure therapy for FM. We used data from a randomised trial, where 140 participants were allocated to 10-week internet-delivered exposure therapy or to a waiting-list control condition. The main outcome variable (FM symptoms) and the hypothesized mediators (FM-related avoidance behaviour, mindful non-reactivity and FM-related worry) were measured weekly throughout treatment. Mediation analyses were conducted using linear mixed effects models with bootstrap replication and time-lagged analysis. Results indicated that all three process variables were significant mediators of FM severity. However, in the time-lagged analyses, only FM-related avoidance behaviour displayed a unidirectional relationship over time with FM symptoms, suggesting a causal effect. Thus, results illustrate that changes in avoidance behaviour mediate the outcome of exposure on FM symptoms, which implies that avoidance behaviour is an important treatment target in exposure therapy.
Learn More >Migraine is the most common disabling primary headache globally. Attacks typically present with unilateral throbbing headache and associated symptoms including, nausea, multisensory hypersensitivity, and marked fatigue. In this article, the authors address the underlying neuroanatomical basis for migraine-related headache, associated symptomatology, and discuss key clinical and preclinical findings that indicate that migraine likely results from dysfunctional homeostatic mechanisms. Whereby, abnormal central nervous system responses to extrinsic and intrinsic cues may lead to increased attack susceptibility.
Learn More >This study sought to examine the association between early life stressors and adolescent headache in the Canadian population, and the potential mediating influence of symptoms of depression and anxiety.
Learn More >Chronic pain and depression are often comorbid exhibiting common clinical presentations and biological connections related to central nervous system sensitization. Epigenetic regulation of gene expression in the brain plays a crucial role in response to long-lasting stress and chronic pain, and microRNA imbalance in the prefrontal cortex (PFC) might be involved in central sensitization. Male Sprague Dawley rats were subjected to unpredictable chronic mild stress (UCMS) and spared nerve injury (SNI) to initiate depressive-like behavior and chronic pain behavior, respectively. The next-generation sequencing technique was employed to analyze PFC microRNAs in both the UCMS and SNI models. Rats exposed to either UCMS or SNI exhibited both depressive-like and chronic pain behaviors. Five specific microRNAs (miR-10a-5p, miR-182, miR-200a-3p, miR-200b-3p, and miR-429) were simultaneously down-regulated in the depressive-like and chronic pain models after 4 weeks of short-term stress. Gene ontology revealed that the 4-week period of stress enhanced neurogenesis. Only the miR-200a-3p level was continuously elevated under prolonged stress, suggesting roles of reduced neurogenesis, inflammatory activation, disturbed circadian rhythm, lipid metabolism, and insulin secretion in the co-existence of pain and depression. Thus we conclude that miR-200a-3p might be a specific biomarker of central sensitization in chronic pain and depression.
Learn More >Spinal hyperexcitability is a key event in the development of persistent pain, and arises partly from alterations in the number and localization of AMPA-type glutamate receptors. However, determining precisely where these changes occur is challenging due to the requirement for multiplex labelling and nanoscale resolution. The recent development of super-resolution light microscopy provides new tools to address these challenges. Here, we apply combined confocal/direct STochastic Optical Reconstruction Microscopy (dSTORM) to reveal changes in calcium-permeable subunits of AMPA-type glutamate receptors (GluA1) at identified SCDH primary afferent terminals in a model of inflammatory pain. L4/5 lumbar spinal cord was collected from adult male C57BL/6J mice 24 hours after unilateral hindpaw injection of saline or 1% carrageenan (n=6/group). Tissue was immunolabelled for markers of peptidergic axon terminals (Substance P; SP), presynaptic active zones (Bassoon), and GluA1. dSTORM revealed a 59% increase in total GluA1 immunolabelling in the SCDH in the carrageenan group, which was not detected by confocal microscopy. Cell type-specific analyses identified a 10-fold increase in GluA1 localized to SP structures, and identified GluA1 nanodomains which scaled with behavioural hypersensitivity, and were associated with synaptic release sites. These findings demonstrate that dSTORM has the sensitivity and power to detect nanoscale anatomical changes in the SCDH, and provides new evidence for synaptic insertion of GluA1+-AMPA-Rs at spinal peptidergic nociceptive terminals in a model of inflammatory pain.
Learn More >The pineal gland plays an important role in biological rhythms, circadian and circannual variations, which are key aspects in several headache disorders.
Learn More >Palliative care (PC) teams increasingly care for patients with cancer into survivorship. Cancer survivorship transcends distinctions between acute, chronic, malignant, and nonmalignant pain. Partnering with oncologists, PC teams manage pain that persists after disease-directed treatment, evaluate changing symptoms as possible signs of cancer recurrence, taper opioids and mitigate risk of opioid misuse, and manage comorbid opioid use disorder (OUD). While interdisciplinary guidelines exist for pain management in survivorship, there is a need to develop a conceptual model that fully translates the biopsychosocial framework of PC into survivorship pain management. This review frames a model for pain management in cancer survivorship that balances analgesia with the imperative to minimize risk of OUD, recognizes signs of disease recurrence, and provides whole-person care. Comprehensive narrative review of the literature. Little guidance exists for co-management of pain, psychological distress, and opioid misuse in survivorship. We identified themes for whole-person pain management in survivorship: use of opioids and co-analgesic medications to prevent recurrent pain from residual tissue damage following cancer treatment, opioid tapering to the lowest effective dose, utilization of nonpharmacologic psychological interventions shown to reduce pain, screening for and management of OUD in partnership with addiction medicine specialists, maintaining vigilance for disease recurrence, and engaging in shared medical decision making. The management of pain in cancer survivorship is complex and requires interdisciplinary care that balances analgesia with the imperative to reduce long-term inappropriate opioid use and manage OUD, while maintaining therapeutic presence with patients in the spirit of PC.
Learn More >Dementia is an irreversible, progressive form of cognitive dysfunction that can affect memory, learning ability, thinking, orientation, comprehension, calculation, linguistic skills and executive function but which does not impair consciousness. Pain prevalence is high among the elderly who are also at elevated risk for dementia. Pain control for dementia patients is important but can be challenging for clinicians as cognitive deficits can make it difficult to identify, localize and assess pain. Cerebral changes associated with dementia may change how people process and experience pain in ways that are not entirely elucidated. Agitation is a frequent symptom of dementia and may be associated with untreated pain as agitation and aggression symptoms decrease when pain is effectively addressed.
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