The headache research priorities: Research goals from the American Headache Society and an international multistakeholder expert group.

OBJECTIVE: To identify and disseminate research priorities for the headache field that should be areas of research focus during the next 10 years. BACKGROUND: Establishing research priorities helps focus and synergize the work of headache investigators, allowing them to reach the most important research goals more efficiently and completely. METHODS: The 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. RESULTS: Twenty-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. CONCLUSIONS: These 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.

Region-specific disruption of the blood-brain barrier following repeated inflammatory dural stimulation in a rat model of chronic trigeminal allodynia.

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.

Functional mitochondrial analysis in acute brain sections from adult rats reveals mitochondrial dysfunction in a rat model of migraine.

Mitochondrial dysfunction has been implicated in many neurological disorders that only develop or are much more severe in adults, yet no methodology exists that allows for medium-throughput functional mitochondrial analysis of brain sections from adult animals. We developed a technique for quantifying mitochondrial respiration in acutely isolated adult rat brain sections with the Seahorse XF Analyzer. Evaluating a range of conditions made quantifying mitochondrial function from acutely derived adult brain sections from the cortex, cerebellum, and trigeminal nucleus caudalis possible. Optimization of this technique demonstrated that the ideal section size was 1 mm wide. We found that sectioning brains at physiological temperatures was necessary for consistent metabolic analysis of trigeminal nucleus caudalis sections. Oxygen consumption in these sections was highly coupled to ATP synthesis, had robust spare respiratory capacities, and had limited nonmitochondrial respiration, all indicative of healthy tissue. We demonstrate the effectiveness of this technique by identifying a decreased spare respiratory capacity in the trigeminal nucleus caudalis of a rat model of chronic migraine, a neurological disorder that has been associated with mitochondrial dysfunction. This technique allows for 24 acutely isolated sections from multiple brain regions of a single adult rat to be analyzed simultaneously with four sequential drug treatments, greatly advancing the ability to study mitochondrial physiology in adult neurological disorders.

Ocular dryness excites two classes of corneal afferent neurons implicated in basal tearing in rats: involvement of transient receptor potential channels.

This study reports the findings of two classes of corneal afferents excited by drying of the cornea (dry responses) in isoflurane-anesthetized rats: cold-sensitive (CS; 87%) and cold-insensitive (CI; 13%) neurons. Compared with CI neurons, CS neurons showed significantly higher firing rates over warmer corneal temperatures (~31-15°C) and greater responses to menthol, drying, and wetting of the cornea but lower responses when hyperosmolar solutions were applied to the ocular surface. We proposed that the dry responses of these corneal afferents derive from cooling and an increased osmolarity of the ocular surface, leading to the production of basal tears. An ocular application of the transient receptor potential channel TRPM8 antagonist BCTC (20 µM) decreased the dry responses by ~45-80% but failed to completely block them, whereas the TRPA1 antagonist HC030031 did not influence the responses to drying of the cornea or hyperosmolar tears. Furthermore, the responses produced by cold stimulation of the cornea accounted for only 28% of the dry responses. These results support the view that the stimulus for basal tearing (corneal dryness) derives partly from cooling of the cornea that activates TRPM8 channels but that non-TRPM8 channels also contribute significantly to the dry responses and to basal tearing. Finally, we hypothesized that activation of TRPM8 by cooling in CS corneal afferents not only gives rise to the sensation of ocular coolness but also to the "wetness" perception (Thunberg's illusion), whereas a precise role of the CI afferents in basal tearing and other ocular dryness-related functions such as eye blink and the "dryness" sensation remain to be elucidated.

Quantitative characterization reveals three types of dry-sensitive corneal afferents: pattern of discharge, receptive field, and thermal and chemical sensitivity.

