Novel Medications for the Treatment of Migraine.

OBJECTIVE: To describe the new classes of medication for headache management and their roles in clinical practice. BACKGROUND: Calcitonin gene-related peptide (CGRP) is a key component in the underlying pathophysiology of migraine. Research focused on targeting CGRP for headache treatment has led to the development of entirely new classes of medications - the gepants and the CGRP monoclonal antibodies (mAbs) - for both acute and preventive treatment. A third class, the ditans, is being developed to target the 5-HT1F receptor to provide acute treatment without vasoconstrictive effects. METHODS: This article reviews the pathophysiology of migraine that has led to these new pharmacologic developments. Available information from randomized controlled trials, abstracts, press releases, and relevant preclinical studies is summarized for each class of medications. RESULTS: At the time of this writing, one ditan has been submitted to the U.S. Food and Drug Administration (FDA) for approval. One gepant is anticipated to be submitted within the first quarter of 2019, and others are in clinical trials. Three CGRP mAbs have been FDA approved and are now available in clinical practice, and a fourth was submitted in the first quarter of 2019. CONCLUSIONS: The development of new migraine-specific classes of medications provides more treatment options for both acute and preventive treatment of migraine.

CGRP receptor antagonist activity of olcegepant depends on the signalling pathway measured.

Background Calcitonin gene-related peptide (CGRP) is a neuropeptide that acts in the trigeminovascular system and is believed to play an important role in migraine. CGRP activates two receptors that are both present in the trigeminovascular system; the CGRP receptor and the amylin 1 (AMY1) receptor. CGRP receptor antagonists, including olcegepant (BIBN4096BS) and telcagepant (MK-0974), can treat migraine. This study aimed to determine the effectiveness of these antagonists at blocking CGRP receptor signalling in trigeminal ganglia (TG) neurons and transfected CGRP and AMY1 receptors in Cos7 cells, to better understand their mechanism of action. Methods CGRP stimulation of four intracellular signalling molecules relevant to pain (cAMP, CREB, p38 and ERK) were examined in rat TG neurons and compared to transfected CGRP and AMY1 receptors in Cos7 cells. Results In TG neurons, olcegepant displayed signal-specific differences in antagonism of CGRP responses. This effect was also evident in transfected Cos7 cells, where olcegepant blocked CREB phosphorylation more potently than expected at the AMY1 receptor, suggesting that the affinity of this antagonist can be dependent on the signalling pathway activated. Conclusions CGRP receptor antagonist activity appears to be assay-dependent. Thus, these molecules may not be as selective for the CGRP receptor as commonly reported.

[Migraine prophylaxis 2019 - the role of CGRP antagonists]. / Migräneprophylaxe 2019 ­ die Rolle der CGRP Antagonisten.

Migraine prophylaxis 2019 - the role of CGRP antagonists Abstract. The CGRP System is part of the pain pathway within the complex pathophysiology of migraine. Monoclonal antibodies targeting the CGRP system are the first class of substances developed specifically for the prevention of migraine, i. e. the reduction of attack frequency and intensity. The efficacy of this class of substances is comparable to established anti-migraine prophylactic medication. Tolerability and safety seem excellent in the published studies as well as in our clinical experience up to now. Limitations for reimbursement are expected for all substances within this class due to a relatively high price as compared to established drugs. The first substance in class is on the market in Switzerland. The role, these substances will play in the stratified treatment of sufferers will have to be established in clinical practice after several of these monoclonal antibodies will be on the market.

Ciguatoxins Evoke Potent CGRP Release by Activation of Voltage-Gated Sodium Channel Subtypes NaV1.9, NaV1.7 and NaV1.1.

