The deuterated pyrazoloquinolinone targeting α6 subunit-containing GABAA receptor as novel candidate for inhibition of trigeminovascular system activation: implication for migraine therapy.

Introduction: The α6 subunit-containing GABAA receptors (α6GABAARs) are highly expressed in the trigeminal ganglia (TG), the sensory hub of the trigeminovascular system (TGVS). Hypo-GABAergic transmission in the TG was reported to contribute to migraine-related behavioral and histopathological phenotypes. Previously, we found that Compound 6, an α6GABAAR-selective positive allosteric modulator (PAM), significantly alleviated TGVS activation-induced peripheral and central sensitization in a capsaicin-induced migraine-mimicking model. Methods: Here, we tested whether the deuterated analogues of Compound 6, namely DK-1-56-1 and RV-I-29, known to have longer half-lives than the parent compound, can exert a similar therapeutic effect in the same model. The activation of TGVS was triggered by intra-cisternal (i.c.) instillation of capsaicin in male Wistar rats. Centrally, i.c. capsaicin increased the quantity of c-Fos-immunoreactive (c-Fos-ir) neurons in the trigeminal cervical complex (TCC). Peripherally, it increased the calcitonin gene-related peptide immunoreactivity (CGRP-ir) in TG, and caused CGRP release, leading to CGRP depletion in the dura mater. Results: DK-I-56-1 and RV-I-29, administered intraperitoneally (i.p.), significantly ameliorated the TCC neuronal activation, TG CGRP-ir elevation, and dural CGRP depletion induced by capsaicin, with DK-I-56-1 demonstrating better efficacy. The therapeutic effects of 3 mg/kg DK-I-56-1 are comparable to that of 30 mg/kg topiramate. Notably, i.p. administered furosemide, a blood-brain-barrier impermeable α6GABAAR-selective antagonist, prevented the effects of DK-I-56-1 and RV-I-29. Lastly, orally administered DK-I-56-1 has a similar pharmacological effect. Discussion: These results suggest that DK-I-56-1 is a promising candidate for novel migraine pharmacotherapy, through positively modulating TG α6GABAARs to inhibit TGVS activation, with relatively favourable pharmacokinetic properties.

1H-MRS reveals abnormal energy metabolism and excitatory-inhibitory imbalance in a chronic migraine-like state induced by nitroglycerin in mice.

BACKGROUND: Chronic migraine is closely related to the dysregulation of neurochemical substances in the brain, with metabolic imbalance being one of the proposed causes of chronic migraine. This study aims to evaluate the metabolic changes between energy metabolism and excitatory and inhibitory neurotransmitters in key brain regions of mice with chronic migraine-like state and to uncover the dysfunctional pathways of migraine. METHODS: A chronic migraine-like state mouse model was established by repeated administration of nitroglycerin (NTG). We used von Frey filaments to assess the mechanical thresholds of the hind paw and periorbital in wild-type and familial hemiplegic migraine type 2 mice. After the experiments, tissue was collected from five brain regions: the somatosensory cortex (SSP), hippocampus, thalamus (TH), hypothalamus, and the spinal trigeminal nucleus caudalis (TNC). Proton magnetic resonance spectroscopy (1H-MRS) was employed to study the changes in brain metabolites associated with migraine, aiming to explore the mechanisms underlying metabolic imbalance in chronic migraine-like state. RESULTS: In NTG-induced chronic migraine-like state model, we observed a significant reduction in energy metabolism during central sensitization, an increase in excitatory neurotransmitters such as glutamate, and a tendency for inhibitory neurotransmitters like GABA to decrease. The TNC and thalamus were the most affected regions. Furthermore, the consistency of N-acetylaspartate levels highlighted the importance of the TNC-TH-SSP pathway in the ascending nociceptive transmission of migraine. CONCLUSION: Abnormal energy metabolism and neurotransmitter imbalance in the brain region of NTG-induced chronic migraine-like state model are crucial mechanisms contributing to the chronicity of migraine.