This study reveals that the cold-sensitive (CS) + dry-sensitive (DS) corneal afferents reported in a previous study consist of two types: 1) low threshold (LT)-CS + DS neurons with <1°C cooling sensitivity, and 2) high threshold (HT)-CS + DS neurons with a wide range of cooling sensitivities (~1-10°C cooling). We also found DS neurons with no cooling sensitivity down to 19°C [cold-insensitive (CI) + DS neurons]. LT-CS + DS neurons showed highly irregular discharge patterns during the dry cornea characterized by numerous spiking bursts, reflecting small temperature changes in the cornea. Their receptive fields (RFs) were mainly located in the cornea's center, the first place for tears to ebb from the surface and be susceptible to external temperature fluctuations. HT-CS and CI + DS neurons showed a gradual rise in firing rate to a stable level over ~60 s after the dry stimulus onset. Their RFs were located mostly in the cornea's periphery, the last place for tears to evaporate. The exquisite sensitivity to cooling in LT-CS + DS neurons was highly correlated with heat sensitivity (~45°C). There was a perfect correlation between noxious heat sensitivity and capsaicin responsiveness in each neuron type. The high sensitivity to noxious osmotic stress was a defining property of the HT-CS and CI + DS neurons, while high sensitivity to menthol was a major characteristic of the LT-CS + DS neurons. These observations suggest that three types of DS neurons serve different innocuous and nociceptive functions related to corneal dryness.

Nociceptive neuropeptide increases and periorbital allodynia in a model of traumatic brain injury.

OBJECTIVE: This study tests the hypothesis that injury to the somatosensory cortex is associated with periorbital allodynia and increases in nociceptive neuropeptides in the brainstem in a mouse model of controlled cortical impact (CCI) injury. METHODS: Male C57BL/6 mice received either CCI or craniotomy-only followed by weekly periorbital von Frey (mechanical) sensory testing for up to 28 days post-injury. Mice receiving an incision only and naïve mice were included as control groups. Changes in calcitonin gene-related peptide (CGRP) and substance P (SP) within the brainstem were determined using enzyme-linked immunosorbent assay and immunohistochemistry, respectively. Activation of ionized calcium-binding adaptor molecule-1-labeled macrophages/microglia and glial fibrillary acidic protein (GFAP)-positive astrocytes were evaluated using immunohistochemistry because of their potential involvement in nociceptor sensitization. RESULTS: Incision-only control mice showed no changes from baseline periorbital von Frey mechanical thresholds. CCI significantly reduced mean periorbital von Frey thresholds (periorbital allodynia) compared with baseline and craniotomy-only at each endpoint, analysis of variance P < .0001. Craniotomy significantly reduced periorbital threshold at 14 days but not 7, 21, or 28 days compared with baseline threshold, P < .01. CCI significantly increased SP immunoreactivity in the brainstem at 7 and 14 days but not 28 days compared with craniotomy-only and controls, P < .001. CGRP levels in brainstem tissues were significantly increased in CCI groups compared with controls (incision-only and naïve mice) or craniotomy-only mice at each endpoint examined, P < .0001. There was a significant correlation between CGRP and periorbital allodynia (P < .0001, r = -0.65) but not for SP (r = 0.20). CCI significantly increased the number of macrophage/microglia in the injured cortex at each endpoint up to 28 days, although cell numbers declined over weeks post-injury, P < .001. GFAP(+) immunoreactivity was significantly increased at 7 but not 14 or 28 days after CCI, P < .001. Craniotomy resulted in transient periorbital allodynia accompanied by transient increases in SP, CGRP, and GFAP immunoreactivity compared with control mice. There was no increase in the number of macrophage/microglia cells compared with controls after craniotomy. CONCLUSION: Injury to the somatosensory cortex results in persistent periorbital allodynia and increases in brainstem nociceptive neuropeptides. Findings suggest that persistent allodynia and increased neuropeptides are maintained by mechanisms other than activation of macrophage/microglia or astrocyte in the injured somatosensory cortex.

Spontaneous trigeminal allodynia in rats: a model of primary headache.