Ciguatoxins (CTXs) are marine toxins that cause ciguatera fish poisoning, a debilitating disease dominated by sensory and neurological disturbances that include cold allodynia and various painful symptoms as well as long-lasting pruritus. Although CTXs are known as the most potent mammalian sodium channel activator toxins, the etiology of many of its neurosensory symptoms remains unresolved. We recently described that local application of 1 nM Pacific Ciguatoxin-1 (P-CTX-1) into the skin of human subjects induces a long-lasting, painful axon reflex flare and that CTXs are particularly effective in releasing calcitonin-gene related peptide (CGRP) from nerve terminals. In this study, we used mouse and rat skin preparations and enzyme-linked immunosorbent assays (ELISA) to study the molecular mechanism by which P-CTX-1 induces CGRP release. We show that P-CTX-1 induces CGRP release more effectively in mouse as compared to rat skin, exhibiting EC50 concentrations in the low nanomolar range. P-CTX-1-induced CGRP release from skin is dependent on extracellular calcium and sodium, but independent from the activation of various thermosensory transient receptor potential (TRP) ion channels. In contrast, lidocaine and tetrodotoxin (TTX) reduce CGRP release by 53-75%, with the remaining fraction involving L-type and T-type voltage-gated calcium channels (VGCC). Using transgenic mice, we revealed that the TTX-resistant voltage-gated sodium channel (VGSC) NaV1.9, but not NaV1.8 or NaV1.7 alone and the combined activation of the TTX-sensitive VGSC subtypes NaV1.7 and NaV1.1 carry the largest part of the P-CTX-1-caused CGRP release of 42% and 34%, respectively. Given the contribution of CGRP to nociceptive and itch sensing pathways, our findings contribute to a better understanding of sensory symptoms of acute and chronic ciguatera that may help in the identification of potential therapeutics.

Triptans and CGRP blockade - impact on the cranial vasculature.

The trigeminovascular system plays a key role in the pathophysiology of migraine. The activation of the trigeminovascular system causes release of various neurotransmitters and neuropeptides, including serotonin and calcitonin gene-related peptide (CGRP), which modulate pain transmission and vascular tone. Thirty years after discovery of agonists for serotonin 5-HT1B and 5-HT1D receptors (triptans) and less than fifteen after the proof of concept of the gepant class of CGRP receptor antagonists, we are still a long way from understanding their precise site and mode of action in migraine. The effect on cranial vasculature is relevant, because all specific anti-migraine drugs and migraine pharmacological triggers may act in perivascular space. This review reports the effects of triptans and CGRP blocking molecules on cranial vasculature in humans, focusing on their specific relevance to migraine treatment.

Endovanilloids are potential activators of the trigeminovascular nocisensor complex.

BACKGROUND: In the dura mater encephali a significant population of trigeminal afferents coexpress the nociceptive ion channel transient receptor potential vanilloid type 1 (TRPV1) receptor and calcitonin gene-related peptide (CGRP). Release of CGRP serves the central transmission of sensory information, initiates local tissue reactions and may also sensitize the nociceptive pathway. To reveal the possible activation of meningeal TRPV1 receptors by endogenously synthetized agonists, the effects of arachidonylethanolamide (anandamide) and N-arachidonoyl-dopamine (NADA) were studied on dural vascular reactions and meningeal CGRP release. METHODS: Changes in meningeal blood flow were measured with laser Doppler flowmetry in a rat open cranial window preparation following local dural applications of anandamide and NADA. The release of CGRP evoked by endovanilloids was measured with ELISA in an in vitro dura mater preparation. RESULTS: Topical application of NADA induced a significant dose-dependent increase in meningeal blood flow that was markedly inhibited by pretreatments with the TRPV1 antagonist capsazepine, the CGRP antagonist CGRP8-37, or by prior systemic capsaicin desensitization. Administration of anandamide resulted in minor increases in meningeal blood flow that was turned into vasoconstriction at the higher concentration. In the in vitro dura mater preparation NADA evoked a significant increase in CGRP release. Cannabinoid CB1 receptors of CGRP releasing nerve fibers seem to counteract the TRPV1 agonistic effect of anandamide in a dose-dependent fashion, a result which is confirmed by the facilitating effect of CB1 receptor inhibition on CGRP release and its reversing effect on the blood flow. CONCLUSIONS: The present findings demonstrate that endovanilloids are potential activators of meningeal TRPV1 receptors and, consequently the trigeminovascular nocisensor complex that may play a significant role in the pathophysiology of headaches. The results also suggest that prejunctional CB1 receptors may modulate meningeal vascular responses.

Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition.

