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Chronic pelvic pain conditions such as interstitial cystitis/bladder pain syndrome (IC/BPS) remain clinical and mechanistic enigmas. Microglia are resident immune cells of the central nervous system (CNS) that respond to changes in the gut microbiome, and studies have linked microglial activation to acute and chronic pain in a variety of models, including pelvic pain. We have previously reported that mice deficient for the lipase acyloxyacyl hydrolase (AOAH) develop pelvic allodynia and exhibit symptoms, comorbidities, and gut dysbiosis mimicking IC/BPS. Here, we assessed the role of AOAH in microglial activation and pelvic pain. RNAseq analyses using the ARCHS4 database and confocal microscopy revealed that AOAH is highly expressed in wild type microglia but at low levels in astrocytes, suggesting a functional role for AOAH in microglia. Pharmacologic ablation of CNS microglia with PLX5622 resulted in decreased pelvic allodynia in AOAH-deficient mice and resurgence of pelvic pain upon drug washout. Skeletal analyses revealed that AOAH-deficient mice have an activated microglia morphology in the medial prefrontal cortex and paraventricular nucleus, brain regions associated with pain modulation. Because microglia express Toll-like receptors and respond to microbial components, we also examine the potential role of dysbiosis in microglial activation. Consistent with our hypothesis of microglia activation by leakage of gut microbes, we observed increased serum endotoxins in AOAH-deficient mice and increased activation of cultured BV2 microglial cells by stool of AOAH-deficient mice. Together, these findings demonstrate a role for AOAH in microglial modulation of pelvic pain and thus identify a novel therapeutic target for IC/BPS.
Learn More >Fibromyalgia is one of the most common causes of widespread chronic pain. It has a huge impact on the quality of life, namely because it appears earlier in life than most of the chronic pain conditions. Furthermore, emotional-cognitive distress factors, such as depression and anxiety, are a common feature in patients with fibromyalgia. The neurobiological mechanisms underlying fibromyalgia remain mostly unknown. Among non-pharmacological treatments, cognitive-behavioral therapy has been used during the last decade, namely with the enrolment of patients in programs of mindfulness-based stress reduction (MBSR) and in mindfulness-based interventions (MBI). We critically analyzed the literature to search for scientific evidence for the use of MBI in fibromyalgia. The studies were evaluated as to several outcomes of fibromyalgia improvement along with aspects of the study design which are currently considered relevant for research in mindfulness. We conclude that despite the sparsity of well-structured longitudinal studies, there are some promising results showing that the MBI are effective in reducing the negative aspects of the disease. Future design of studies using MBI in fibromyalgia management should be critically discussed. The importance of active controls, evaluation of sustained effects along with investigation of the subserving neurobiological mechanisms and detailed reports of possible adverse effects should be considered.
Learn More >This pilot study aims to test the usability of the iACTwithPain platform, an online ACT-based intervention for people with chronic pain, to obtain information on which intervention and usability aspects need improvement and on expected retention rates.
Learn More >In the central nervous system, post-inhibitory rebound firing (RF) may mediate overactivity of neurons under pathophysiological condition. RF is also observed in dorsal root ganglion (IRA) neurons. However, the functional significance of RF in primary sensory neurons has remained unknown. After peripheral sensory nerve/neuron injury, DRG neurons exhibit hyperexcitability. Therefore, RF may play a role in neuropathic pain.
Learn More >The anandamide is a relevant ligand due to its capacity of interacting with several proteins, including the T-type calcium channels, which play an important role in neuropathic pain and depression disorders. Hence, a detailed characterization of the chemical properties and conformational stability of anandamide may provide valuable information to understand its behavior in a biological context. Herein, conceptual DFT and QTAIM analyses were performed to theoretically characterize the chemical reactivity properties and the structural stability of conformations of anandamide, using the BP86/cc-pVTZ level of theory. Global reactivity description, based on conceptual DFT, indicates that the hardness increases and the electrophilicity index decreases for both, the hairpin and U-shape conformers relative to the extended conformers. Also, an increase in the chemical potential value and a decrease in the electronegativity and the electrophilicity index is observed in the ethanolamide open ring conformers in comparison with the corresponding closed ring structures. In addition, regarding the characterization of local reactivity descriptors, the maximum values of the Fukui and Parr functions indicate that the most probable location for a nucleophilic attack is either the hydroxyl oxygen located in the ethanolamide closed ring conformers or the carbonyl oxygen present in the open ring conformers. The most probable location for an electrophilic attack is in the alkyl double bond region in all anandamide conformers. According to the QTAIM results, the intramolecular hydrogen bond formation stabilizing the structure of anandamide has interaction energy values for the closed ring conformations of 12.33-12.46 kcal mol, indicating a strong interaction. Lastly, molecular docking calculations determined that a region in the pore, denominate as pore-blocking, is a probable site for the interaction of anandamide with the human Ca3.2 isoform of the T-type calcium channel family. The pore-blocking site contains hydrophobic residues where the non-polar part in the final alkyl region of anandamide established mainly alkyl-alkyl interactions, while the polar part (the ethanolamide group) interacts with the polar residue S900. The information based on conceptual DFT presented may aid in the design of drugs with similar chemical characteristics as those identified in anandamide so as to bind anandamide-interacting proteins, including the T-type calcium channels.
