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Globally, migraine is a leading cause of disability with a huge impact on both the work and private life of affected persons. To overcome the societal migraine burden, better treatment options are needed. Increasing evidence suggests that ATP-sensitive potassium (K) channels are involved in migraine pathophysiology. These channels are essential both in blood glucose regulation and cardiovascular homeostasis. Experimental infusion of the K channel opener levcromakalim to healthy volunteers and migraine patients induced headache and migraine attacks in 82-100% of participants. Thus, this is the most potent trigger of headache and migraine identified to date. Levcromakalim likely induces migraine via dilation of cranial arteries. However, other neuronal mechanisms are also proposed. Here, basic K channel distribution, physiology, and pharmacology are reviewed followed by thorough review of clinical and preclinical research on K channel involvement in migraine. K channel opening and blocking have been studied in a range of preclinical migraine models and, within recent years, strong evidence on the importance of their opening in migraine has been provided from human studies. Despite major advances, translational difficulties exist regarding the possible anti-migraine efficacy of K channel blockage. These are due to significant species differences in the potency and specificity of pharmacological tools targeting the various K channel subtypes.
Learn More >Sickle cell disease (SCD) is a common genetic blood disorder associated with acute and chronic pain, progressive multiorgan damage, and early mortality. Recent advances in technologies to manipulate the human genome, a century of research and the development of techniques enabling the isolation, efficient genetic modification, and reimplantation of autologous patient hematopoietic stem cells (HSCs), mean that curing most patients with SCD could soon be a reality in wealthy countries. In parallel, ongoing research is pursuing more facile treatments, such as in-vivo-delivered genetic therapies and new drugs that can eventually be administered in low- and middle-income countries where most SCD patients reside.
Learn More >Formal training in mindfulness-based practices promotes reduced experimental and clinical pain, which may be driven by reduced emotional pain reactivity and undergirded by alterations in the default mode network, implicated in mind-wandering and self-referential processing. Recent results published in this journal suggest that mindfulness, defined here as the day-to-day tendency to maintain a non-reactive mental state in the absence of training, associates with lower pain reactivity, greater heat-pain thresholds, and resting-state default mode network functional connectivity in healthy adults in a similar manner to trained mindfulness. The extent to which these findings extend to chronic pain samples and replicate in healthy samples is unknown. Using data from healthy adults (n = 36) and episodic migraine patients (n = 98) and replicating previously published methods, we observed no significant association between mindfulness and heat-pain threshold, pain intensity or unpleasantness, or pain catastrophizing in healthy controls, or between mindfulness and headache frequency, severity, impactor pain catastrophizing in patients. There was no association between default mode network connectivity and mindfulness in either sample when probed via seed-based functional connectivity analyses. In post-hoc whole brain exploratory analyses, a meta-analytically derived default mode network node (i.e., posterior cingulate cortex) showed connectivity with regions unassociated with pain processing as a function of mindfulness, such that healthy adults higher in mindfulness showed greater functional connectivity between the posterior cingulate cortex-and cerebellum. Collectively, these findings suggest that the relationship between mindfulness and default mode network functional connectivity may be nuanced or non-robust, and encourage further investigation of how mindfulness relates to pain. Perspective: This study found few significant associations between dispositional mindfulness and pain, pain reactivity and default mode connectivity in healthy adults and migraine patients. The relationship between mindfulness and default mode network connectivity may be nuanced or non-robust.
Learn More >Over the last decade, the content, delivery and media of pain education have been adjusted in line with scientific discovery in pain and educational sciences, and in line with consumer perspectives. This paper describes a decade-long process of exploring consumer perspectives on pain science education concepts to inform clinician-derived educational updates (undertaken by the authors). Data were collected as part of a quality audit via a series of online surveys in which consent (non-specific) was obtained from consumers for their data to be used in published research. Consumers who presented for care for a persistent pain condition and were treated with a pain science education informed approach were invited to provide anonymous feedback about their current health status and pain journey experience 6, 12 or 18 months after initial assessment. Two-hundred eighteen consumers reported improvement in health status at follow-up. Results of the surveys from three cohorts of consumers that reported improvement were used to generate iterative versions of 'Key Learning Statements'. Early iteration of these Key Learning Statements was used to inform the development of Target Concepts and associated community-targeted pain education resources for use in public health and health professional workforce capacity building initiatives. Perspective This paper reflects an explicit interest in the insights of people who have been challenged by persistent pain and then recovered, to improve pain care. Identifying pain science concepts that consumers valued learning provided valuable information to inform resources for clinical interactions and community-targeted pain education campaigns.