Migraine is the sixth most prevalent disease worldwide but the mechanisms that underlie migraine chronicity are poorly understood. Cytoskeletal flexibility is fundamental to neuronal-plasticity and is dependent on dynamic microtubules. Histone-deacetylase-6 (HDAC6) decreases microtubule dynamics by deacetylating its primary substrate, α-tubulin. We use validated mouse models of migraine to show that HDAC6-inhibition is a promising migraine treatment and reveal an undiscovered cytoarchitectural basis for migraine chronicity. The human migraine trigger, nitroglycerin, produced chronic migraine-associated pain and decreased neurite growth in headache-processing regions, which were reversed by HDAC6 inhibition. Cortical spreading depression (CSD), a physiological correlate of migraine aura, also decreased cortical neurite growth, while HDAC6-inhibitor restored neuronal complexity and decreased CSD. Importantly, a calcitonin gene-related peptide receptor antagonist also restored blunted neuronal complexity induced by nitroglycerin. Our results demonstrate that disruptions in neuronal cytoarchitecture are a feature of chronic migraine, and effective migraine therapies might include agents that restore microtubule/neuronal plasticity.

Migraines are a common brain disorder that affects 14% of the world's population. For many people the main symptom of a migraine is a painful headache, often on one side of the head. Other symptoms include increased sensitivity to light or sound, disturbed vision, and feeling sick. These sensory disturbances are called aura and they often occur before the headache begins. One particularly debilitating subset of migraines are chronic migraines, in which patients experience more than 15 headache days per month. Migraine therapies are often only partially effective or poorly tolerated, making it important to develop new drugs for this condition, but unfortunately, little is known about the molecular causes of migraines. To bridge this gap, Bertels et al. used two different approaches to cause migraine-like symptoms in mice. One approach consisted on giving mice nitroglycerin, which dilates blood vessels, produces hypersensitivity to touch, and causes photophobia in both humans and mice. In the second approach, mice underwent surgery and potassium chloride was applied onto the dura, a thick membrane that surrounds the brain. This produces cortical spreading depression, an event that is linked to migraine auras and involves a wave of electric changes in brain cells that slowly propagates across the brain, silencing brain electrical activity for several minutes. Using these approaches, Bertels et al. studied whether causing chronic migraine-like symptoms in mice is associated with changes in the structures of neurons, focusing on the effects of migraines on microtubules. Microtubules are cylindrical protein structures formed by the assembly of smaller protein units. In most cells, microtubules assemble and disassemble depending on what the cell needs. Neurons need stable microtubules to establish connections with other neurons. The experiments showed that provoking chronic migraines in mice led to a reduction in the numbers of connections between different neurons. Additionally, Bertels et al. found that inhibiting HDAC6 (a protein that destabilizes microtubules) reverses the structural changes in neurons caused by migraines and decreases migraine symptoms. The same effects are seen when a known migraine treatment strategy, known as CGRP receptor blockade, is applied. These results suggest that chronic migraines may involve decreased neural complexity, and that the restoration of this complexity by HDAC6 inhibitors could be a potential therapeutic strategy for migraine.

CGRP inhibitors for migraine prophylaxis: a safety review.

INTRODUCTION: Since calcitonin gene-related peptide (CGRP) plays an important role in the pathophysiology of migraine via the activation of the trigeminovascular system, the newest prophylactic treatments directly block CGRP or its receptor. However, the safety of these novel antimigraine drugs is not yet sufficiently established. AREAS COVERED: Based on the blockade of CGRP or its receptor, this review considers: (i) the effects of the novel prophylactic antimigraine drugs (i.e. gepants and monoclonal antibodies) in clinical trials; and (ii) the potentially negative effects of blocking CGRP or its receptor in terms of safety. EXPERT OPINION: In the last decade, clinical trials have demonstrated the efficacy of new drugs for the preventive treatment of migraine which aim to (i) block CGRP or its receptor; (ii) increase tolerability as compared to the currently available prophylactics; and/or (iii) be more effective and safer than other treatments. However, these trials are limited to study the safety on the short term, and a cardiovascular risk with prolonged use cannot be excluded. Clearly, basic science experimental studies and long-term clinical trials (i.e. Phase IV) are required to delineate the safety of the newest prophylactic antimigraine drugs without causing unwanted side effects due to chronic CGRP (receptor) blockade.

Potential for treatment benefit of small molecule CGRP receptor antagonist plus monoclonal antibody in migraine therapy.

