ObjectiveTo identify and disseminate research priorities for the headache field that should be areas of research focus during the next 10 years.BackgroundEstablishing research priorities helps focus and synergize the work of headache investigators, allowing them to reach the most important research goals more efficiently and completely.MethodsThe Headache Research Priorities organizing and executive committees and working group chairs led a multistakeholder and international group of experts to develop headache research priorities. The research priorities were developed and reviewed by clinicians, scientists, people with headache, representatives from headache organizations, health-care industry representatives, and the public. Priorities were revised and finalized after receiving feedback from members of the research priorities working groups and after a public comment period.ResultsTwenty-five research priorities across eight categories were identified: human models, animal models, pathophysiology, diagnosis and management, treatment, inequities and disparities, research workforce development, and quality of life. The priorities address research models and methods, development and optimization of outcome measures and endpoints, pain and non-pain symptoms of primary and secondary headaches, investigations into mechanisms underlying headache attacks and chronification of headache disorders, treatment optimization, research workforce recruitment, development, expansion, and support, and inequities and disparities in the headache field. The priorities are focused enough that they help to guide headache research and broad enough that they are widely applicable to multiple headache types and various research methods.ConclusionsThese research priorities serve as guidance for headache investigators when planning their research studies and as benchmarks by which the headache field can measure its progress over time. These priorities will need updating as research goals are met and new priorities arise. The American Headache Society led a large, international, multistakeholder process to identify headache research topics that should be prioritized during the next 10 years. With input from headache clinicians, scientists, people with headache, representatives from headache organizations, health-care industry representatives, and the public, 25 research priorities within 8 categories were identified. These research priorities can help guide headache researchers when planning their studies and as benchmarks by which the headache field can measure its progress over time.

Catherine D. Chong has received research funding from the American Heart Association, Amgen, National Institutes of Health, and United States Department of Defense. Sait Ashina has been a consultant for Abbvie/Allergan, Amgen, Biohaven, Eli Lilly, Novartis, Pfizer, Supernus, Teva, Theranica, Percept, and Impel Neuropharma. Joshua Kamins serves on the speaker bureau for Lundbeck. Ann Scher has received research support from Eli Lilly. Carlyn Patterson Gentile has received salary support in the past 24 months from grants from the American Academy of Neurology, the International Headache Academy sponsored by the American Headache Society, and the Children's Hospital of Philadelphia/University of Pennsylvania NeuroNEXT fellowship. Alan Finkel declares no conflicts of interest. Michael L. Oshinsky is a federal employee of NIH and has no conflict of interest to report. Within the prior 24 months Todd J. Schwedt has received compensation for consulting with AbbVie, Allergan, Amgen, Axsome, Biodelivery Science, Biohaven, Collegium, Eli Lilly, Linpharma, Lundbeck, Satsuma, Scilex, and Theranica and royalties from UpToDate. He has stock options in Aural Analytics and Nocira. He has received research funding from the American Heart Association, Amgen, Henry Jackson Foundation, National Institutes of Health, Patient Centered Outcomes Research Institute, Spark Neuro, and United States Department of Defense.

Introduction: The Helping to End Addiction Long-term(SM) Initiative supports a wide range of programs to develop new or improved prevention and opioid addiction treatment strategies. An essential component of this effort is to accelerate development of non-opioid pain therapeutics. In all fields of medicine, therapeutics development is an arduous process and late-stage translational efforts such as clinical trials to validate targets are particularly complex and costly. While there are plentiful novel targets for pain treatment, successful clinical validation is rare. It is therefore crucial to develop processes whereby therapeutic targets can be reasonably "de-risked' prior to substantial late-stage validation efforts. Such rigorous validation of novel therapeutic targets in the preclinical space will give potential private sector partners the confidence to pursue clinical validation of promising therapeutic concepts and compounds. Areas covered: In 2020, the National Institutes of Health (NIH) held the Target Validation for Non- Addictive Therapeutics Development for Pain workshop to gather insights from key opinion leaders in academia, industry, and venture-financing. Expert opinion: The result was a roadmap for pain target validation focusing on three modalities: 1) human evidence; 2) assay development in vitro; 3) assay development in vivo