Learn More >Overactivated microglia in the spinal cord leads to neuropathic pain sensitivity. The FGF 10, a Fibroblast Growth Factor (FGFs) that is prevalent in neurons, has been demonstrated to suppress microglial polarization. The objective of this study was to investigate the role of FGF 10 in neuropathic pain and the underlying regulatory mechanisms. Immunofluorescence staining and western blot detection revealed that FGF 10 expression was upregulated in the ipsilateral spinal dorsal horn of Spared Nerve Injury (SNI) rat models and was mainly detected in neurons and microglia. To test the anti-microgliosis actions of FGF 10, SNI rats were intrathecally administered with different concentrations of recombinant FGF 10. Behavioral tests and immunostaining results showed that FGF 10 relieved hyperalgesia in SNI rats and inhibited microglial activity in the ipsilateral spinal dorsal horn in a dose-dependent manner. Besides, BV2 cells were cultured and treated with LPS to activate microglia to explore the underlying mechanisms of FGF 10-induced analgesic effects in vitro. As a result, FGF 10 administration suppressed the LPS-induced microglial augmentation in a dose-dependent manner, followed by increased PPAR-γ and decreased NFκB phosphorylation (p-NFκB) levels. Moreover, PPAR-γ agonist (pioglitazone) and antagonist (GW9662) were administrated into spinal cords of SNI rats, revealing that pioglitazone had similar anti-nociceptive and anti-microglial effects to FGF 10. Conversely, GW9662 reversed all beneficial effects of FGF 10 on SNI rats. In addition, phosphorylated levels of NFκB were reduced by pioglitazone or FGF 10 treatment but raised by GW9662 administration in FGF 10-treated SNI rats. Our findings show that FGF 10 has analgesic effects in rats after peripheral nerve injury and justify the role of PPAR-γ/NFκB signaling in FGF 10-regulated anti-microgliosis.
Learn More >JNJ-10450232 (NTM-006) is a new molecular entity that comprises structural similarities to acetaminophen and provides comparable analgesia in animals and humans without causing the hepatotoxicity associated with acetaminophen overdose in preclinical models. This double-blind, placebo-controlled, first-in-human study evaluated the safety, tolerability, and pharmacokinetics of JNJ-10450232 (NTM-006) following single (50-6000 mg) and multiple (250-2500 mg twice daily for 8 days) doses in healthy male volunteers. JNJ-10450232 (NTM-006) was absorbed within 1-3 h, except at high doses at which C was delayed and bimodal, while increases in AUC were more than dose proportional. CL/F and Vd/F decreased approximately 3-fold with increasing single doses up to 6000 mg and multiple doses up to 1000 mg, resulting in similar t values that ranged from 8-10 h across doses. JNJ-10450232 (NTM-006) was generally safe and well tolerated, and no dose-limiting toxicities were observed. Transient increases in indirect bilirubin were noted at post-baseline timepoints due to UGT1A1 inhibition, without any evidence of adverse hepatic effects. Macular rash and generalized erythema were the most common drug-related adverse events after multiple doses.
Learn More >Visceral hypersensitivity and low grade mucosal inflammation are frequently observed in a subpopulation of irritable bowel syndrome (IBS) patients. The responsible mechanism is unclear. Resolvins are a novel class of anti-inflammatory lipid mediators that regulate resolution of inflammation and pain. We hypothesize that resolvin D1 (RvD1) synthesis is reduced in IBS-D colonic mucosa and contribute to the development of visceral hypersensitivity.
Learn More >The diagnosis of migraine is mainly clinical and self-reported, which makes additional examinations unnecessary in most cases. Migraine can be subtyped into chronic (CM) and episodic (EM). Despite the very high prevalence of migraine, there are no evidence-based guidelines for differentiating between these subtypes other than the number of days of migraine headache per month. Thus, we consider it timely to perform a systematic review to search for physiological evidence from functional activity (as opposed to anatomical structure) for the differentiation between CM and EM, as well as potential functional biomarkers. For this purpose, Web of Science (WoS), Scopus, and PubMed databases were screened.
Learn More >Prior research indicates that sexual functioning and chronic pain commonly co-exist and impact each other; however, there are limitations in current research as to the prevalence and severity of sexual dysfunction in patients with chronic pain.
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