OBJECTIVE: To provide the first clinical report that 2 calcitonin gene-related peptide (CGRP) therapies, a small molecule CGRP receptor antagonist and an anti-CGRP receptor antibody, can be used concomitantly to treat refractory migraine. METHODS: Case reports are presented of 2 patients participating in a long-term safety study of rimegepant 75 mg oral tablets for acute treatment (NCT03266588). After Food and Drug Administration approval of erenumab, both patients started subcutaneous erenumab monthly as allowed per protocol. RESULTS: Patients were women 44 and 36 years of age with ≥2 decades of self-reported suboptimal response to multiple migraine medications. Patient 1 used rimegepant for 6 months and then started erenumab 70 mg subcutaneous monthly. Despite a response to preventive treatment with erenumab, she experienced substantial relief treating 7 of 7 acute attacks with rimegepant and eliminated regular, frequent use of ibuprofen and a caffeinated analgesic. Patient 2 used rimegepant for 60 days before starting erenumab 140 mg subcutaneously monthly. While on erenumab, 9 of 9 attacks treated with rimegepant responded. She stopped near-daily use of injectable ketorolac and diphenhydramine. While using rimegepant alone or together with erenumab, patients reported no related adverse events. CONCLUSIONS: Rimegepant 75 mg may be effective for acute treatment during concomitant erenumab preventive administration. The mechanism underlying the benefits of concomitant use of a small molecule CGRP receptor antagonist and an anti-CGRP receptor antibody is unknown and requires further study. CLINICALTRIALSGOV IDENTIFIER: NCT03266588. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with migraine using erenumab, rimegepant is effective for acute treatment.

Calcitonin gene-related peptide (CGRP): role in migraine pathophysiology and therapeutic targeting.

Introduction: The neuropeptide calcitonin gene-related peptide (CGRP) is recognized as a critical player in migraine pathophysiology. Excitement has grown regarding CGRP because of the development and clinical testing of drugs targeting CGRP or its receptor. While these drugs alleviate migraine symptoms in half of the patients, the remaining unresponsive half of this population creates an impetus to address unanswered questions that exist in this field.Areas covered: We describe the role of CGRP in migraine pathophysiology and CGRP-targeted therapeutics currently under development and in use. We also discuss how a second CGRP receptor may provide a new therapeutic target.Expert opinion: CGRP-targeting drugs have shown a remarkable safety profile. We speculate that this may reflect the redundancy of peptides within the CGRP family and a second CGRP receptor that may compensate for reduced CGRP activity. Furthermore, we propose that an inherent safety feature of peptide-blocking antibodies is attributed to the fundamental nature of peptide release, which occurs as a large bolus in short bursts of volume transmission. These facts support the development of more refined CGRP therapeutic drugs, as well as drugs that target other neuropeptides. We believe that the future of migraine research is bright with exciting advances on the horizon.

Pharmacological treatment of migraine: CGRP and 5-HT beyond the triptans.

Migraine is a highly disabling neurovascular disorder characterized by a severe headache (associated with nausea, photophobia and/or phonophobia), and trigeminovascular system activation involving the release of calcitonin-gene related peptide (CGRP). Novel anti-migraine drugs target CGRP signaling through either stimulation of 5-HT1F receptors on trigeminovascular nerves (resulting in inhibition of CGRP release) or direct blockade of CGRP or its receptor. Lasmiditan is a highly selective 5-HT1F receptor agonist and, unlike the triptans, is devoid of vasoconstrictive properties, allowing its use in patients with cardiovascular risk. Since lasmiditan can actively penetrate the blood-brain barrier, central therapeutic as well as side effects mediated by 5-HT1F receptor activation should be further investigated. Other novel anti-migraine drugs target CGRP signaling directly. This neuropeptide can be targeted by the monoclonal antibodies eptinezumab, fremanezumab and galcanezumab, or by CGRP-neutralizing L-aptamers called Spiegelmers. The CGRP receptor can be targeted by the monoclonal antibody erenumab, or by small-molecule antagonists called gepants. Currently, rimegepant and ubrogepant have been developed for acute migraine treatment, while atogepant is studied for migraine prophylaxis. Of these drugs targeting CGRP signaling directly, eptinezumab, erenumab, fremanezumab, galcanezumab, rimegepant and ubrogepant have been approved for clinical use, while atogepant is in the last stage before approval. Although all of these drugs seem highly promising for migraine treatment, their safety should be investigated in the long-term. Moreover, the exact mechanism(s) of action of these drugs need to be elucidated further, to increase both safety and efficacy and to increase the number of responders to the different treatments, so that all migraine patients can satisfactorily be treated.

