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.

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

Introduction: The Helping to End Addiction Long-term 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.

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.

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.

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.

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.

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.

Botulinum neurotoxin type-A when utilized in animals with trigeminal sensitization induced a antinociceptive effect.

Method: Neuropathic pain was induced by surgical constriction of the infraorbital nerve in rats. A control group underwent a sham procedure consisting of surgical exposure of the nerve. Subgroups of each group received either BoNT/A or isotonic saline solution.

Long-Term Pain Reduction Does Not Imply Improved Functional Outcome in Patients Treated With Combined Supraorbital and Occipital Nerve Stimulation for Chronic Migraine.

Background: Dual supraorbital and occipital nerve stimulation (SONS and ONS) have shown promising efficacy in treating primary headaches. However, its functional outcome is not well studied.

Objective: To present functional outcome studies of combined SONS and ONS for chronic migraine using verified metrics.

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.

Noninvasive vagus nerve stimulation as treatment for trigeminal allodynia.

Implanted vagus nerve stimulation (VNS) has been used to treat seizures and depression. In this study, we explored the mechanism of action of noninvasive vagus nerve stimulation (nVNS) for the treatment of trigeminal allodynia. Rats were repeatedly infused with inflammatory mediators directly onto the dura, which led to chronic trigeminal allodynia.

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.

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.

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.

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.

Acetate causes alcohol hangover headache in rats.

Background: The mechanism of veisalgia cephalgia or hangover headache is unknown. Despite a lack of mechanistic studies, there are a number of theories positing congeners, dehydration, or the ethanol metabolite acetaldehyde as causes of hangover headache.

Methods: We used a chronic headache model to examine how pure ethanol produces increased sensitivity for nociceptive behaviors in normally hydrated rats.

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.

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.

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.

Influence of NMDA and non-NMDA antagonists on acute and inflammatory pain in the trigeminal territory: a placebo control study.

NMDA and non-NMDA receptors are involved in spinal transmission of nociceptive information in physiological and pathological conditions. Our objective was to study the influence of NMDA and non-NMDA receptor antagonists on pain control in the trigeminal system using a formalin-induced orofacial pain model. Motor performance was also evaluated.