The Intersection of Migraine and Epistaxis: Clinical Observations and Analysis.

Migraine prevalence has risen over the last few decades, which may be attributed to lifestyle changes. Epistaxis is unusual in migraine. Here we present a case series of four patients, who are presented with headaches associated with epistaxis. A detailed history revealed cardinal symptoms of migraine according to the International Headache Society, including hemicranial throbbing headache of moderate to severe intensity lasting for a duration of four to 72 hours, along with associated features of nausea, vomiting, photophobia, and phonophobia. Investigations, including ENT (ear, nose, and throat) examination, nasal endoscopy, gastroscopy, bronchoscopy, hematological, and coagulation parameters, were negative. All patients were started on prophylactic treatment for migraine, and they responded well. Epistaxis occurs at the peak of headache following which symptoms tend to resolve. The pathophysiology behind this is stimulation of the trigeminovascular system leading to dilatation of external and internal carotid arteries.

The preclinical discovery and development of atogepant for migraine prophylaxis.

INTRODUCTION: Atogepant is a selective calcitonin gene-related peptide (CGRP) receptor antagonist that is utilized in adults for the prevention of episodic and chronic migraine. Cumulative findings support the involvement of CGRP in migraine pathophysiology, and atogepant functions by competitively antagonizing CGRP receptors, which results in the inhibition of trigeminovascular nociception. The mechanism of action addresses the cause of migraine pain, providing an effective preventive treatment option. AREAS COVERED: The key milestones in its development, including preclinical achievements, phase I, II, and III clinical trials, and regulatory approvals are reviewed. Additionally, clinical efficacy, safety profile, and tolerability of atogepant are discussed. The literature review is based on a comprehensive search of English peer-reviewed articles from various electronic databases, including PubMed and ClinicalTrials.gov. EXPERT OPINION: The development of atogepant represents a significant breakthrough in migraine prevention, particularly due to its improved safety profile that reduces the risk of liver injury, which was a major limitation of first-generation gepants. Drug-drug interaction studies with atogepant highlight the necessity for more inclusive study populations. Given that migraine disproportionately affects females, future clinical development programs should include diverse patient demographics to ensure the findings are generalizable to all individuals suffering from migraine.

Induction of cGMP-mediated migraine attacks is independent of CGRP receptor activation.

BACKGROUND: The cAMP and cGMP pathways are implicated in the initiation of migraine attacks, but their interactions remain unclear. Calcitonin gene-related peptide (CGRP) triggers migraine attacks via cAMP, whereas the phosphodiesterase-5 inhibitor sildenafil induces migraine attacks via cGMP. Our objective was to investigate whether sildenafil could induce migraine attacks in individuals with migraine pre-treated with the CGRP-receptor antibody erenumab. METHODS: In this randomized, double-blind, placebo-controlled, cross-over study, adults with migraine without aura received a single subcutaneous injection of 140 mg erenumab on day 1. They were then randomized to receive sildenafil 100 mg or placebo on two experimental days, each separated by at least one week, between days 8 and 21. The primary endpoint was the difference in the incidence of migraine attacks between sildenafil and placebo during the 12-h observation period after administration. RESULTS: In total, 16 participants completed the study. Ten participants (63%) experienced a migraine attack within 12 h after sildenafil administration compared to three (19%) after placebo (p = 0.016). The median headache intensity was higher after sildenafil than after placebo (area under the curve (AUC) for the 12-h observation period, p = 0.026). Furthermore, sildenafil induced a significant decrease in mean arterial blood pressure (AUC, p = 0.026) and a simultaneous increase in heart rate (AUC, p < 0.001) during the first hour after administration compared to placebo. CONCLUSION: These findings provide evidence that migraine induction via the cGMP pathway can occur even under CGRP receptor blockade. TRIAL REGISTRATION: ClinicalTrials.gov: Identifier NCT05889455.

Pharmacological management of migraine: current strategies and future directions.