The effects of CGRP in vascular tissue - Classical vasodilation, shadowed effects and systemic dilemmas.

Vascular tissue consists of endothelial cells, vasoactive smooth muscle cells and perivascular nerves. The perivascular sensory neuropeptide CGRP has demonstrated potent vasodilatory effects in any arterial vasculature examined so far, and a local protective CGRP-circuit of sensory nerve terminal CGRP release and smooth muscle cell CGRP action is evident. The significant vasodilatory effect has shadowed multiple other effects of CGRP in the vascular tissue and we therefore thoroughly review vascular actions of CGRP on endothelial cells, vascular smooth muscle cells and perivascular nerve terminals. The actions beyond vasodilation includes neuronal re-uptake and neuromodulation, angiogenic, proliferative and antiproliferative, pro- and anti-inflammatory actions which vary depending on the target cell and anatomical location. In addition to the classical perivascular nerve-smooth muscle CGRP circuit, we review existing evidence for a shadowed endothelial autocrine pathway for CGRP. Finally, we discuss the impact of local and systemic actions of CGRP in vascular regulation and protection from hypertensive and ischemic heart conditions with special focus on therapeutic CGRP agonists and antagonists.

Patient selection for migraine preventive treatment with anti-CGRP(r) monoclonal antibodies.

Introduction: Migraine is the most common neurological disorder and represents the first cause of disability in under 50s in both genders. Available preventive drugs were primarily developed for indications other than migraine and with an unclear mechanism of action in migraine pathophysiology. Areas covered: This article reviews current preventive treatments and their shortcomings and the road that, through the understanding of calcitonin gene-related peptide (CGRP) role in migraine pathophysiology, carried to the approval of the 3 first-in-class monoclonal antibodies (mAbs) acting on the CGRP pathway. Data from phase 2 and phase 3 clinical trials of erenumab, galcanezumab and fremanezumab, both for episodic and chronic migraine prevention, are consistent for safety and efficacy. Expert opinion: Anti-calcitonin gene-related peptide mAbs have potential advantages over conventional treatments such as ease of use, quick onset of action, persistent efficacy, placebo-like safety profile and absence of pharmacological interactions. Pharmacoeconomic studies should evaluate the economic impact of these drugs taking into account the overall direct and indirect costs related to untreated migraine and to migraine treated with the other available preventive therapies. Given the high cost of these therapies, it is essential to implement all possible strategies to optimize their effectiveness by optimization of patients' selection.

Erenumab for episodic migraine prophylaxis.

Introduction: This paper reviews placebo-controlled randomized double-blind studies with erenumab for the prevention of migraine. Erenumab is a fully human monoclonal antibody (mAb), which specifically blocks the calcitonin gene-related peptide (GGRP) receptor. Areas covered: This manuscript was based on articles written in English located on PubMed using the following search terms: episodic and chronic migraine, migraine prophylaxis and prevention, CGRP, CGRP receptor, CGRP receptor antagonist, erenumab, treatment failures, and trigeminal nerve. Expert commentary: The primary endpoints in Phase II and III preventive episodic migraine trials have been reached successfully, and so have multiple secondary endpoints. Monthly subcutaneous injections of either erenumab 70 mg or 140 mg reduced mean monthly migraine days (MMDs) after 3 and 6 months significantly greater than placebo when compared to baseline values with an onset of action within the first week. About 50% of subjects have at least a 50% reduction of MMDs. Several patient-reported outcome measures demonstrate improved quality of life with erenumab. This antibody also shows efficacy in a prior preventive treatment failure population. The tolerability of erenumab is good, which is reflected by low dropout rates in all erenumab clinical trials. Within the first year of treatment, no specific group or type of adverse events were observed.

New Insights into the Regulation of CGRP-Family Receptors.