See Article, page 1128 Pain represents one of the most diverse and heterogeneous human health conditions, and accordingly, the development of therapeutics for treating pain is inherently challenging and risky. A Biotechnology Innovation Organization (BIO) industry analysis in 2018 found that clinical trials for pain therapeutics have only a 2% probability of success, compared to a 10% success rate across all diseases.1 If we exclude the calcitonin gene-related peptide (CGRP) antibodies and small-molecule antagonists for the treatment of migraine, in the last 15 years, there have been very few novel therapeutics that have made it into the hands of clinicians and patients for treating pain, most of which are opioids.1 The review by Eisenach and Rice2 in this issue of Anesthesia & Analgesia, titled “Improving Pre-Clinical Development of Novel Interventions to Treat Pain: Insanity Is Doing the Same Thing Over and Over and Expecting Different Results,” identifies shortcomings in preclinical and translational pain research that could have contributed to the failure over the last 40 years of the translation of preclinical pain science to novel therapeutics. In addition, this review suggests changes to the pain research enterprise to increase the likelihood of the translation of that research into novel effective pain therapeutics with minimal or no addictive potential. The recommendations by Eisenach and Rice2 fall essentially into 2 categories: (1) those related to enhancing the rigor and reproducibility of research in pain science, and (2) the types of animal models used for pain discovery and translational research. The authors rightly note that their comments related to the rigor and reproducibility of research are not specific to the preclinical pain research field. Basic research and drug development efforts in academia and industry, across all areas of biomedical sciences, could benefit from improving experimental and analytical rigor, reducing research bias, and increasing transparency in reporting their results, all of which contribute to enhanced reproducibility. For at least 10 years, the National Institutes of Health (NIH) Center for Scientific Review (CSR), National Institute of Neurological Disorders and Stroke (NINDS), and many other NIH Institutes have been adapting their review criteria for grant proposals and how funding decisions are made, specifically, based on the quality of the research in the proposal as well as the rigor of previous research that serves as the scientific premise for the grant proposal. In addition, NIH has provided the research community a plethora of educational resources to enhance rigor and reproducibility, which includes transparent reporting of research data and experimental protocols.3,4 The burden for implementing the changes required to increase rigor and transparency in the research enterprise does not lie solely with the federal sponsors of research. The researchers themselves, the institutions where the research is performed, the financial supporters (federal or private foundations), and the editorial staff of scientific journals are all responsible for assuring that data that are generated, reported, and shared are rigorous. The recommendations by Eisenach and Rice2 in their current review, which are described as internal validity of animal models, should be taken seriously by the preclinical pain research community. Important aspects of rigorous experiments that are critical to the proper interpretation of the generated data include the use of appropriate mathematical methods to determine sample and effect sizes; randomization of animals allocated to experimental groups; preset inclusion/exclusion criteria; blinding of both individuals conducting the experiments and those analyzing the results; and protections against “dropping out” subjects or samples in experiments because their outcomes are outliers, without revealing it. The pain-related funding announcements issued by the NIH Helping to End Addiction Long-term (HEAL) initiative have included specific language requiring applicants to incorporate many of these scientific methods to ensure rigorous experimental designs. Independent replication is also strongly encouraged. For example, the funding announcement, “RFA-NS-22-034 HEAL Initiative: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment,” asks applicants to include plans to reproduce the findings of the project in another laboratory.5 These techniques for increasing