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Pain in Parkinson's disease (PD) is a common and heterogeneous non-motor symptom. Though the characteristics and predictors of pain in general and of central pain in particular are still largely unknown.
Learn More >This study investigated the activation of mitogen-activated protein kinases in the spinal dorsal horn to explore the mechanisms underlying morphine-induced acute and chronic hyperalgesia in mice.
Learn More >Increasing evidence suggests that nerve fibers responding to noxious stimuli (nociceptors) modulate immunity in a variety of tissues including the skin. Yet, a role for nociceptors in regulating sterile cutaneous inflammation remains unexplored. To tackle this question, we have developed a detailed description of the sterile inflammation caused by overexposure to UVB irradiation (i.e. sunburn) in the mouse plantar skin. Using this model, we observed that chemical depletion of nociceptor terminals did not alter the early phase of the inflammatory response to UVB, but it caused a significant increase in the number of dendritic cells and αβ T cells as well as enhanced extravasation during the later stages of inflammation. Finally, we showed that such regulation was driven by the nociceptive neuropeptide Calcitonin Gene Related Peptide. In conclusion, we propose that nociceptors do not only play a crucial role in inflammation through avoidance reflexes and behaviors but can also regulate sterile cutaneous immunity in vivo.
Learn More >PIEZO2 is a mechanosensitive cation channel that has a key role in sensing touch, tactile pain, breathing and blood pressure. Here we describe the cryo-electron microscopy structure of mouse PIEZO2, which is a three-bladed, propeller-like trimer that comprises 114 transmembrane helices (38 per protomer). Transmembrane helices 1-36 (TM1-36) are folded into nine tandem units of four transmembrane helices each to form the unusual non-planar blades. The three blades are collectively curved into a nano-dome of 28-nm diameter and 10-nm depth, with an extracellular cap-like structure embedded in the centre and a 9-nm-long intracellular beam connecting to the central pore. TM38 and the C-terminal domain are surrounded by the anchor domain and TM37, and enclose the central pore with both transmembrane and cytoplasmic constriction sites. Structural comparison between PIEZO2 and its homologue PIEZO1 reveals that the transmembrane constriction site might act as a transmembrane gate that is controlled by the cap domain. Together, our studies provide insights into the structure and mechanogating mechanism of Piezo channels.
Learn More >The sphenopalatine ganglion (SPG) has previously been targeted in trigeminal neuralgia (TN), but its role in this condition has not been established.
Learn More >The potential role of the intestinal microbiota in modulating visceral pain has received increasing attention during recent years. This has led to the identification of signaling pathways that have been implicated in communication between gut bacteria and peripheral pain pathways. In addition to the well-characterised impact of the microbiota on the immune system, which in turn affects nociceptor excitability, bacteria can modulate visceral afferent pathways by effects on enterocytes, enteroendocrine cells and the neurons themselves. Proteases produced by bacteria, or by host cells in response to bacteria, can increase or decrease the excitability of nociceptive dorsal root ganglion (DRG) neurons depending on the receptor activated. Short chain fatty acids generated by colonic bacteria are involved in gut-brain communication, and intracolonic short chain fatty acids have pro-nociceptive effects in rodents but may be anti-nociceptive in humans. Gut bacteria modulate the synthesis and release of enteroendocrine cell mediators including serotonin and glucagon-like peptide-1, which activate extrinsic afferent neurons. Deciphering the complex interactions between visceral afferent neurons and the gut microbiota may lead to the development of improved probiotic therapies for visceral pain.
Learn More >Familial hemiplegic migraine 2 is a pathology linked to mutation of the ATP1A2 gene producing loss of function of the α2 Na/K-ATPase (NKA). W887R/+ knock-in (KI) mice are used to model the familial hemiplegic migraine 2 condition and are characterized by 50% reduced NKA expression in the brain and reduced rate of K and glutamate clearance by astrocytes. These alterations might, in turn, produce synaptic changes in synaptic transmission and plasticity. Memory and learning deficits observed in familial hemiplegic migraine patients could be ascribed to a possible alteration of hippocampal neuronal plasticity and measuring possible changes of long-term potentiation in familial hemiplegic migraine 2 KI mice might provide insights to strengthen this link.
Learn More >The purpose of this cross-sectional, descriptive study was to assess differences in neuropathic symptoms, physical and emotional well-being, and quality of life in cancer patients at the end of life compared to those without neuropathic symptoms. Neuropathic symptoms were defined as numbness and tingling in the hands and/or feet. A secondary analysis of data from two hospices in Central Florida was performed. Adults (n = 717) with a cancer diagnosis, an identified family caregiver, and who were receiving hospice services, were eligible. The prevalence of numbness/tingling in the hands or feet was 40% in this sample of hospice patients with cancer. Participants with neuropathic symptoms of numbness/tingling had a significantly higher prevalence of pain (76.7% vs. 67.0%; p = .006), difficulty with urination (29.4% vs. 20.3%; p = .007), shortness of breath (64.9% vs. 54.1%; p = .005), dizziness/lightheadedness (46.0% vs. 28.2%; p < .001), sweats (35.5% vs. 20.3%; p < .001), worrying (50.7% vs. 37.3%; p = .001), feeling irritable (38.5% vs. 28.7%; p = .008), feeling sad (48.2% vs. 37.8%; p = .008), and difficulty concentrating (46.2% vs. 32.5%; p < .001). They also reported significantly higher overall symptom intensity and symptom distress scores (p = < .001), higher pain severity (p = .001) and pain distress (p = .002), and decreased quality of life (p = .002) compared to those without numbness/tingling. Neuropathic symptoms are emotionally distressing at the end of life and associated with higher symptom burden and diminished quality of life.
Learn More >Despite improved knowledge about the benefits and harms of treatments for chronic back pain in the past several decades, there is a large and consequential mismatch between treatments found safe and effective and those routinely covered by health insurance. As a result, care for back pain has, if anything, deteriorated in recent decades-expenses are higher, harms are greater, and use of ineffective treatments is more common. Deficiencies in health care delivery processes and payment models are centrally involved in the failure to improve care for back pain. A key step for accelerating progress is changing insurance coverage policies to facilitate use of the safest and most helpful approaches while discouraging riskier and less effective treatments. Relatively simple changes in reimbursement policies may minimize harm and improve quality of life for many patients with chronic back and similar pain syndromes. Such changes might also reduce health care expenditures because the costs of treatments currently covered by insurance and their associated harms may well outweigh the costs of the relatively safe and effective treatments recommended by current guidelines but poorly covered by insurance. There is no justification for continuing the status quo-patients and clinicians deserve better.
Learn More >Pain and disability are the main clinical manifestations of osteoarthritis, for which only symptomatic therapies are available. Hence, there is a need for therapies that can simultaneously alter disease progression and provide pain relief. KBP is a dual amylin- and calcitonin-receptor agonist with antiresorptive and chondroprotective properties. In this study we investigated the effect of KBP in a rat model of osteoarthritis.
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