The calcitonin gene-related peptide (CGRP) receptor system has emerged as an important drug target for migraine. This is highlighted by the recent regulatory approval of the first drug targeting the CGRP signalling pathway, the CGRP receptor antibody erenumab. The cellular compartments in which receptors are found affects drug access and whether they can exert their effects. G protein-coupled receptors (GPCRs) were thought to signal only at the cell surface, but it is now recognised that some GPCRs, including the CGRP receptor, undergo sustained signalling from endosomes, once internalised in response to ligand. What does this mean for drugs like erenumab? This review covers recent insights into the regulation of CGRP family receptors and examines what implications this may have on drug activity.

Calcitonin gene-related peptide (CGRP) triggers Ca2+ responses in cultured astrocytes and in Bergmann glial cells from cerebellar slices.

The neuropeptide calcitonin gene-related peptide (CGRP) is transiently expressed in cerebellar climbing fibers during development while its receptor is mainly expressed in astrocytes, in particular Bergmann glial cells. Here, we analyzed the effects of CGRP on astrocytic calcium signaling. Mouse cultured astrocytes from cerebellar or cerebral cortex as well as Bergmann glial cells from acutely isolated cerebellar slices were loaded with the Ca(2+) sensor Fura-2. CGRP triggered transient increases in intracellular Ca(2+) in astrocytes in culture as well as in acute slices. Responses were observed in the concentration range of 1 nm to 1 mm, in both the cell body and its processes. The calcium transients were dependent on release from intracellular stores as they were blocked by thapsigargin but not by the absence of extracellular calcium. In addition, after CGRP application a further delayed transient increase in calcium activity could be observed. Finally, cerebellar astrocytes from neonatal mice expressed receptor component protein, a component of the CGRP receptor, as revealed by immunofluorescence and confocal microscopy. It is thus proposed that the CGRP-containing afferent fibers in the cerebellum (the climbing fibers) modulate calcium in astrocytes by releasing the neuropeptide during development and hence possibly influence the differentiation of Purkinje cells.

Endothelium removal augments endothelium-independent vasodilatation in rat mesenteric vascular bed.

BACKGROUND AND PURPOSE: The vascular endothelium regulates vascular tone by releasing various endothelium-derived vasoactive substances to counteract excess vascular response. We investigated whether the vascular endothelium regulates vasodilatation via released endothelium-derived contracting factors (EDCFs), by examining the effect of endothelium removal on responses to periarterial nerve stimulation (PNS) and various vasodilator agents. EXPERIMENTAL APPROACH: The rat mesenteric vascular bed was perfused with Krebs solution. Vasodilator responses to PNS and 5 min perfusion of vasodilator agents in preparations with endothelium were compared with those in the same preparations without endothelium. The endothelium was removed by 30 s perfusion with sodium deoxycholate. KEY RESULTS: Endothelium removal significantly augmented vasodilator responses to PNS and calcitonin gene-related peptide (CGRP), isoprenaline (beta-adrenoceptor agonist), SNP and 8-bromo-cGMP (8-Br-cGMP; cGMP analogue) but not BAY41-2272 (soluble guanylate cyclase activator). The augmentation of SNP-induced vasodilatation after denudation was much greater than that of CGRP- or isoprenaline-induced vasodilatation. In the preparations with an intact endothelium, L-NAME (nitric oxide synthase inhibitor) significantly augmented vasodilator responses to PNS and CGRP, isoprenaline, SNP and 8-Br-cGMP, but not BAY41-2272. Indomethacin (cyclooxygenase inhibitor) and seratrodast (thromboxane A(2) receptor antagonist), but not phosphoramidon (endothelin-1-converting enzyme inhibitor) or BQ-123 (selective endothelin type A receptor antagonists), significantly augmented vasodilator responses to PNS and CGRP, isoprenaline, SNP and BAY41-2272. CONCLUSION AND IMPLICATION: These results suggest that the endothelium in rat mesenteric arteries regulates and maintains vascular tone via counteracting not only vasoconstriction through releasing endothelium-derived relaxing factors, but also vasodilatation, in part by releasing an EDCF, thromboxane A(2).

Enhanced vascular responses to adrenomedullin in mice overexpressing receptor-activity-modifying protein 2.