INTRODUCTION: Migraine is a complex neurological disorder that affects a significant portion of the global population. As traditional pharmacological approaches often fall short in alleviating symptoms, the development of innovative therapies has garnered significant interest. This text aims to summarize the current pharmacological options for managing migraine and to explore the potential impact of novel therapies. AREAS COVERED: We focused on conventional treatments, emerging therapies, and novel compounds in clinical development, including therapies targeting the trigeminovascular system, cannabis-based therapies, hormonal and metabolic therapies, and other options. English peer-reviewed articles were searched in PubMed, Scopus, and ClinicalTrials.gov electronic databases. EXPERT OPINION: Several novel treatment options for migraine have become available in recent years. Emerging pharmacological therapies targeting the trigeminovascular system, cannabis-based therapies, hormonal and metabolic interventions, and other emerging treatment modalities, may prove to be valuable for the treatment of migraine. Further research, clinical trials, and substantiated evidence are necessary to validate the efficacy, safety, and long-term outcomes of these therapeutic options.

Subarachnoid Hemorrhage Depletes Calcitonin Gene-Related Peptide Levels of Trigeminal Neurons in Rat Dura Mater.

Subarachnoid hemorrhage (SAH) remains a major cause of cerebrovascular morbidity, eliciting severe headaches and vasospasms that have been shown to inversely correlate with vasodilator calcitonin gene-related peptide (CGRP) levels. Although dura mater trigeminal afferents are an important source of intracranial CGRP, little is known about the effects of SAH on these neurons in preclinical models. The present study evaluated changes in CGRP levels and expression in trigeminal primary afferents innervating the dura mater 72 h after experimentally induced SAH in adult rats. SAH, eliciting marked damage revealed by neurological examination, significantly reduced the density of CGRP-immunoreactive nerve fibers both in the dura mater and the trigeminal caudal nucleus in the medulla but did not affect the total dural nerve fiber density. SAH attenuated ex vivo dural CGRP release by ~40% and in the trigeminal ganglion, reduced both CGRP mRNA levels and the number of highly CGRP-immunoreactive cell bodies. In summary, we provide novel complementary evidence that SAH negatively affects the integrity of the CGRP-expressing rat trigeminal neurons. Reduced CGRP levels suggest likely impaired meningeal neurovascular functions contributing to SAH complications. Further studies are to be performed to reveal the importance of impaired CGRP synthesis and its consequences in central sensory processing.

Voltage-gated Calcium Channels as Potential Therapeutic Targets in Migraine.

Migraine is a complex and highly incapacitating neurological disorder that affects around 15% of the general population with greater incidence in women, often at the most productive age of life. Migraine physiopathology is still not fully understood, but it involves multiple mediators and events in the trigeminovascular system and the central nervous system. The identification of calcitonin gene-related peptide as a key mediator in migraine physiopathology has led to the development of effective and highly selective antimigraine therapies. However, this treatment is neither accessible nor effective for all migraine sufferers. Thus, a better understanding of migraine mechanisms and the identification of potential targets are still clearly warranted. Voltage-gated calcium channels (VGCCs) are widely distributed in the trigeminovascular system, and there is accumulating evidence of their contribution to the mechanisms associated with headache pain. Several drugs used in migraine abortive or prophylactic treatment target VGCCs, which probably contributes to their analgesic effect. This review aims to summarize the current evidence of VGGC contribution to migraine physiopathology and to discuss how current pharmacological options for migraine treatment interfere with VGGC function. PERSPECTIVE: Calcitonin gene-related peptide (CGRP) represents a major migraine mediator, but few studies have investigated the relationship between CGRP and VGCCs. CGRP release is calcium channel-dependent and VGGCs are key players in familial migraine. Further studies are needed to determine whether VGCCs are suitable molecular targets for treating migraine.

