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Migraine is a common neurological disease with a still-unclear etiology and pathogenesis. Patent foramen ovale (PFO) is a kind of congenital heart disease that leads to a right-to-left shunt (RLS). Although previous studies have shown that PFO has an effect on migraine, a clear conclusion about the link between PFO and migraine is lacking. We first summarized the PFO potential mechanisms associated with migraine, including microembolus-triggered cortical spreading depression (CSD), the vasoactive substance hypothesis, impaired cerebral autoregulation (CA), and a common genetic basis. Further, we analyzed the changes in brain structure and function in migraine patients and migraine patients with PFO. We found that in migraine patients with PFO, the presence of PFO may affect the structure of the cerebral cortex and the integrity of white matter, which is mainly locked in subcortical, deep white matter, and posterior circulation, and may lead to changes in brain function, such as cerebellum and colliculus, which are involved in the processing and transmission of pain. In summary, this paper provides neuroimaging evidence and new insights into the correlation between PFO and migraine, which will help to clarify the etiology and pathogenesis of migraine, and aid in the diagnosis and treatment of migraine in the future.
Learn More >The development of therapeutic agonists for G protein-coupled receptors (GPCRs) is hampered by the propensity of GPCRs to couple to multiple intracellular signalling pathways. This promiscuous coupling leads to numerous downstream cellular effects, some of which are therapeutically undesirable. This is especially the case for adenosine A receptors (ARs) whose clinical potential is undermined by the sedation and cardiorespiratory depression caused by conventional agonists. We have discovered that the AR-selective agonist, benzyloxy-cyclopentyladenosine (BnOCPA), is a potent and powerful analgesic but does not cause sedation, bradycardia, hypotension or respiratory depression. This unprecedented discrimination between native ARs arises from BnOCPA's unique and exquisitely selective activation of Gob among the six Gαi/o subtypes, and in the absence of β-arrestin recruitment. BnOCPA thus demonstrates a highly-specific Gα-selective activation of the native AR, sheds new light on GPCR signalling, and reveals new possibilities for the development of novel therapeutics based on the far-reaching concept of selective Gα agonism.
Learn More >Pain modulation of dopamine-producing nuclei is known to contribute to the affective component of chronic pain. However, pain modulation of pain-related cortical regions receiving dopaminergic inputs is understudied. The present study demonstrates that mice with chronic inflammatory injury of the hind paws develop persistent mechanical hypersensitivity and transient anxiety. Peripheral inflammation induced by injection of complete Freund's Adjuvant (CFA) induced potentiation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) currents with a presynaptic component in layer II/III of the ACC. After four days of inflammatory pain, the dopamine-mediated inhibition of AMPAR currents was significantly reduced in the ACC. Furthermore, dopamine enhanced presynaptic modulation of excitatory transmission, but only in mice with inflammatory pain. High-performance liquid chromatography (HPLC) analysis of dopamine tissue concentration revealed that dopamine neurotransmitter concentration in the ACC was reduced three days following CFA. Our results demonstrate that inflammatory pain induces activity-dependent changes in excitatory synaptic transmission and alters dopaminergic homeostasis in the ACC.
Learn More >Prolonged screen exposure is often cited as a trigger for pediatric headache. We present initial findings evaluating the association between adolescent screen use type, duration, and school disability.
Learn More >Chronic neuropathic pain often leads to cognitive impairment, but the exact mechanism remains unclear. Gamma-aminobutyric acid A receptors (GABARs) are the major inhibitory receptors in the brain, of which the α5-containing GABARs (GABARs-α5) are implicated in a range of neuropsychiatric disorders with cognitive deficits. However, whether GABARs-α5 are involved in chronic neuropathic pain-related cognitive impairment remains unknown. In this study, the rats with chronic neuropathic pain induced by right sciatic nerve ligation injury (SNI) exhibited cognitive impairment with declined spontaneous alternation in Y-maze test and discrimination index in novel object recognition test. The GABARs-α5 expressing on parvalbumin and somatostatin interneurons increased remarkably in hippocampus, resulting in decreased mean frequency of spontaneous inhibitory postsynaptic currents in hippocampal pyramidal neurons. Significantly, antagonizing the GABARs-α5 by L655708 rescued weakened inhibitory synaptic transmission and cognitive impairment induced by chronic neuropathic pain. Taken together, these data suggest that the GABARs-α5 play a crucial role in chronic neuropathic pain-induced cognitive impairment by weakening inhibitory synaptic transmission, which may provide insights into the pharmacologic treatment of chronic neuropathic pain-related cognitive impairment.
Learn More >Opioid use is well-documented in several countries: some countries struggle with overuse while others have almost no access to opioids. For Europe, limited data are available. This study analysed Hungarian opioid utilisation in ambulatory care between 2006 and 2020.
Learn More >The COVID-19 pandemic transformed everyday life, but the implications were most impactful for vulnerable populations, including patients with chronic pain. Moreover, persistent pain is increasingly recognised as a key manifestation of long COVID. This narrative review explores the consequences of the COVID-19 pandemic for chronic pain. Publications were identified related to the COVID-19 pandemic influence on the burden of chronic pain, development of new-onset pain because of long COVID with proposed mechanisms and COVID-19 vaccines and pain interventions. Broadly, mechanisms underlying pain due to SARS-CoV-2 infection could be caused by 'systemic inflammatory-immune mechanisms', 'direct neuropathic mechanisms' or 'secondary mechanisms due to the viral infection or treatment'. Existing chronic pain populations were variably impacted and social determinants of health appeared to influence the degree of effect. SARS-CoV-2 infection increased the absolute numbers of patients with pain and headache. In the acute phase, headache as a presenting symptom predicted a milder course. New-onset chronic pain was reportedly common and likely involves multiple mechanisms; however, its prevalence decreases over time and symptoms appear to fluctuate. Patients requiring intensive support were particularly susceptible to long COVID symptoms. Some evidence suggests steroid exposure (often used for pain interventions) may affect vaccine efficacy, but there is no evidence of clinical repercussions to date. Although existing chronic pain management could help with symptomatic relief, there is a need to advance research focusing on mechanism-based treatments within the domain of multidisciplinary care.
Learn More >Burn injuries are among the highly prevalent medical conditions worldwide that occur mainly in children, military veterans and victims of fire accidents. It is one of the leading causes of temporary as well as permanent disabilities in patients. Burn injuries are accompanied by pain that persists even after recovery from tissue damage which puts immense pressure on the healthcare system. The pathophysiology of burn pain is poorly understood due to its complex nature and lack of considerable preclinical and clinical shreds of evidence, that creates a substantial barrier to the development of new analgesics. Burns damage the skin layers supplied with nociceptors such as NAV1.7, TRPV1, and TRPA1. Burn injury-mediated co-localization and simultaneous activation of TRPA1 and TRPV1 in nociceptive primary afferent C-fibers which contributes to the development and maintenance of chronic pain. Burn injuries are accompanied by central sensitization, a key feature of pain pathophysiology mainly driven by a series of cascades involving aberrations in the glutamatergic system, microglial activation, release of neuropeptides, cytokines, and chemokines. Activation of p38 mitogen-activated protein kinase, altered endogenous opioid signaling, and distorted genomic expression are other pathophysiological factors responsible for the development and maintenance of burn pain. Here we discuss comprehensive literature on molecular mechanisms of burn pain and potential targets that could be translated into near future therapeutics.
Learn More >Anti-CGRP monoclonal antibodies (CGRPmAbs) enlarged migraine prevention options. They work targetedly, safely, and efficiently in many patients. Inexplicably, a proportion of patients show scarce improvement.
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