Adrenomedullin (AM) levels are elevated in cardiovascular disease, but little is known of the role of specific receptor components. AM acts via the calcitonin receptor-like receptor (CLR) interacting with a receptor-activity-modifying protein (RAMP). The AM1 receptor is composed of CLR and RAMP2, and the calcitonin gene-related peptide (CGRP) receptor of CLR and RAMP1, as determined by molecular and cell-based analysis. This study examines the relevance of RAMP2 in vivo. Transgenic (TG) mice that overexpress RAMP2 in smooth muscle were generated. The role of RAMP2 in the regulation of blood pressure and in vascular function was investigated. Basal blood pressure, acute angiotensin II-raised blood pressure, and cardiovascular properties were similar in wild-type (WT) and TG mice. However, the hypotensive effect of IV AM, unlike CGRP, was enhanced in TG mice (P<0.05), whereas a negative inotropic action was excluded by left-ventricular pressure-volume analysis. In aorta relaxation studies, TG vessels responded in a more sensitive manner to AM (EC50, 8.0+/-1.5 nmol/L) than WT (EC50, 17.9+/-3.6 nmol/L). These responses were attenuated by the AM receptor antagonist, AM(22-52), such that residual responses were identical in all mice. Remaining relaxations were further inhibited by CGRP receptor antagonists, although neither affected AM responses when given alone. Mesenteric and cutaneous resistance vessels were also more sensitive to AM in TG than WT mice. Thus RAMP2 plays a key role in the sensitivity and potency of AM-induced hypotensive responses via the AM1 receptor, providing evidence that this receptor is a selective target for novel therapeutic approaches.

CGRP as the target of new migraine therapies - successful translation from bench to clinic.

Treatment of migraine is on the cusp of a new era with the development of drugs that target the trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) or its receptor. Several of these drugs are expected to receive approval for use in migraine headache in 2018 and 2019. CGRP-related therapies offer considerable improvements over existing drugs as they are the first to be designed specifically to act on the trigeminal pain system, they are more specific and they seem to have few or no adverse effects. CGRP receptor antagonists such as ubrogepant are effective for acute relief of migraine headache, whereas monoclonal antibodies against CGRP (eptinezumab, fremanezumab and galcanezumab) or the CGRP receptor (erenumab) effectively prevent migraine attacks. As these drugs come into clinical use, we provide an overview of knowledge that has led to successful development of these drugs. We describe the biology of CGRP signalling, summarize key clinical evidence for the role of CGRP in migraine headache, including the efficacy of CGRP-targeted treatment, and synthesize what is known about the role of CGRP in the trigeminovascular system. Finally, we consider how the latest findings provide new insight into the central role of the trigeminal ganglion in the pathophysiology of migraine.

Increased depressor response to N-arachidonoyl-dopamine during high salt intake: role of the TRPV1 receptor.

OBJECTIVE: This study was designed to test the hypothesis that the systemic administration of N-arachidonoyl-dopamine (NADA), an endovanilloid, causes a depressor effect via activation of transient receptor potential vanilloid type 1 (TRPV1) channels during high-salt intake. METHODS: Wistar rats were fed a normal (0.4%) or high (4%) sodium diet for 10 days, and arteries and veins were cannulated for measurement of mean arterial pressure (MAP) or injection of drugs and collection of plasma. Radioimmunoassay and western blot were used to determine the plasma calcitonin gene-related peptide (CGRP) level and TRPV1 protein content, respectively. RESULTS: The NADA-induced dose-dependent decrease in MAP was greater in high-sodium than normal-treated rats, and was abolished by capsazepine, a selective TRPV1 antagonist, or CGRP8-37, a selective CGRP receptor antagonist, but not by SR141716A, a selective cannabinoid 1 receptor antagonist. Capsaicin, a selective TRPV1 receptor agonist, or CGRP dose-dependently decreased MAP in normal or high-sodium-treated rats, with a greater effect in the latter. Baseline and NADA-induced increases in plasma CGRP levels were higher in high-sodium than normal-treated rats. TRPV1 protein expression in mesenteric arteries was higher in high-sodium than normal-treated rats. In vitro, NADA caused a greater CGRP release from mesenteric arteries of high-sodium than normal-treated rats, which was blocked by capsazepine. CONCLUSION: High sodium increases the sensitivity of blood pressure responses to NADA. The enhanced depressor effect induced by NADA during high-sodium intake is prevented by blockade of the TRPV1 or CGRP receptors, but not cannabinoid 1 receptor. High sodium upregulates mesenteric TRPV1 expression, and increases NADA-induced CGRP release in vitro and in vivo.