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Oncostatin M induces hyperalgesic priming and amplifies signaling of cAMP to ERK by RapGEF2 and PKA.
Hyperalgesic priming is characterized by enhanced nociceptor sensitization by pronociceptive mediators, prototypically PGE . Priming has gained interest as a mechanism underlying the transition to chronic pain. Which stimuli induce priming and what cellular mechanisms are employed remains incompletely understood. In adult male rats, we present the cytokine Oncostatin M (OSM), a member of the IL-6 family, as an inducer of priming by a novel mechanism. We used a high content microscopy based approach to quantify the activation of endogenous PKA-II and ERK of thousands sensory neurons in culture. Incubation with OSM increased and prolonged ERK activation by agents that increase cAMP production such as PGE , forskolin, and cAMP analogs. These changes were specific to IB4/CaMKIIα positive neurons, required protein translation, and increased cAMP-to-ERK signaling. In both, control and OSM-treated neurons, cAMP/ERK signaling involved RapGEF2 and PKA but not Epac. Similar enhancement of cAMP-to-ERK signaling could be induced by GDNF, which acts mostly on IB4/CaMKIIα-positive neurons, but not by NGF, which acts mostly on IB4/CaMKIIα-negative neurons. In vitro, OSM pretreatment rendered baseline TTX-R currents ERK-dependent and switched forskolin-increased currents from partial to full ERK-dependence in small/medium sized neurons. In summary, priming induced by OSM uses a novel mechanism to enhance and prolong coupling of cAMP/PKA to ERK1/2 signaling without changing the overall pathway structure.
Learn More >Chronic pain is highly prevalent, associated with substantial personal and economic burdens, and increased risk for mental disorders. Individuals in green professions (agriculturists, horticulturists, foresters) show increased prevalence of chronic pain and other risk factors for mental disorders. Available healthcare services in rural areas are limited. Acceptance towards face-to-face therapy is low. Internet and mobile-based interventions (IMIs) based on Acceptance and Commitment Therapy (ACT) might be a promising alternative for this population and may enable effective treatment of chronic pain. The present study aims to evaluate the clinical and cost-effectiveness of an ACT-based IMI for chronic pain in green professions in comparison with enhanced treatment as usual (TAU+).
Learn More >Recent studies have explored the effectiveness of open-label placebos (OLPs) for a variety of conditions, including chronic pain, cancer-related fatigue and irritable bowel syndrome. OLPs are thought to sidestep traditional ethical worries about placebos because they do not involve deception: with an OLP, patients or subjects are told outright that they are not given an active substance. As deception is framed as the primary hurdle to ethical placebo use, the door is ostensibly opened to ethical studies of OLPs. In this article, I suggest that even though OLPs seemingly do not involve deception, there are other ethical considerations in their clinical investigation and subsequent use. Research ethics often focusses on informed consent-of which, deception and honesty are a piece-as a means to justify research practices with human subjects. Yet, it is but one of the ethical considerations that should be taken into account. With research into placebo effects in particular, I argue that the history of clinical placebo use grounds special considerations for OLP research that go beyond respect for the autonomy of individual patients through informed consent and encompass structural concerns about the type of patient for whom a placebo has historically been thought appropriate.
Learn More >Subcutaneous sumatriptan, a 5HT agonist, is the most effective drug in cluster headache acute treatment. About 25% of the patients do not respond to subcutaneous sumatriptan; the reasons for this are unknown. In this study, we compare clinical characteristics of cluster headache patients responding and non-responding to subcutaneous sumatriptan.
Learn More >Genetic ablation or pharmacological inhibition of the heat-activated cation channel TRPM3 alleviates inflammatory heat hyperalgesia, but the underlying mechanisms are unknown. We induced unilateral inflammation of the hind paw in mice, and directly compared expression and function of TRPM3 and two other heat-activated TRP channels (TRPV1 and TRPA1) in sensory neurons innervating the ipsilateral and contralateral paw. We detected increased mRNA levels in dorsal root ganglion neurons innervating the inflamed paw, and augmented TRP channel-mediated calcium responses, both in the cell bodies and the intact peripheral endings of nociceptors. In particular, inflammation provoked a pronounced increase in nociceptors with functional co-expression of TRPM3, TRPV1 and TRPA1. Finally, pharmacological inhibition of TRPM3 dampened TRPV1- and TRPA1-mediated responses in nociceptors innervating the inflamed paw, but not in those innervating healthy tissue. These insights into the mechanisms underlying inflammatory heat hypersensitivity provide a rationale for developing TRPM3 antagonists to treat pathological pain.