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The literature regarding the action mechanism of acupuncture for migraine published from 2013 to 2023 was searched in China National Knowledge Infrastructure (CNKI), Wanfang, VIP, Chinese Science and Technology Periodical Database, PubMed, Medline, and Cochrane Library. The pathogenesis of migraine and potential mechanisms of acupuncture treatment were summarized from the aspects of trigeminovascular system (TGVS), metabolic-related mechanisms, genetic factors, and alterations in brain structure and function. The results revealed that current research on the mechanisms of acupuncture for migraine predominantly centered around the TGVS, with studies confirming the specific regulatory effects of acupuncture on trigeminal system-related components, such as cortical spreading depression (CSD), astrocytes, and neurogenic kinin. While metabolic-related mechanisms and genetic factors are gaining attention, further in-depth exploration is needed to fully understand their roles in the mechanism of acupuncture for migraine. The study of brain structure and function in migraine has advanced, albeit with some controversies. Future research should prioritize larger sample sizes and standardized study designs to delve deeper into the mechanisms of acupuncture in treating migraine.

Is calcitonin gene-related peptide (CGRP) the missing link in food histamine-induced migraine? A review of functional gut-to-trigeminovascular system connections.

Calcitonin gene-related peptide (CGRP) and histamine plasma concentrations increase during migraine attacks. Both mediators are potent vasodilators, and they have been shown to reciprocally contribute to the release of each other in the trigeminovascular system, possibly driving migraine development. A high-histamine-content diet triggers migraine in patients who have histamine degradation deficiency owing to diaminooxidase (DAO) gene mutations. Therefore, studying functional links between exogenous histamine and CGRP seems promising for the understanding of diet-induced migraine generation. Notably, there is a lack of knowledge about the interplay of the enteric nervous system and the spinal/trigeminal somatosensory system with regard to CGRP and histamine. Based on background evidence, we propose that a functional interconnection between exogenous histamine and CGRP contributes to migraine development.

The evolving concept of multimorbidity and migraine.

Migraine presents with high prevalence and similar clinical course with different disorders such as neurological, psychiatric, cardio- and cerebrovascular, gastrointestinal, metabolic-endocrine, and immunological conditions, which can often cooccur themselves. Multifaceted mechanisms subtend these comorbidities with a bidirectional link. First, a shared genetic load can explain the cooccurrence. Second, comorbid pathologies can promote disproportionate energetic needs, thalamocortical network dysexcitability, and systemic transient or persistent proinflammatory state, which may trigger the activation of a broad self-protective network that includes the trigeminovascular system in conjunction with the neuroendocrine hypothalamic system. This response results in maintenance of brain homeostasis by modulating subcortical-cortical excitability, energetic balance, osmoregulation, and emotional response. In this process, the CGRP is released in the trigeminovascular system. However, the calcitonin gene-related peptide (CGRP) plays several actions also outside the brain to maintain the homeostatic needs and is involved in the physiological functions of different systems, whose disorders are associated with migraine. This aspect further increases the complexity of migraine treatment, where standard therapies often have systemic adverse effects. On the other hand, some preventives can improve comorbid conditions. In summary, we propose that migraine management should involve a multidisciplinary approach to identify and mitigate potential risk factors and comorbidity and tailor therapies individually.

Activation of ATP-sensitive potassium channels triggers migraine attacks independent of calcitonin gene-related peptide receptors: a randomized placebo-controlled trial.

BACKGROUND: The present study aimed to investigate whether levcromakalim, a KATP channel opener, induces migraine attacks in people with migraine pre-treated with erenumab, a monoclonal CGRP receptor antibody. METHODS: In this double-blind, placebo-controlled, two-way cross-over study, adults with migraine without aura received a subcutaneous injection of 140 mg of erenumab on day 1. Subsequently, they were randomized to receive a 20-minute infusion of 0.05 mg/ml levcromakalim or placebo on two experimental days separated by at least one week (between days 8 and 21). The primary endpoint was the difference in the incidence of migraine attacks between levcromakalim and placebo during the 12-hour post-infusion period. RESULTS: In total, 16 participants completed the study. During the 12-hour observation period, 14 (88%) of 16 participants experienced migraine attacks after levcromakalim, compared to two (12%) after placebo (p < 0.001). The area under the curve for median headache intensity was greater after levcromakalim than placebo (p < 0.001). Levcromakalim elicited dilation of the superficial temporal artery during the first hour after infusion, a response absent following placebo (p < 0.001). CONCLUSIONS: The induction of migraine attacks via opening of KATP channels appears independent of CGRP receptor activation.Trial Registration: ClinicalTrials.gov, Identifier NCT05889442.