research quality should be taught at the undergraduate and graduate training levels and across all career stages, reinforced through discussions at poster and oral presentations at scientific meetings, and emphasized during the review of grant applications and articles for publication. These concepts for rigorous experimental design should not be an afterthought to conducting the research, only coming up when writing the Methods section of an article. In January 2019, NIH convened a workshop titled, “A Critical Evaluation of Animal Pain Models.”6 The purpose of this workshop was to discuss the use of animal models of pain and migraine for development of clinical therapeutics. The goals of the workshop were to have a frank discussion on the benefits and shortcomings of the current pain models and to make recommendations for using these models for screening compounds for pain disorders. Participants in the workshop discussed and recommended which animal models should be used for particular pain types and/or conditions, as well as the outcome measures and end points that should be used in those models. Regarding the use of animal models, Eisenach and Rice2 furthermore provide useful suggestions for increasing the external validity of those used for discovery and translational preclinical pain research. These authors noted that the reflexive behaviors used in the vast majority of rodent pain research studies do not reflect the manifestations of pain in many human pain disorders. Increasing the external validity of these models would require reproducing the disease state(s) and type(s) of pain in the pathological human pain conditions, which, in many instances, according to these authors, would be difficult in rodents. As a part of the NIH HEAL initiative and in our programs and funding opportunities, we have incorporated these and similar suggestions for increasing the validity of the animal models and end points/outcome measures for translational pain research. Two such recent funding announcements are focused squarely on addressing these needs within the pain research community: “NOT-NS-22-095 HEAL Initiative: Notice of Special Interest (NOSI): Development and Validation of Pain-Related Models and Endpoints to Facilitate Non-Addictive Analgesic Discovery” and “RFA-NS-22-070 HEAL Initiative: Development and Validation of Nonrodent Mammalian Models of Pain.”7,8 Both of these funding opportunities require rigorous internal and external validation studies and stress the importance of models and outcome measures that can recapitulate relevant aspects of human pain pathological phenotypes and etiology, such that end points or markers of disease are similar and measurable in both the model system and in the human pain condition. Applicants are also encouraged to incorporate independent replication studies as a critical component of model validation. RFA-NS-22-070 explicitly encourages the use of objective, nonevoked measures of spontaneous pain8. RFA-NS-22-070 promotes incorporation of preclinical assessments and behavioral outcome measures that are homologous to clinically relevant outcomes in humans, such as restoration of function (eg, species-relevant naturally occurring behaviors) as indication(s) of effective pain management, and central nervous system-dependent responses that include activation of cortical circuits, rather than spinal reflexes alone.8 The ultimate goal of these funding opportunities is to provide the pain research community with a diverse set of well-validated models and measures, which will allow researchers to make well-informed decisions regarding fit for purpose model selection based on specific translational goals and stage of therapeutic development. These and other NIH funding announcements also call for multidisciplinary teams, which include clinical expertise relevant to specific pain condition(s) that are the focus of the application. Clinical investigators provide an important perspective that should be incorporated into experimental designs to determine how representative a particular model is of the human disease population and to assure that end points are translatable to humans. Eisenach and Rice2 also note that back translating discoveries made in human pain populations into animal models could also increase their ability to be used in translational research. Along these same lines of thought, the HEAL initiative is encouraging integrated basic and clinical research in pain conducted