Learn More >DNA methylation is an epigenetic modification that regulates gene transcription. DNA methyltransferase 1 (DNMT1) plays an important role in DNA methylation. However, the involvement of DNMT1 and DNA methylation in the pathogenesis of atopic dermatitis (AD) remains unclear. In this study, microarray analysis revealed that peripheral blood mononuclear cells of AD patients with low DNMT1 expression (DNMT1-low) highly expressed dendritic cell (DC) activation-related genes. Also, DNMT1-low AD patients exhibited a higher itch score compared to AD patients with high DNMT1 expression (DNMT1-high). By using an AD-like mouse model induced by the application of Dermatophagoides farinae body ointment, we found that Dnmt1 expression was decreased, while the expression of C-C chemokine receptor type 7 (Ccr7) was upregulated in mouse skin DCs. Furthermore, mice exposed to social defeat stress exhibited Dnmt1 downregulation and Ccr7 upregulation in skin DCs. Additionally, dermatitis and itch-related scratching behavior were exacerbated in AD mice exposed to stress. The relationship between low DNMT1 and itch induction was found in both human AD patients and AD mice. In mouse bone marrow-derived DCs, Ccr7 expression was inhibited by 5-aza-2-deoxycytidine, a methylation inhibitor. Furthermore, in mouse skin DCs, methylation of CpG sites in Ccr7 was modified by either AD induction or social defeat stress. Collectively, these findings suggest that social defeat stress exacerbates AD pathology through Dnmt1 downregulation and Ccr7 upregulation in mouse skin DCs. The data also suggest a role of DNMT1 downregulation in the exacerbation of AD pathology.
Learn More >: Psychological factors of patients may influence physicians' decisions on prescribing opioid analgesics. However, few studies have sought to identify these factors. The present study had a double objective: (1) To identify the individual factors that differentiate patients who had been prescribed opioids for the management of chronic back pain from those who had not been prescribed opioids and (2) to determine which factors make significant and independent contributions to the prediction of opioid prescribing. : A total of 675 patients from four primary care centers were included in the sample. Variables included sex, age, pain intensity, depressive symptoms, pain catastrophizing, and pain acceptance. : Although no differences were found between men and women, participants with chronic noncancer pain who were prescribed opioids were older, reported higher levels of pain intensity and depressive symptoms, and reported lower levels of pain-acceptance. An independent association was found between pain intensity and depressive symptoms and opioid prescribing. : The findings suggest that patient factors influence physicians' decisions on prescribing opioids. It may be useful for primary care physicians to be aware of the potential of these factors to bias their treatment decisions.
Learn More >Chronic pruritus is one dermatologic manifestation of an underlying substance use disorder. Recent literature has uncovered similarities between the general neurological mechanisms of addiction and chronic itch, largely involving activation of the dopaminergic reward circuits within the brain and imbalances between opioid mu- and kappa-opioid receptor activation. It is likely that use of specific drugs, like central nervous system (CNS) stimulants and opioids, results in further activation and imbalances within these pathways, perpetuating both addiction and pruritus simultaneously. Opioid users often present to dermatology clinics with a generalized pruritus, while individuals using CNS stimulants like cocaine and methylenedioxymetamphetamine (MDMA), as well as legally prescribed drugs like treatments for ADHD, frequently complain of crawling, delusional infestation-like sensations underneath the skin. Because of these overlapping mechanisms and similar clinical presentations to many other chronically itchy conditions, it is necessary for dermatologists to consider and investigate an underlying substance use disorder in order to effectively treat these patients.
Learn More >Variability exists in opioid prescribing practices among surgeons, frequently resulting in the prescription of excessive opioids. This study evaluated the ability of a single educational intervention targeted toward general surgery residents to reduce the quantity of postoperative opioids prescribed.
Learn More >Parents with chronic pain have a higher likelihood of having depression and anxiety and more often have children with these conditions. Depressive and anxious symptoms in children worsen pain-related disability and may be derived from exposure to their parents' symptoms. We assessed a model of intergenerational chronic pain-related disability that relies upon depressive and anxious symptoms of a mother and their child. Adolescents in grades 5-10 from 5 schools, and their mothers, completed standardized electronic questionnaires about pain. In maternal-offspring dyads (n = 1179), the mean offspring age was 12.7 years (SD = 1.7, range = 10-17) and 51% were girls. Logistic regression was used to investigate mother-offspring associations of chronic pain presence, and mediation models using multiple linear regression were used to investigate the proposed model. Adolescents of mothers with chronic pain had 1.67 (95%CI = 1.29-2.16) times increased odds of chronic pain, with each year of exposure to maternal chronic pain associated with a 5% (OR 95%CI = 1.01-1.10) increased likelihood of offspring chronic pain. Worse maternal pain-related disability was associated with worse offspring pain-related disability (β = 0.20, 95%CI = 0.06-0.34). The mediation model indicated maternal and adolescent offspring symptoms of depression explained 36% of the relationship between maternal and offspring pain-related disability, with 11% explained by the intergenerational transmission of depression (serial mediation). We conclude that worse pain-related disability is associated between parent and child, and that depressive symptoms common to both mother and child play a key role in this relationship.
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