Hypersensitivity to PACAP-38 in post-traumatic headache: a randomized clinical trial.

Pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38), known for its role in migraine pathogenesis, has been identified as a novel drug target. Given the clinical parallels between post-traumatic headache (PTH) and migraine, we explored the possible role of PACAP-38 in the pathogenesis of PTH. To this end, we conducted a randomized, double-blind, placebo-controlled, two-way crossover trial involving adult participants diagnosed with persistent PTH resulting from mild traumatic brain injury. Participants were randomly assigned to receive a 20-min continuous intravenous infusion of either PACAP-38 (10 pmol/kg/min) or placebo (isotonic saline) on two separate experimental days, with a 1-week washout period in between. The primary outcome was the difference in incidence of migraine-like headache between PACAP-38 and placebo during a 12-h observational period post-infusion. The secondary outcome was the difference in the area under the curve (AUC) for baseline-corrected median headache intensity scores during the same 12-h observational period. Of 49 individuals assessed for eligibility, 21 were enrolled and completed the trial. The participants had a mean age of 35.2 years, and 16 (76%) were female. Most [19 of 21 (90%)] had a migraine-like phenotype. During the 12-h observational period, 20 of 21 (95%) participants developed migraine-like headache after intravenous infusion of PACAP-38, compared with two (10%) participants after placebo (P < 0.001). Furthermore, the baseline-corrected AUC values for median headache intensity scores during the 12-h observational period was higher after PACAP-38 than placebo (P < 0.001). These compelling results demonstrate that PACAP-38 is potent inducer of migraine-like headache in people with persistent PTH. Thus, targeting PACAP-38 signalling might be a promising avenue for the treatment of PTH.

Can upper cervical manual therapy affect the blink reflex in subjects with migraine and neck pain?

BACKGROUND: Neck pain is a common complaint among migraineurs possibly due to the anatomic connections between cervical and trigeminal afferents in the trigeminocervical complex (TCC). Manual therapy (MT) is used in the management of headache disorders, with demonstrable neurophysiological effects. The blink reflex (BR) is one method of analyzing neurophysiological effects in headache patients. The purpose of this study was to investigate the effect of upper cervical spine MT on BR in subjects with migraine and neck pain. METHODS & MATERIALS: Twenty subjects were assigned to a medication plus MT (MedMT) group (n = 10) and medication plus sham MT (sham MT) group (n = 10). After random assignment, all patients underwent testing for the BR (R1, R2, R2c responses). Then, subjects in group MedMT and group sham MT received either 4 sessions of MT or sham MT to the upper cervical spine. After completion of the intervention, BR testing was repeated. RESULTS: There were no significant differences in both side R1 latency between group MT and group sham MT (P > 0.050). For both sides, R2 latencies were significantly prolonged in MedMT group compared with sham MT group (P < 0.050). Subjects in MedMT group showed significant prolongation in right and left R2c latency compared with sham MT group (P < 0.050). DISCUSSION: The present study demonstrated that upper cervical MT affected trigeminal nociceptive neurotransmission in subjects with migraine and neck pain as reflected by changes in the BR. The increase in BR late response latencies of BR indicates an inhibitory effect of upper cervical spine MT on the TCC in these subjects. Trial Registration: The trial design was registered at the Iranian Registry of Clinical Trials (IRCT ID: IRCT20160621028567N2, url: https://www.irct.ir/) before the first patient was enrolled.

PACAP-38 related modulation of the cranial parasympathetic projection: A novel mechanism and therapeutic target in severe primary headache.