by interdisciplinary teams, utilizing cross-cutting research approaches to understand the biology of human pain, including pain heterogeneity, susceptibility, and comorbid conditions (NOT-NS-23-009).9 Such an approach will expand our capacity to pursue challenging problems in basic biological understanding, therapeutics development, and effective management of human pain conditions. Furthermore, there is a growing expectation in the HEAL initiative pain funding announcements that the perspectives of clinicians and individuals with lived experience will be included in guiding the preclinical development of the pain therapeutic development projects. This additional perspective is also suggested by Eisenach and Rice2 in their current review. Input from patients and caregivers on the therapeutic goals of the project, even at this early stage, can help researchers develop products that will address the symptoms and needs of these affected individuals. The need for studies on primary human tissues and cells from subjects, with and without pain, to discover therapeutic targets that are relevant to human pain conditions has been a strong recommendation from multiple stakeholders in the pain research community, including at an NIH-convened workshop in 2020 titled, “Target Validation for Non-Addictive Therapeutics Development for Pain,” as well as both the HEAL Partnership Committee and the HEAL Multidisciplinary Working Group (MDWG).10–12 These latter 2 are external advisory groups for developing and aligning the goals of the NIH HEAL initiative. To address this recommendation, we developed 2 funding announcements (RFA-NS-22-018 and RFA-NS-22-021), that, together, create the Program to Reveal and Evaluate Cells-to-gene Information that Specify Intricacies, Origins, and the Nature of Human Pain (PRECISION) or the PRECISION Human Pain Network.13,14 The PRECISION Human Pain Network aims to capitalize on recent technological advances in high-throughput analyses of molecular, anatomic, and functional measurements for single-cell and tissue-level characterizations and to address the increasing need to enhance data interoperability and harmonization among data producers using human pain-associated tissues. The PRECISION Human Pain Network will support a group of centers where human tissue will be collected and processed to build comprehensive data sets of molecular signatures, cell types, and cellular function phenotypes that underlie human pain signal transduction, transmission, and processing. In collaboration with these centers, a data coordination and integration center will be responsible for the curation, harmonization, and integration of core data sets to generate digital resources that will be available to the entire pain research community. Thus, the primary goal of the PRECISION Human Pain Network it is to generate a comprehensive data resource for discovery and validation of relevant human genes, proteins, and cellular functional phenotypes that can be used as targets for small molecules and biologics for the treatment of pain, as well as develop, optimize, and cross-validate methods that can be utilized by the broader research community. In summary, the apt review by Eisenach and Rice2 not only identifies and clearly enumerates many potential problems with historical preclinical pain research, but also provides useful suggestions for how to improve the basic and translational preclinical pain research enterprise. Their review comes at a critical time, as the epidemic of chronic pain, opioid addiction, and overdose deaths are taking a terrible toll. It is our hope that reviews such as this and the new programs and funding opportunities for the NIH HEAL initiative,15 along with many other resources for increasing research rigor and reproducibility at NIH, will break through the logjam of issues and problems that have prevented the development of new treatments for pain. DISCLOSURES Name: Michael L. Oshinsky, PhD. Contribution: This author helped contribute ideas, provide references, organize content, and write and revise the article; and approved the final manuscript. Name: Julia L. Bachman, PhD. Contribution: This author helped contribute ideas, provide references, organize content, and write and revise the article. Name: Durga P. Mohapatra, PhD. Contribution: This author helped contribute ideas, provide references, organize content, and write and revise the article. This manuscript was handled by: Thomas R. Vetter, MD, MPH.

