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The neuromodulator calcitonin gene-related peptide (CGRP) is known to facilitate nociceptive transmission in the superficial laminae of the spinal trigeminal nucleus caudalis (Sp5C). The central effects of CGRP in the Sp5C are very likely to contribute to the activation of central nociceptive pathways leading to attacks of severe headaches like migraine. To examine the potential impacts of CGRP on laminae I/II neurons at cellular and synaptic levels, we performed whole-cell patch-clamp recordings in juvenile mouse brainstem slices. First, we tested the effect of CGRP on cell excitability, focusing on neurons with tonically firing action potentials upon depolarizing current injection. CGRP (100 nM) enhanced tonic discharges together with membrane depolarization, an excitatory effect that was significantly reduced when the fast synaptic transmissions were pharmacologically blocked. However, CGRP at 500 nM was capable of exciting the functionally isolated cells, in a nifedipine-sensitive manner, indicating its direct effect on membrane intrinsic properties. In voltage-clamped cells, 100 nM CGRP effectively increased the frequency of excitatory synaptic inputs, suggesting its preferential presynaptic effect. Both CGRP-induced changes in cell excitability and synaptic drives were prevented by the CGRP receptor inhibitor BIBN 4096BS. Our data provide evidence that CGRP increases neuronal activity in Sp5C superficial laminae by dose-dependently promoting excitatory synaptic drive and directly enhancing cell intrinsic properties. We propose that the combination of such pre- and postsynaptic actions of CGRP might underlie its facilitation in nociceptive transmission in situations like migraine with elevated CGRP levels.
Learn More >Clinical models of chronic low back pain (cLBP) highlight the role of excessive attention to pain and kinesiophobia on the origin of disability. At the motor control level, various mechanisms are involved in the impairments observed in patients with cLBP. We aimed to assess the role of maladaptative attentional behaviors by using a complex systems approach and a visual display as a distraction during walking. Sixteen patients with cLBP with no previous surgery or significant leg pain and 16 healthy matched controls were included. Patients walked on a treadmill at preferred walking speed with and without distraction. Stride time (ST) fractal complexity was assessed using detrended fluctuation analysis. A two-way analysis of variance with repeated measures on distraction was performed on fractal exponents. We found a significant group × distraction interaction effect on fractal complexity of ST series (F(1,30) = 9.972, P = 0.004). Post hoc analysis showed that, without distraction, patients with cLBP had significantly lower ST complexity than controls, but when distracted, they regained gait complexity, recovering the level of controls. Our results suggest that excessive attention to pain causes loss of complexity and adaptability in cLBP and explain alterations of motor control with pain. Fractal analysis seems to be a promising method to explore movement variability and individual adaptability in musculoskeletal disorders.
Learn More >Persistent postsurgical pain (PPSP) is common after breast and thoracic surgeries. Understanding which risk factors consistently contribute to PPSP will allow clinicians to apply preventive strategies, as they emerge, to high-risk patients. The objective of this work was to systematically review and meta-analyze the literature on risk factors of PPSP after breast and thoracic surgeries. A systematic literature search using Ovid Medline, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Embase, PsycINFO, and Scopus databases was conducted. Study screening with inclusion and exclusion criteria, data extraction, and risk of bias assessment was performed independently by 2 authors. The data for each surgical group were analyzed separately and meta-analyzed where possible. The literature search yielded 5584 articles, and data from 126 breast surgery and 143 thoracic surgery articles were considered for meta-analysis. In breast surgery, younger age, higher body mass index, anxiety, depression, diabetes, smoking, preoperative pain, moderate to severe acute postoperative pain, reoperation, radiotherapy, and axillary lymph node dissection were the main factors associated with higher risk of PPSP. In thoracic surgery, younger age, female sex, hypertension, preoperative pain, moderate to severe acute postoperative pain, surgical approach, major procedure, and wound complications were associated with PPSP. This systematic review demonstrated certain consistent risk factors of PPSP after breast and thoracic surgeries, as well as identified research gaps. Understanding the factors that increase susceptibility to PPSP can help selectively allocate resources to optimize perioperative care in high-risk patients and help develop targeted, risk-stratified interventions for PPSP prevention.
Learn More >This paper is the forty-second consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2019 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug abuse and alcohol (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).
Learn More >Given the potential for obesity to complicate migraine treatment outcomes, there is a need to understand patterns and correlates of acute medication use among individuals with this comorbidity. Experience sampling methodology (ESM) was used to characterize patterns of acute medication use among those with migraine and overweight/obesity and to examine individual and momentary factors related to medication use (both migraine-specific and nonspecific medications). Women with migraine and overweight/obesity (N = 170) seeking behavioral migraine treatment completed questionnaires followed by 28 days of daily ESM headache diaries. Participants used medications to treat 71.9% of attacks, 20% of which were treated with migraine-specific medications. Participants were more likely to use medication in the context of longer and more severe attacks that started earlier in the day. Presence of aura and greater work-related pain interference uniquely related to migraine-specific medication use. Questionnaire-assessed factors were not related to medication use, although older age and higher educational attainment related to more frequent use. A substantial proportion of attacks were left untreated, suggesting unmet treatment needs in this population. Results also suggest that ESM-assessed factors are more salient correlates of medication use compared to questionnaires. Additional investigation of barriers to medication use is needed.
Learn More >To evaluate the impact of two calcitonin gene-related peptide (CGRP)-targeted monoclonal antibodies (mAbs), erenumab and galcanezumab, on the pharmacokinetic (PK) profile, safety, and tolerability of ubrogepant.
Learn More >Migraine has been associated with many comorbidities. However, lifestyle factors and the presence of comorbid diseases have not previously been extensively studied in the same sample. This study aimed to compare the prevalence of unhealthy lifestyle factors and comorbid diseases between patients with migraine and migraine-free controls with subgroup analyses to determine the pathophysiology and possible consequences.
Learn More >Many patients with diabetic peripheral neuropathy experience chronic pain and inadequate relief despite best available medical treatments.
Learn More >Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, and in rodents, TRPA1 is involved in the induction of airway inflammation and hyperreactivity. Here, the discovery and early clinical development of GDC-0334, a highly potent, selective, and orally bioavailable TRPA1 antagonist, is described. GDC-0334 inhibited TRPA1 function on airway smooth muscle and sensory neurons, decreasing edema, dermal blood flow (DBF), cough, and allergic airway inflammation in several preclinical species. In a healthy volunteer Phase 1 study, treatment with GDC-0334 reduced TRPA1 agonist-induced DBF, pain, and itch, demonstrating GDC-0334 target engagement in humans. These data provide therapeutic rationale for evaluating TRPA1 inhibition as a clinical therapy for asthma.
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