BACKGROUND AND PURPOSE: Little is known of how cranial autonomic symptoms (CAS) in cluster headache and migraine may contribute to their severe headache phenotype. This strong association suggests the involvement of the cranial parasympathetic efferent pathway. To investigate its contribution, we studied the role of pituitary adenylate cyclase activating polypeptide-38 (PACAP-38), a potent sensory and parasympathetic neuropeptide, in modulating pre- and post-ganglionic cranial parasympathetic projection neurons, and their influence on headache-related trigeminal-autonomic responses. EXPERIMENTAL APPROACH: Using PACAP-38 and PACAP-38 responsive receptor antagonists, electrophysiological, behavioural and facial neurovascular-blood flow was measured in rats to probe trigeminal- and parasympathetic-neuronal, periorbital thresholds and cranial-autonomic outcomes, as they relate to primary headaches. KEY RESULTS: Sumatriptan attenuated the development of PACAP-38 mediated activation and sensitization of trigeminocervical neurons and related periorbital allodynia. PACAP-38 also caused activation and enhanced responses of dural-responsive pre-ganglionic pontine-superior salivatory parasympathetic neurons. Further, the PACAP-38 responsive receptor antagonists dissected a role of VPAC1 and PAC1 receptors in attenuating cranial-autonomic and trigeminal-neuronal responses to activation of the cranial parasympathetic projection, which requires post-ganglionic parasympathetic neurotransmission. CONCLUSION AND IMPLICATIONS: Given the prevailing view that sumatriptan acts to some degree via a peripheral mechanism, our data support that PACAP-38 mediated receptor activation modulates headache-related cranial-autonomic and trigeminovascular responses via peripheral and central components of the cranial parasympathetic projection. This provides a mechanistic rationale for the association of CAS with more severe headache phenotypes in cluster headache and migraine, and supports the cranial parasympathetic projection as a potential novel locus for treatment by selectively targeting PACAP-38 or PACAP-38 responsive VPAC1 /PAC1 receptors.

Menthol dural application alters meningeal arteries tone and enhances excitability of trigeminocervical neurons in rats.

Headaches, including migraines, can have a causal relationship to exposure to cold, and this relationship may be both positive and negative, as cold can both provoke and alleviate cephalgia. The role of thermoreceptors responsible for transduction of low temperatures belongs to the transient receptor potential cation channel subfamily melastatin member 8 (TRPM8). These channels mediate normal cooling sensation and have a role in both cold pain and cooling-mediated analgesia; they are seen as a potential target for principally new anti-migraine pharmaceuticals. Using a validated animal migraine models, we evaluated effects of menthol, the TRPM8-agonist, on trigeminovascular nociception. In acute experiments on male rats, effects of applied durally menthol solution in various concentrations on the neurogenic dural vasodilatation (NDV) and firing rate of dura-sensitive neurons of the trigeminocervical complex (TCC) were assessed. Application of menthol solution in concentrations of 5 % and 10 % was associated with NDV suppression, however amplitude reduction of the dilatation response caused not by the vascular dilatation degree decrease, but rather due to the significant increase of the meningeal arterioles' basal tone. In electrophysiological experiments the 1 % and 30 % menthol solutions intensified TCC neuron responses to the dural electrical stimulation while not changing their background activity. Revealed in our study excitatory effects of menthol related to the vascular as well as neuronal branches of the trigeminovascular system indicate pro-cephalalgic effects of TRPM8-activation and suggest feasibility of further search for new anti-migraine substances among TRPM8-antagonists.

Ion Channel Disturbances in Migraine Headache: Exploring the Potential Role of the Kynurenine System in the Context of the Trigeminovascular System.

Migraine is a primary headache disorder, which is an enormous burden to the healthcare system. While some aspects of the pathomechanism of migraines remain unknown, the most accepted theory is that activation and sensitization of the trigeminovascular system are essential during migraine attacks. In recent decades, it has been suggested that ion channels may be important participants in the pathogenesis of migraine. Numerous ion channels are expressed in the peripheral and central nervous systems, including the trigeminovascular system, affecting neuron excitability, synaptic energy homeostasis, inflammatory signaling, and pain sensation. Dysfunction of ion channels could result in neuronal excitability and peripheral or central sensitization. This narrative review covers the current understanding of the biological mechanisms leading to activation and sensitization of the trigeminovascular pain pathway, with a focus on recent findings on ion channel activation and modulation. Furthermore, we focus on the kynurenine pathway since this system contains kynurenic acid, which is an endogenous glutamate receptor antagonist substance, and it has a role in migraine pathophysiology.