The use of spontaneous painful disease in companion pet animals has been highlighted as one of the changes that could be made to help improve translation of basic science to new therapeutics, acting as a bridge between preclinical and clinical studies, with the goal of accelerating the approval of new therapeutics. This review focuses on the utility of companion pet dogs for translational research by reviewing what outcome measures can be measured, and importantly, the relevance of these outcome measures to human translational research. It also details the practical considerations involved in incorporating companion dogs into human therapeutic development.

Interoception, the sense of the body's internal physiological state, underpins homeostatic reflexes, motivational states, and sensations contributing to emotional experiences. The continuous nature of interoceptive processing, coupled to behavior, is implicated in the neurobiological construction of the sense of self. Aberrant integration and control of interoceptive signals, originating in the brain and/or the periphery, can perturb the whole system. Interoceptive abnormalities are implicated in the pathophysiology of psychiatric disorders and in the symptomatic expression of developmental, neurodegenerative, and neurological disorders. Moreover, interoceptive mechanisms appear central to somatic disorders of brain-body interactions, including functional digestive disorders, chronic pain, and comorbid conditions. The present article provides an overview of disorders of interoception and suggests future directions for better understanding, diagnosis, and management of these disorders.

Randomized clinical trials have demonstrated the efficacy of opioid analgesics for the treatment of acute and chronic pain conditions, and for some patients, these medications may be the only effective treatment available. Unfortunately, opioid analgesics are also associated with major risks (eg, opioid use disorder) and adverse outcomes (eg, respiratory depression and falls). The risks and adverse outcomes associated with opioid analgesics have prompted efforts to reduce their use in the treatment of both acute and chronic pain. This article presents Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus recommendations for the design of opioid-sparing clinical trials. The recommendations presented in this article are based on the following definition of an opioid-sparing intervention: any intervention that (1) prevents the initiation of treatment with opioid analgesics, (2) decreases the duration of such treatment, (3) reduces the total dosages of opioids that are prescribed for or used by patients, or (4) reduces opioid-related adverse outcomes (without increasing opioid dosages), all without causing an unacceptable increase in pain. These recommendations are based on the results of a background review, presentations and discussions at an IMMPACT consensus meeting, and iterative drafts of this article modified to accommodate input from the co-authors. We discuss opioid sparing definitions, study objectives, outcome measures, the assessment of opioid-related adverse events, incorporation of adequate pain control in trial design, interpretation of research findings, and future research priorities to inform opioid-sparing trial methods. The considerations and recommendations presented in this article are meant to help guide the design, conduct, analysis, and interpretation of future trials.

On the cover: The entorhinal cortex (EC) often exhibits the earliest histological alterations in Alzheimer's disease (AD).Recent studies have documented impaired neuronal activity in the EC that precedes neurodegeneration.In this issue of Trends in Neurosciences, Kei Igarashi discusses the emerging hypothesis that memory impairments and spatial navigation defi cits at the initial stage of AD may be caused by EC activity dysfunction, and the potential implications of these fi ndings for mitigating AD progression by protecting the EC.Cover image by Aehyun Shin.

OBJECTIVE:To determine whether phonophobia and dynamic mechanical (brush) allodynia are associated in episodic migraine (EM).METHODS:Adult patients with EM were prospectively recruited. A structured questionnaire was used to obtain demographic and migraine related data. Phonophobia was tested quantitatively using a real time sound processor and psychoacoustic software. Sound stimuli were pure tones at frequencies of 1000 Hz, 4000 Hz and 8000 Hz, delivered to both ears at increasing intensities, until an aversive level was reached. Allodynia was assessed by brushing the patient's skin with a gauze pad at different areas. Patients were tested both between and during acute attacks. Sound aversion thresholds (SATs) in allodynic and non-allodynic patients were compared.RESULTS:Between attacks, SATs were lower in allodynic compared with non-allodynic patients, with an average difference of -5.7 dB (p=0.04). During acute attacks, the corresponding average SAT difference (allodynic-non-allodynic) was -15.7 dB (p=0.0008). There was a significant negative correlation between allodynia scores and SATs, both within and between attacks.CONCLUSIONS:The results support an association between phonophobia and cutaneous allodynia in migraine.

