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Migraine is a complex brain disorder, characterized by attacks of unilateral headache and global dysfunction in multisensory information processing, whose underlying cellular and circuit mechanisms remain unknown. The finding of enhanced excitatory, but unaltered inhibitory, neurotransmission at intracortical synapses in mouse models of familial hemiplegic migraine (FHM) suggested the hypothesis that dysregulation of the excitatory-inhibitory balance in specific circuits is a key pathogenic mechanism. Here, we investigated the thalamocortical (TC) feed-forward inhibitory microcircuit in FHM1 mice of both sexes carrying a gain-of-function mutation in Ca2.1. We show that TC synaptic transmission in somatosensory cortex is enhanced in FHM1 mice. Due to similar gain-of-function of TC excitation of layer 4 excitatory and fast-spiking inhibitory neurons elicited by single thalamic stimulations, neither the excitatory-inhibitory balance nor the integration time window set by the TC feed-forward inhibitory microcircuit were altered in FHM1 mice. However, during repetitive thalamic stimulation, the typical shift of the excitatory-inhibitory balance towards excitation and the widening of the integration time window were both smaller in FHM1 compared to wild-type mice, revealing a dysregulation of the excitatory-inhibitory balance, whereby the balance is relatively skewed towards inhibition. This is due to an unexpected differential effect of the FHM1 mutation on short-term synaptic plasticity at TC synapses on cortical excitatory and fast-spiking inhibitory neurons. Our findings point to enhanced transmission of sensory, including trigeminovascular nociceptive, signals from thalamic nuclei to cortex and TC excitatory-inhibitory imbalance as mechanisms that may contribute to headache, increased sensory gain, and sensory processing dysfunctions in migraine.Migraine is a complex brain disorder, characterized by attacks of unilateral headache and by global dysfunction in multisensory information processing, whose underlying cellular and circuit mechanisms remain unknown. Here we provide insights into these mechanisms by investigating thalamocortical (TC) synaptic transmission and the function of the TC feed-forward inhibitory microcircuit in a mouse model of a rare monogenic migraine. This microcircuit is critical for gating information flow to cortex and for sensory processing. We reveal increased TC transmission and dysregulation of the cortical excitatory-inhibitory balance set by the TC feed-forward inhibitory microcircuit, whereby the balance is relatively skewed towards inhibition during repetitive thalamic activity. These alterations may contribute to headache, increased sensory gain, and sensory processing dysfunctions in migraine.
Learn More >Rapid conduction of nerve impulses is critical in life and relies on action potential (AP) leaps through the nodes of Ranvier (NRs) along myelinated nerves. While NRs are the only sites where APs can be regenerated during nerve conduction on myelinated nerves, ion channel mechanisms underlying the regeneration and conduction of APs at mammalian NRs remain incompletely understood. Here, we show that TREK-1 and TRAAK, the thermosensitive and mechanosensitive two-pore-domain potassium (K2P) channels, are clustered at NRs of rat trigeminal Aβ-afferent nerves with a density over 3,000-fold higher than that on their somas. These K2P channels, but not voltage-gated K channels as in other parts of nerves, are required for rapid AP repolarization at the NRs. Furthermore, these channels permit high-speed and high-frequency AP conduction along the myelinated afferent nerves, and loss of function of these channels at NRs retards nerve conduction and impairs sensory behavioral responses in animals.
Learn More >Pediatric functional abdominal pain disorders (FAPD) are associated with adverse outcomes including increased somatization (e.g., heightened physiological sensations that include gastroenterological and non-gastroenterological symptoms) and increased functional disability. Caregiver distress and child anxiety are separately associated with the adverse outcomes of pediatric FAPD. However, the cumulative role of caregiver (i.e., stress, anxiety, and depression) and child psychological functioning (anxiety) in relation to adverse outcomes associated with FAPD, and particularly somatization, is unclear. Thus, the present investigation sought to examine the role of caregiver distress and child anxiety in relation to pain-related functioning (i.e., somatization, pain intensity, functional disability) in youth with FAPD. Data were gathered as part of a larger study examining a psychological treatment for youth with FAPD. Participants (ages 9-14) with FAPD completed measures of child anxiety, pain, and pain-related functioning. Caregivers completed a measure of caregiver distress (e.g., stress, anxiety, depressive symptoms). Pearson correlations revealed significant positive associations between child anxiety and child functional disability. Additionally, caregiver anxiety, child anxiety, and child somatization were all significantly and positively correlated with one another. Therefore, we assessed whether child anxiety may potentially mediate the relationship between caregiver anxiety and child somatization in this cross-sectional study. The indirect association between caregiver anxiety and child somatization via child anxiety was not significant. Future research including longitudinal designs to further understand the relationship between caregiver anxiety, child anxiety, and child pain-related functioning, would enhance understanding of how these potentially modifiable psychological factors may impact adverse outcomes of FAPD.
Learn More >The aim of this cross-sectional study was to investigate the cortical metabolite concentrations in patients suffering from migraine with aura (MWA). We hypothesized that occipital γ-aminobutyric acid (GABA) levels are lower in MWA patients.