Migraine headache pathophysiology.

In both episodic and chronic migraine, headache is the most disabling symptom that requires medical care. The migraine headache is the most well-studied symptom of migraine pathophysiology. The trigeminal system and the central processing of sensory information transmitted by the trigeminal system are of considerable importance in the pathophysiology of migraine headache. Glutamate is the main neurotransmitter that drives activation of the ascending trigeminal and trigeminothalamic pathways. The neuropeptide, calcitonin gene-related peptide (CGRP) that is released by the trigeminal system, plays a crucial role in the neurobiology of headache. Peripheral and central sensitizations associated with trigeminal sensory processing are neurobiologic states that contribute to both the development of headache during a migraine attack and the maintenance of chronic migraine.

The evolutionary meaning of migraine.

INTRODUCTION: Migraine's astonishing prevalence and preserved genetic background contrast with the definition of a disease and the biological meaning of experiencing recurrent, severe headache attacks is still puzzling. METHODS: To provide a comprehensive explanation of the migraine evolutionary meaning, we review (i) the putative role of the autonomic nervous system in migraine attacks, (ii) the inter-ictal autonomic, functional, and metabolic signature of migraine patients, (iii) the bio-behavioral perspective of pain, and (iv) the allostatic perception of migraine chronification. RESULTS: Migraineurs have inter-ictal cortical hyperexcitability and metabolic dysfunction that predisposes to brain energetic imbalance. Multiple precipitating factors may lead to brain energy consumption over the migraine attack generation threshold. In response, the brain engenders adaptive, evolutionary conserved, autonomic-behavior responses through the antidromic activation of the trigeminovascular system. The sickness behavior and severe pain experienced during migraine attacks result in avoiding mental and physical activity, allowing brain energy restoration. Chronic exposure to stressors may result in an allostatic overload, leading to maladaptive chronic activation of these responses. In this bio-behavioral perspective, the chronification of migraine should be envisioned as a pathological process, whereas the migraine itself should not. CONCLUSION: Migraine has an evolutionary (Darwinian) meaning.

Hypersensitivity to opening of ATP-sensitive potassium channels in post-traumatic headache.

OBJECTIVE: To investigate whether levcromakalim (a KATP channel opener) induces migraine-like headache in people with persistent post-traumatic headache who had no known history of migraine. METHODS: In a randomized, double-blind, placebo-controlled, 2-way crossover trial, participants were randomly assigned to receive a 20-minute continuous intravenous infusion of levcromakalim (50 µg/mL) or placebo (isotonic saline) on two separate experimental days with a 1-week wash-out period in between. The primary endpoint was the difference in incidence of migraine-like headache between levcromakalim and placebo during a 12-hour observational period after infusion start. The secondary endpoint was the difference in area under the curve for baseline-corrected median headache intensity scores between levcromakalim and placebo during the 12-hour observational period. RESULTS: A total of 21 participants with persistent post-traumatic headache were randomized and completed the trial. During the 12-hour observational period, 12 (57%) of 21 participants reported experiencing migraine-like headache following the levcromakalim infusion, compared with three after placebo (P = 0.013). Moreover, the baseline-corrected median headache intensity scores were higher following the levcromakalim infusion than after placebo (P = 0.003). CONCLUSION: Our findings suggest that KATP channels play an important role in the pathogenesis of migraine-like headache in people with persistent post-traumatic headache. This implies that KATP channel blockers might represent a promising avenue for drug development. Further research is warranted to explore the potential therapeutic benefits of KATP channel blockers in managing post-traumatic headache.Trial Registration: ClinicalTrials.gov Identifier: NCT05243953.