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The two voltage gated sodium channels Nav1.7 and Nav1.8 are expressed in the peripheral nervous system and involved in various pain conditions including inflammatory and neuropathic pain. Rodent models bearing deletions or mutations of the corresponding genes, Scn9a and Scn10a, were created in order to understand the role of these channels in the pathophysiological mechanism underlying pain symptoms. This review summarizes the pain behavior profiles reported in Scn9a and Scn10a rodent models. The complete loss-of-function or knockout (KO) of Scn9a or Scn10a and the conditional KO (cKO) of Scn9a in specific cell populations were shown to decrease sensitivity to various pain stimuli. The Possum mutant mice bearing a dominant hypermorphic mutation in Scn10a revealed higher sensitivity to noxious stimuli. Several gain-of-function mutations were identified in patients with painful small fiber neuropathy. Future knowledge obtained from preclinical models bearing these mutations will allow understanding how these mutations affect pain. In addition, the review gives perspectives for creating models that better mimic patients' pain symptoms in view to developing novel analgesic strategies.
Learn More >Migraine is a neurovascular disorder that affects over 1 billion people worldwide. Its widespread prevalence, and associated disability, have a range of negative and substantial effects not only on those immediately affected but also on their families, colleagues, employers, and society. To reduce this global burden, concerted efforts are needed to implement and improve migraine care that is supported by informed health-care policies. In this Series paper, we summarise the data on migraine epidemiology, including estimates of its very considerable burden on the global economy. First, we present the challenges that continue to obstruct provision of adequate care worldwide. Second, we outline the advantages of integrated and coordinated systems of care, in which primary and specialist care complement and support each other; the use of comprehensive referral and linkage protocols should enable continuity of care between these systems levels. Finally, we describe challenges in low and middle-income countries, including countries with poor public health education, inadequate access to medication, and insufficient formal education and training of health-care professionals resulting in misdiagnosis, mismanagement, and wastage of resources.
Learn More >This is the first double-blind, randomized, controlled trial evaluating the efficacy and safety of intravenous immunoglobulin (IVIg) versus placebo in patients with idiopathic small fiber neuropathy (I-SFN).
Learn More >Migraine is a highly disabling neurological disorder that directly affects more than 1 billion individuals worldwide. Available treatment options differ between countries and include acute, preventive, and non-pharmacological therapies. Because of major progress in the understanding of migraine pathogenesis, novel mechanism-based medications have emerged and expanded the armamentarium of treatments. We provide a comprehensive overview of the current standard of care that will enable informed clinical management. First, we discuss the efficacy, tolerability, and safety profile of various pharmacological therapies for acute and preventive treatment of migraine. Second, we review the current knowledge on non-pharmacological therapies, such as neuromodulation and biobehavioural approaches, which can be used for a multidisciplinary approach to clinical management. Third, we emphasise that any effective treatment strategy starts with building a therapeutic plan tailored to individual clinical characteristics, preferences, and needs. Finally, we explore the outlook of emerging mechanism-based treatments that could address unmet challenges in clinical management of migraine.
Learn More >The inter-session Intraclass Correlation Coefficient (ICC) is a commonly investigated and clinically important metric of reliability for pressure pain threshold (PPT) measurement. However, current investigations do not account for inter-repetition variability when calculating inter-session ICC, even though a PPT measurement taken at different sessions must also imply different repetitions. The primary aim was to evaluate and report a novel metric of reliability in PPT measurement: the inter-session-repetition ICC. One rater recorded ten repetitions of PPT measurement over the lumbar region bilaterally at two sessions in twenty healthy adults using a pressure algometer. Variance components were computed using linear mixed-models and used to construct ICCs; most notably inter-session ICC and inter-session-repetition ICC. At 70.1% of the total variance, the source of greatest variability was between subjects ([Formula: see text] = 222.28 N), whereas the source of least variability (1.5% total variance) was between sessions ([Formula: see text] = 4.83 N). Derived inter-session and inter-session-repetition ICCs were 0.88 (95%CI: 0.77 to 0.94) and 0.73 (95%CI: 0.53 to 0.84) respectively. Inter-session-repetition ICC provides a more conservative estimate of reliability than inter-session ICC, with the magnitude of difference being clinically meaningful. Quantifying individual sources of variability enables ICC construction to be reflective of individual testing protocols.