Identifying the mechanism behind delayed ethanol-induced headache (DEIH), otherwise known as the hangover headache, may provide insight into the mechanisms behind common headache triggers. Acetate was previously shown to be the key ethanol metabolite behind DEIH in the recurrent inflammatory stimulation (IS) rat model of headache. The reversal of trigeminal sensitivity following ethanol exposure with caffeine previously suggested a role of adenosine in DEIH. To characterize this, behavioral analysis and measurement of brainstem adenosine and glutamate with microdialysis and HPLC was performed while pharmacologically manipulating adenosine signaling in the IS and Spontaneous Trigeminal Allodynia (STA) rat models of headache. Blocking adenosine A2A receptor activation with istradefylline or acetate transport into astrocytes with the monocarboxylate transporter competitive inhibitor, alpha-cyano-4-hydroxycinnamate (4-CIN), prevented acetate-induced trigeminal sensitivity. Blocking adenosine A1, A2B, and A3 receptor signaling did not prevent trigeminal sensitivity. Compared to control rats, IS rats had greater increases in extracellular adenosine and glutamate within the trigeminal nucleus caudalis (TNC) of the brainstem during local acetate perfusion. Blocking transport of acetate into astrocytes with 4-CIN prevented the increase in adenosine and glutamate. Blocking A2A receptor activation prevented the increase in extracellular glutamate, but not adenosine in the TNC. These data are the first to demonstrate the physiological consequence of acetate on adenosinergic systems within trigeminal pain by suggesting that acetate-induced trigeminal sensitivity in DEIH is mediated by adenosine A2A receptor activation which modulates extracellular glutamate levels in the TNC. Significance Statement It is unknown how several common headache triggers induce headache pain. Since migraineurs are more sensitive to these triggers, studying the mechanisms behind their effects may reveal unique migraine pathophysiology. In this study, we explored the common headache trigger, ethanol, which migraineurs are particularly sensitive to. When ethanol is ingested, its quickly metabolized to acetaldehyde and subsequently into acetate. We find that acetate increases brainstem adenosine and causes trigeminal sensitivity, which is exacerbated in the rat headache model. Blocking either acetate uptake or adenosine signaling prevents trigeminal sensitivity and brainstem glutamatergic signaling, suggesting that adenosine is involved in the hangover headache and that differences in acetate metabolism may account for the increased sensitivity to ethanol in migraineurs. ### Competing Interest Statement The authors have declared no competing interest. * (IS) : Inflammatory stimulation (IS rats) : inflammatory stimulation model (STA rats) : spontaneous trigeminal allodynia model (DEIH) : Delayed ethanol-induced headache (TNC) : Trigeminal nucleus caudalis

The estimation of long-standing pain in companion animals through the measurement of different dimensions impacted by pain is a fundamental requirement if pain management, and pain therapeutic development, are to advance. Although pain management in veterinary medicine has advanced considerably in the last 20 years, there is much critical work to do in the area of measurement of chronic pain. To date, most work has centered on musculoskeletal pain, and has been focused around the measurement of limb use and the development of owner-completed questionnaires, or clinical metrology instruments (CMI). Recent areas of research have extended to developing measures of activity, sensory function (quantitative sensory testing; nociceptive withdrawal reflexes), and quality of life (QoL). Across all these areas, more data on validity are needed, and studies should be extended to other painful disease states. By necessity, assessing measurement tools requires testing in field studies, which incur considerable time and expense. Facilitating these studies could be optimized with a collaborative (industry, academia and private practice) approach, and the utility of the information produced from all field studies would be enhanced by full and transparent reporting and data sharing, including data already generated by industry in the form of studies submitted to the regulatory authorities.

In the face of increasing recognition and interest in treating chronic pain in companion animals, we struggle with a lack of therapeutic options. A significant barrier to the development of new therapeutics, or the critical evaluation of current therapies, is our inability to accurately measure chronic pain and its impact on companion animals. Over the last 20 years, much progress has been made in developing methods to measure chronic pain via subjective and objective methods — particularly in owner assessment tools and measurements of limb use and activity. Most work has been focused on chronic joint pain conditions, but there has been relatively little work in other areas of chronic pain, such as neuropathic and cancer pain. Although progress has been made, there is a considerable interest in improving our assessment of chronic pain, as evidenced by the multiple disciplines across industry, academia, and clinical practice from the veterinary and human medical fields that participated in the Pain in Animals Workshop held at the National Institutes of Health in 2017. This review is one product of that meeting and summarizes the current state of knowledge surrounding the measurement of chronic pain (musculoskeletal, cancer, neuropathic), and its impact, in cats and dogs.

Shoulder tip pain may occur after thoracic surgical procedures. The pain is caused by diaphragmatic irritation and is referred to the shoulder. Shoulder tip pain is often resistant to treatment with conventional analgesics. The sphenopalatine ganglion block has been described to manage many painful conditions. We report here the first use of this block to treat shoulder tip pain in 2 thoracic surgical patients. In both patients, the block produced rapid and sustained relief of the shoulder tip pain. We suggest that sphenopalatine ganglion block be considered to treat postoperative shoulder tip pain after thoracic surgical procedures.