Learn More >Chronic pain has been associated with changes in pain-related brain structure and function, including advanced brain aging. Non-pharmacological pain management is central to effective pain management. However, it is currently unknown how use of non-pharmacological pain management is associated with pain-related brain changes. The objective of the current study was to examine the association between brain-predicted age difference and use of non-pharmacological pain management (NPM) in a sample of middle-aged and older adults with and without chronic knee pain across two time points. One-hundred and 12 adults (mean age = 57.9 ± 8.2 years) completed sociodemographic measures, clinical pain measures, structural T1-weighted brain magnetic resonance imaging, and self-reported non-pharmacological pain management. Using a validated approach, we estimated a brain-predicted age difference (brain-PAD) biomarker, calculated as brain-predicted age minus chronological age, and the change in brain-PAD across 2 years. Repeated measures analysis of covariance was conducted to determine associations of non-pharmacological pain management and brain-PAD, adjusting for age, sex, study site, and clinical pain. There was a significant timepain/NPM interaction effect in brain-PAD ( < 0.05). Tests of simple main effects indicated that those persistently using NPM had a "younger" brain-PAD over time, suggesting a potential protective factor in persistent NPM use. Future studies are warranted to determine the influence of NPM in brain aging and pain-related neurological changes.
Learn More >Environmental sensitivity is commonly reported by people with fibromyalgia syndrome. People living with fibromyalgia syndrome frequently report hypersensitivity to noxious and non-noxious sensations. To date, there has been little empirical validation of sensory disturbance to non-noxious triggers. Environmental sensitivity is used as a diagnostic feature only in Bennet's alternative criteria for diagnosis of fibromyalgia, where it was ranked the second most important of the components for diagnosis, after number of pain sites. The aim of this study was to use a validated sensory measure to determine if people with fibromyalgia have greater sensory disturbances compared to people with other chronic pain conditions.
Learn More >Kappa-opioid receptors (KOR) are widely expressed throughout the central nervous system, where they modulate a range of physiological processes depending on their location, including stress, mood, reward, pain, inflammation, and remyelination. However, clinical use of KOR agonists is limited by adverse effects such as dysphoria, aversion, and sedation. Within the drug-development field KOR agonists have been extensively investigated for the treatment of many centrally mediated nociceptive disorders including pruritis and pain. KOR agonists are potential alternatives to mu-opioid receptor (MOR) agonists for the treatment of pain due to their anti-nociceptive effects, lack of abuse potential, and reduced respiratory depressive effects, however, dysphoric side-effects have limited their widespread clinical use. Other diseases for which KOR agonists hold promising therapeutic potential include pruritis, multiple sclerosis, Alzheimer's disease, inflammatory diseases, gastrointestinal diseases, cancer, and ischemia. This review highlights recent drug-development efforts targeting KOR, including the development of G-protein-biased ligands, mixed opioid agonists, and peripherally restricted ligands to reduce side-effects. We also highlight the current KOR agonists that are in preclinical development or undergoing clinical trials.
Learn More >Adverse childhood experiences (ACEs) increase the likelihood of reduced physical and psychological health in adulthood. Though understanding and psychological management of traumatic experiences is growing, the empirical exploration of ACEs and physical clinical outcomes remains under-represented and under-explored. This topical review aimed to highlight the role of ACEs in the experience of chronic pain, pain management services and clinical decision making by: (1) providing an overview of the relationship between ACEs and chronic pain; (2) identifying biopsychosocial mechanisms through which ACEs may increase risk of persistent pain; (3) highlighting the impact of ACEs on patient adherence and completion of pain management treatment; and (4) providing practical clinical implications for pain management. Review findings demonstrated that in chronic pain, ACEs are associated with increased pain complications, pain catastrophizing and depression and the combination of these factors further heightens the risk of early treatment attrition. The pervasive detrimental impacts of the COVID-19 pandemic on ACEs and their cyclical effects on pain are discussed in the context of psychological decline during long treatment waitlists. The review highlights how people with pain can be further supported in pain services by maintaining trauma-informed practices and acknowledging the impact of ACEs on chronic pain and detrimental health outcomes. Clinicians who are ACE-informed have the potential to minimize the negative influence of ACEs on treatment outcomes, ultimately optimizing the impact of pain management services.
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