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Obesity in adolescents is increasing in frequency and is associated with short-term and long-term negative consequences that include the exacerbation of co-occurring chronic pain.
Learn More >Changing Behavior through Physical Therapy (CBPT), a cognitive-behavioral-based program, has been shown to improve outcomes after lumbar spine surgery in patients with a high psychosocial risk profile; however, little is known about potential mechanisms associated with CBPT treatment effects. The purpose of this study was to explore potential mediators underlying CBPT efficacy after spine surgery.
Learn More >One out of seven women will develop a state of chronic postoperative pain following robot-assisted hysterectomy for endometrial cancer. Recently, metabolic studies have indicated that circulating lipids and lipoproteins could act as nociceptive modulators and thereby influence the induction and perpetuation of pain. The objectives of this explorative study were (1) to examine the preoperative serologic variations in concentrations of lipids, lipoproteins, and various low-molecular metabolites in patients with and without chronic postoperative pain after robot-assisted hysterectomy and (2) to explore if any of these serological biomarkers were predictive for development of chronic postoperative pain.
Learn More >Chronic pain is known to be associated with functional and structural changes in the brain. Inflammatory bowel disease (IBD) presents with chronic abdominal pain in almost 35% of all patients. This study investigates structural and functional changes in magnetic resonance imaging (MRI) after transcranial direct current stimulation (tDCS) applied to ameliorate pain in IBD.
Learn More >People with sensory overresponsiveness (SOR) perceive nonpainful stimuli as noxious and demonstrate hyperalgesia and lingering sensation to laboratory pain stimuli. Electroencephalography (EEG) of cortical activity at rest is widely used to explore endophenotypes but has not yet been tested in people with SOR. Therefore, we investigated the characteristics of resting-state EEG in participants with SOR.
Learn More >Transient receptor potential melastatin member 8 (TRPM8) is a Ca-permeable cation channel that serves as the primary cold and menthol sensor in humans. Activation of TRPM8 by cooling compounds relies on allosteric actions of agonist and membrane lipid phosphatidylinositol-4,5-bisphosphate (PIP), but lack of structural information has thus far precluded a mechanistic understanding of ligand and lipid sensing by TRPM8. Using cryo-electron microscopy, we determined the structures of TRPM8 in complex with the synthetic cooling compound icilin, PIP, and Ca and in complex with the menthol analog WS-12 and PIP Our structures reveal the binding sites for cooling agonists and PIP in TRPM8. Notably, PIP binds to TRPM8 in two different modes, which illustrate the mechanism of allosteric coupling between PIP and agonists. This study provides a platform for understanding the molecular mechanism of TRPM8 activation by cooling agents.
Learn More >Opioid analgesics are powerful pain relievers; however, over time, pain control diminishes as analgesic tolerance develops. The molecular mechanisms initiating tolerance have remained unresolved to date. We have previously shown that desensitization of the μ-opioid receptor and interaction with β-arrestins is controlled by carboxyl-terminal phosphorylation. Here we created knockin mice with a series of serine- and threonine-to-alanine mutations that render the receptor increasingly unable to recruit β-arrestins. Desensitization is inhibited in locus coeruleus neurons of mutant mice. Opioid-induced analgesia is strongly enhanced and analgesic tolerance is greatly diminished. Surprisingly, respiratory depression, constipation, and opioid withdrawal signs are unchanged or exacerbated, indicating that β-arrestin recruitment does not contribute to the severity of opioid side effects and, hence, predicting that G-protein-biased µ-agonists are still likely to elicit severe adverse effects. In conclusion, our findings identify carboxyl-terminal multisite phosphorylation as key step that drives acute μ-opioid receptor desensitization and long-term tolerance.
Learn More >Chronic pain in adults with sickle cell disease (SCD) may be the result of altered processing in the central nervous system as indicated by quantitative sensory testing (QST). Sensory pain quality descriptors on the McGill Pain Questionnaire (MPQ) are indicators of typical or altered pain mechanisms but have not been validated with QST-derived classifications.
Learn More >Chronic itch is a debilitating condition characterised by excessive scratching and is a symptom frequently reported in skin diseases such as atopic dermatitis. It has been proposed that release of the cysteine protease Cathepsin S (CatS) from skin keratinocytes or immune cells resident in or infiltrating the skin could act as a pruritogen in chronic itch conditions. CatS is known to activate protease-activated receptor 2 (PAR2). We therefore hypothesised that enzymatic activation of neuronally expressed PAR2 by CatS was responsible for activation of sensory neurons and transmission of itch signals. Intradermally-injected human recombinant (hr)-CatS or the PAR2 agonist, SLIGRL-NH behaved as pruritogens by causing scratching behaviour in mice. Hr-CatS-induced scratching behaviour was prevented by CatS inhibitors and PAR2 antagonists and reduced by 50% in TRPV1 mice compared with wild-type mice, whilst no significant reduction in scratching behaviour was observed in TRPA1 mice. Cultured dorsal root ganglion (DRG) cells showed an increase in [Ca] following incubation with hr-CatS, and the percentage of neurons that responded to hr-CatS decreased in the presence of a PAR2 antagonist or in cultures of neurons from TRPV1 mice. Taken together, our results indicate CatS acts as a pruritogen via PAR2 activation in TRPV1-expressing sensory neurons.
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