Learn More >Migraine is a disabling neurological disorder, diagnosis of which is based on clinical criteria. A shortcoming of these criteria is that they do not fully capture the heterogeneity of migraine, including the underlying genetic and neurobiological factors. This complexity has generated momentum for biomarker research to improve disease characterisation and identify novel drug targets. In this Series paper, we present the progress that has been made in the search for biomarkers of migraine within genetics, provocation modelling, biochemistry, and neuroimaging research. Additionally, we outline challenges and future directions for each biomarker modality. We also discuss the advances made in combining and integrating data from multiple biomarker modalities. These efforts contribute to developing precision medicine that can be applied to future patients with migraine.
Learn More >Pain-related factors increase the risk for opioid addiction, and pain may function as a negative reinforcer to increase opioid taking and seeking. However, experimental pain-related manipulations generally do not increase opioid self-administration in rodents. This discrepancy may reflect insufficient learning of pain-relief contingencies or confounding effects of pain-related behavioral impairments. Here, we determined if pairing noxious stimuli with opioid self-administration would promote pain-related reinstatement of opioid seeking or increase opioid choice over food.
Learn More >Tricyclic antidepressants that inhibit serotonin and noradrenaline reuptake, such as amitriptyline, are among the first-line treatments for neuropathic pain, which is caused by a lesion or disease affecting the somatosensory nervous system. These treatments are, however, partially efficient to alleviate neuropathic pain symptoms and better treatments are still highly required. Interactions between neurons and glial cells participate in neuropathic pain processes, and, importantly, connexins – transmembrane proteins involved in cell-cell communication – contribute to these interactions. In a neuropathic pain model in rats, mefloquine, a connexin inhibitor, has been shown to potentiate the anti-hyperalgesic effect of amitriptyline, a widely used antidepressant. In the present study, we further investigated this improvement of amitriptyline action by mefloquine, using the cuff model of neuropathic pain in mice. We first observed that oral mefloquine co-treatment prolonged the effect of amitriptyline on mechanical hypersensitivity by 12 hours after administration. Additionally, we showed that this potentiation was not due to pharmacokinetic interactions between the two drugs. Besides, lesional and pharmacological approaches showed that the prolonged effect was induced through noradrenergic descending pathways and the recruitment of α2 adrenergic receptors. Another connexin blocker, carbenoxolone, also improved amitriptyline action. Additional in vitro studies suggested that mefloquine may also directly act on serotonin transporters and on adenosine A1 and A2A receptors, but drugs acting on these other targets failed to amplify amitriptyline action. Together, our data indicate that pharmacological blockade of connexins potentiates the therapeutic effect of amitriptyline in neuropathic pain.
Learn More >During the past few years, the research of chronic neuropathic pain has focused on neuroinflammation within the central nervous system and its impact on pain chronicity. As part of the ERA-Net NEURON consortium we aimed to identify immune cell patterns in cerebrospinal fluid (CSF) of patients with herpes zoster neuralgia (HZ) and polyneuropathy (PNP), which may contribute to pain chronicity in these neuropathic pain conditions.CSF of 41 patients (10 HZ, 31 PNP) was analyzed by flow cytometry identifying lymphocyte subsets: CD4+- (T-helper-cells), CD8+- (cytotoxic T-cells), CD19+- (B-cells), and CD56+- (natural killer; NK) cells. At baseline and at follow-up, the somatosensory phenotype was assessed with QST. Additionally, the patients answered epidemiological questionnaires and the PainDETECT. Immune cell profiles and somatosensory profiles, as well as PDQ-scores were analyzed and correlated in order to determine specific immune cell patterns, which contribute to chronic pain.We found a negative correlation (p= 0.004, r=-0.596) between the frequency of natural killer cells and mechanical pain sensitivity (MPS), one of the most relevant QST markers for central sensitization; a high frequency of NK-cells correlated with low MPS. The analysis of the individual follow-up showed a worsening of the pain condition if NK-cell frequency was low.Low NK-cell frequency is associated with signs of central sensitization (MPS), whereas high NK-cell frequency might prevent central sensitization. Therefore, NK-cells seem to play a protective role within the neuroinflammatory cascade and may be used as marker for pain chronicity.
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