Animal models are essential for studying the pathophysiology of headache disorders and as a screening tool for new therapies. Most animal models modify a normal animal in an attempt to mimic migraine symptoms. They require manipulation to activate the trigeminal nerve or dural nociceptors. At best, they are models of secondary headache. No existing model can address the fundamental question: How is a primary headache spontaneously initiated? In the process of obtaining baseline periorbital von Frey thresholds in a wild-type Sprague-Dawley rat, we discovered a rat with spontaneous episodic trigeminal allodynia (manifested by episodically changing periorbital pain threshold). Subsequent mating showed that the trait is inherited. Animals with spontaneous trigeminal allodynia allow us to study the pathophysiology of primary recurrent headache disorders. To validate this as a model for migraine, we tested the effects of clinically proven acute and preventive migraine treatments on spontaneous changes in rat periorbital sensitivity. Sumatriptan, ketorolac, and dihydroergotamine temporarily reversed the low periorbital pain thresholds. Thirty days of chronic valproic acid treatment prevented spontaneous changes in trigeminal allodynia. After discontinuation, the rats returned to their baseline of spontaneous episodic threshold changes. We also tested the effects of known chemical human migraine triggers. On days when the rats did not have allodynia and showed normal periorbital von Frey thresholds, glycerol trinitrate and calcitonin gene related peptide induced significant decreases in the periorbital pain threshold. This model can be used as a predictive model for drug development and for studies of putative biomarkers for headache diagnosis and treatment.

The beneficial role of companion animals in translational pain research.

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.

Preclinical target validation for non-addictive therapeutics development for pain.

INTRODUCTION: The Helping to End Addiction Long-termSM 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.

Diseases, Disorders, and Comorbidities of Interoception.

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.

Is phonophobia associated with cutaneous allodynia in migraine?

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.

Pain remapping in migraine: a novel characteristic following trigeminal nerve injury.

The location of pain during the headache phase of migraine varies between individuals as well as between attacks in some individuals. We have observed a "remapping" or a change in the location of migraine pain following injury to the trigeminal system that is a novel characteristic to migraine and has not been described in other trigeminal pain syndromes of the head, neck, and face. Recognition of this clinical feature implies that the pathophysiology of migraine is impressionable and may be why diagnosis and treatment are often delayed.

Tension-type headache with medication overuse: pathophysiology and clinical implications.

Tension-type headache (TTH) is the most prevalent primary headache disorder. An important factor in the long-term prognosis of TTH is the overuse of acute medications used to treat headache. There are many reasons why patients with TTH overuse acute medications, including biobehavioral influences, dependency, and a lack of patient education. Chronic daily headache occurs in 4.1% of the general population, and chronic tension-type headache and medication overuse headache (MOH) occur in approximately 2.2% and 1.5%, respectively. A proper diagnosis is essential for the treatment of these patients. Treatment should include pathological considerations concerning TTH and MOH, which include peripheral and central mechanisms. Because TTH with MOH carries the worst prognosis, more clinical studies focusing on the complex interaction and treatments of TTH and MOH are needed.

Sphenopalatine Ganglion Block to Treat Shoulder Tip Pain After Thoracic Surgery: Report of 2 Cases.

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.

The Role of Adenosine Signaling in Headache: A Review.

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.

Physiology of the auditory afferents in an acoustic parasitoid fly.

The fly, Ormia ochracea, possess a novel auditory organ, which allows it to detect airborne sounds. The mechanical coupling of its pair of tympanal membranes provides the basis for a unique means of sensing the direction of a sound source. In this study, we characterized the neuroanatomy, frequency tuning, and neurophysiological response properties of the acoustic afferents. Our experiments demonstrate that the fly's nervous system is able to encode and localize the direction of a sound source, although the binaural auditory cues available in the acoustic sound field are miniscule. Almost all of the acoustic afferents recorded in this study responded to short and long sound pulses with a phasic burst of one to four action potentials. A few afferents responded tonically for the duration of the sound stimulus. A prominent class of afferents responds to suprathreshold stimuli with only a single spike discharge, independent of stimulus level, frequency, or duration. We also tested the response of the afferents to speakers separated by 180 degrees along the azimuth of the fly. We found that the afferent responses have a shorter latency because of ipsilateral stimulation. This could be a temporal code of the direction of a sound source. The threshold frequency tuning for the afferents revealed a range of sensitivities to the frequency of the cricket host's calling song frequency. The difference in the number of afferents above threshold on either side of the animal is a population code, which can also be used for sound localization.