Guest Editorials Accelerating Clinical Research Using Headache Common Data Elements Michael L. Oshinsky , PhD, Michael L. Oshinsky , PhD National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, MD, USASearch for more papers by this authorSarah Tanveer , BSc, Sarah Tanveer , BSc The Emmes Corporation, Rockville, MD, USASearch for more papers by this authorAndrew Hershey , MD, PhD, Andrew Hershey , MD, PhD Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USASearch for more papers by this author Michael L. Oshinsky , PhD, Michael L. Oshinsky , PhD National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, MD, USASearch for more papers by this authorSarah Tanveer , BSc, Sarah Tanveer , BSc The Emmes Corporation, Rockville, MD, USASearch for more papers by this authorAndrew Hershey , MD, PhD, Andrew Hershey , MD, PhD Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USASearch for more papers by this author First published: 27 August 2018 https://doi.org/10.1111/head.13352Citations: 3Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Disclosures Michael L. Oshinsky reports no relevant disclosures apart from being an NIH employee. Sarah Tanveer reports no relevant disclosures apart from being an NIH employee. Andrew Hershey assisted in development in PedMIDAS, one of the Headache CDE instrument recommendations. Citing Literature Volume58, Issue7July/August 2018Pages 928-930 RelatedInformation

Background The blood-brain barrier (BBB) has been hypothesized to play a role in migraine since the late 1970s. Despite this, limited investigation of the BBB in migraine has been conducted. We used the inflammatory soup rat model of trigeminal allodynia, which closely mimics chronic migraine, to determine the impact of repeated dural inflammatory stimulation on BBB permeability. Methods The sodium fluorescein BBB permeability assay was used in multiple brain regions (trigeminal nucleus caudalis (TNC), periaqueductal grey, frontal cortex, sub-cortex, and cortex directly below the area of dural activation) during the episodic and chronic stages of repeated inflammatory dural stimulation. Glial activation was assessed in the TNC via GFAP and OX42 immunoreactivity. Minocycline was tested for its ability to prevent BBB disruption and trigeminal sensitivity. Results No astrocyte or microglial activation was found during the episodic stage, but BBB permeability and trigeminal sensitivity were increased. Astrocyte and microglial activation, BBB permeability, and trigeminal sensitivity were increased during the chronic stage. These changes were only found in the TNC. Minocycline treatment prevented BBB permeability modulation and trigeminal sensitivity during the episodic and chronic stages. Discussion Modulation of BBB permeability occurs centrally within the TNC following repeated dural inflammatory stimulation and may play a role in migraine.

The purpose of the National Institute of Neurological Disorders and Stroke (NINDS) Headache CDE Version 2.0 project is to review and revise the Version 1.0 Headache CDE recommendations in order to ensure that the CDEs remain a current and useful tool for investigators. The goal is to enable researchers to use relevant CDEs for their research studies, and to ensure improved quality of dataset compilation. This project will significantly reduce study start-up time, facilitate data sharing among researchers, produce better quality research, and help educate new clinical investigators.

Migraine is the third most prevalent disease on the planet, yet our understanding of its mechanisms and pathophysiology is surprisingly incomplete. Recent studies have built upon decades of evidence that adenosine, a purine nucleoside that can act as a neuromodulator, is involved in pain transmission and sensitization. Clinical evidence and rodent studies have suggested that adenosine signaling also plays a critical role in migraine headache. This is further supported by the widespread use of caffeine, an adenosine receptor antagonist, in several headache treatments. In this review, we highlight evidence that supports the involvement of adenosine signaling in different forms of headache, headache triggers, and basic headache physiology. This evidence supports adenosine A2A receptors as a critical adenosine receptor subtype involved in headache pain. Adenosine A2A receptor signaling may contribute to headache via the modulation of intracellular Cyclic adenosine monophosphate (cAMP) production or 5' AMP-activated protein kinase (AMPK) activity in neurons and glia to affect glutamatergic synaptic transmission within the brainstem. This evidence supports the further study of adenosine signaling in headache and potentially illuminates it as a novel therapeutic target for migraine.