Learn More >Excessive alcohol consumption is associated with spontaneous burning pain, hyperalgesia and allodynia. Although acetaldehyde has been implicated in the painful alcoholic neuropathy, the mechanism by which the ethanol metabolite causes pain symptoms is unknown. Acute ethanol ingestion caused delayed mechanical allodynia in mice. Inhibition of alcohol dehydrogenase (ADH) or deletion of transient receptor potential ankyrin 1 (TRPA1), a sensor for oxidative and carbonyl stress, prevented allodynia. Acetaldehyde generated by ADH in both liver and Schwann cells surrounding nociceptors was required for TRPA1-induced mechanical allodynia. Plp1-Cre;Trpa1fl/fl mice with a tamoxifen-inducible specific deletion of TRPA1 in Schwann cells revealed that channel activation by acetaldehyde in these cells initiates a NADPH oxidase-1 (NOX-1)-dependent production of hydrogen peroxide (H2O2) and 4-hydroxynonenal (4-HNE), which sustains allodynia by paracrine targeting of nociceptor TRPA1. Chronic ethanol ingestion caused prolonged mechanical allodynia and loss of intraepidermal small nerve fibers in WT mice. While Trpa1-/- or Plp1-Cre;Trpa1fl/fl mice did not develop mechanical allodynia, they did not show any protection from the small fiber neuropathy. Human Schwann cells express ADH/TRPA1/NOX1 and recapitulate the proalgesic functions of mouse Schwann cells. TRPA1 antagonists might attenuate some symptoms of alcohol-related pain.
Learn More >Monitoring trends in prescription analgesic use among adults with musculoskeletal conditions provides insight into how changing prescribing practices, guidelines, and policy measures may affect those who need pain management.
Learn More >Sickle cell disease (SCD) is an inherited red blood cell disorder affecting millions worldwide, and it results in many potential medical complications throughout the life course. The hallmark of SCD is pain. Many patients experience daily chronic pain as well as intermittent, unpredictable acute vaso-occlusive painful episodes called pain crises. These pain crises often require acute medical care through the day hospital or emergency department. Following presentation, a number of these patients are subsequently admitted with continued efforts of treatment focused on palliative pain control and hydration for management. Mitigating pain crises is challenging for both the patients and their providers, given the perceived unpredictability and subjective nature of pain.
Learn More >Transcripts of noxious stimulus-detecting TrpA1 channels are alternatively spliced. Despite the importance of nociception for survival, the in vivo significance of expressing different TrpA1 isoforms is largely unknown. Here, we develop a novel genetic approach to generate Drosophila knockin strains expressing single TrpA1 isoforms. Drosophila TrpA1 mediates heat and UVC-triggered nociception. We show that TrpA1-C and TrpA1-D, two alternative isoforms, are co-expressed in nociceptors. When examined in heterologous cells, both TrpA1-C and TrpA1-D are activated by heat and UVC. By contrast, analysis of knockin flies reveals the striking functional specificity; TrpA1-C mediates UVC-nociception, whereas TrpA1-D mediates heat-nociception. Therefore, in vivo functions of TrpA1-C and TrpA1-D are different from each other and are different from their in vitro properties. Our results indicate that a given sensory stimulus preferentially activates a single TrpA1 isoform in vivo and that polymodal nociception requires co-expression of TrpA1 isoforms, providing novel insights of how alternative splicing regulates nociception.
Learn More >Rodent disease models can play an indispensable role in drug development. Confirming that translationally-relevant disease mechanisms are engaged in such models is a crucial facet of this process. Accordingly, we have validated the role of calcitonin gene-related peptide signaling in a mouse model of glyceryl trinitrate-provoked migraine-like pain and a spontaneous rat model of migraine-like pain by assessing their pharmacological responsiveness to the small molecule calcitonin gene-related peptide receptor antagonist olcegepant, and the humanised monoclonal calcitonin gene-related peptide antibody ALD405.
Learn More >Effective management of patients with pain requires accurate information about the prevalence, outcomes, and co-occurrence of common pain conditions. However, the transition from ICD-9-CM to ICD-10-CM diagnostic coding in 2015 left researchers without methods for comparing the prevalence of pain conditions before and after the transition. In this study, we developed and assessed a diagnostic framework to serve as a crosswalk between ICD-9-CM and ICD-10-CM diagnosis codes for common pain-related health conditions. We refined existing ICD-9-CM definitions for diagnostic clusters of common pain conditions consistent with the US National Pain Strategy and developed corresponding ICD-10-CM definitions. We then assessed the stability of prevalence estimates and associated patient socio-demographic features of each diagnostic cluster during one-year periods before and after the transition to ICD-10-CM in three US health care systems using electronic health records data for in-person encounters. Prevalence estimates and socio-demographic characteristics were similar before and after the transition. The Pain Condition ICD-9-CM to ICD-10-CM Crosswalk includes a full spectrum of common pain conditions to enable prevalence estimates of multiple and chronic overlapping pain conditions. This allows the tool to serve as a foundation for a broad array of pain-related health services research utilizing electronic databases. Perspective: This article details the development and assessment of the Pain Condition ICD-9-CM to ICD-10-CM Crosswalk, a diagnostic framework for assessing pain condition prevalence across the ICD-9-CM to ICD-10-CM transition. This framework can serve as a standardized tool for research on pain conditions, including health services and epidemiologic research.
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