Calcitonin Gene-related Peptide Receptor Research Articles

Novel Oral CGRP Receptor Antagonist Atogepant in the Prevention of Migraine.

Advancements in molecular biology and neuroscience have uncovered calcitonin gene-related peptide (CGRP), a neuropeptide consisting of thirty-seven amino acids that plays a crucial role in migraine pathogenesis. CGRP receptor antagonist or gepant is an oral medication that can impede the nociceptive signaling pathway related to CGRP. Atogepant, the latest CGRP antagonist approved by the Food and Drug Administration (FDA) for prophylaxis of episodic migraine, works by non-competitively blocking CGRP receptors, thereby curtailing neurogenic inflammation and pain sensitization. Numerous trials have demonstrated that atogepant is an effective therapy for migraine prevention, with its extended half-life and minimal risks of cardiovascular or liver toxicity making it the first drug in its class primarily authorized for that purpose. In terms of monthly migraine days, monthly headache days, and acute medication usage days, atogepant demonstrated a statistically significant difference from baseline. It was well-tolerated with low adverse event rates. The most commonly reported adverse events were constipation and nausea. Atogepant appears to be beneficial for migraine prevention, and it may be more useful in those who do not want to take the medication as an injection or who do not require a lengthy duration of pharmacological impact. In this article, we provide a systematic review of the literature on atogepant and migraine, emphasizing current achievements in this field of study.

Alcohol-mediated susceptibility to lung fibrosis is associated with group 2 innate lymphoid cells in mice.

Chronic alcohol ingestion promotes acute lung injury and impairs immune function. However, the mechanisms involved are incompletely understood. Here, we show that alcohol feeding enhances bleomycin-induced lung fibrosis and inflammation via the regulation of type 2 innate immune responses, especially by group 2 innate lymphoid cells (ILC2s). Neuroimmune interactions have emerged as critical modulators of lung inflammation. We found alcohol consumption induced the accumulation of ILC2 and reduced the production of the neuropeptide calcitonin gene-related peptide (CGRP), primarily released from sensory nerves and pulmonary neuroendocrine cells (PNECs). CGRP potently suppressed alcohol-driven type 2 cytokine signals in vivo. Vagal ganglia TRPV1+ afferents mediated immunosuppression occurs through the release of CGRP. Inactivation of the TRPV1 receptor enhanced bleomycin-induced fibrosis. In addition, mice lacking the CGRP receptor had the increased lung inflammation and fibrosis and type 2 cytokine production as well as exaggerated responses to alcohol feeding. Together, these data indicate that alcohol consumption regulates the interaction of CGRP and ILC2, which is a critical contributor of lung inflammation and fibrosis.

Adrenomedullin Enhances Mouse Gustatory Nerve Responses to Sugars via T1R-Independent Sweet Taste Pathway.

On the tongue, the T1R-independent pathway (comprising glucose transporters, including sodium-glucose cotransporter (SGLT1) and the KATP channel) detects only sugars, whereas the T1R-dependent (T1R2/T1R3) pathway can broadly sense various sweeteners. Cephalic-phase insulin release, a rapid release of insulin induced by sensory signals in the head after food-related stimuli, reportedly depends on the T1R-independent pathway, and the competitive sweet taste modulators leptin and endocannabinoids may function on these two different sweet taste pathways independently, suggesting independent roles of two oral sugar-detecting pathways in food intake. Here, we examined the effect of adrenomedullin (ADM), a multifunctional regulatory peptide, on sugar sensing in mice since it affects the expression of SGLT1 in rat enterocytes. We found that ADM receptor components were expressed in T1R3-positive taste cells. Analyses of chorda tympani (CT) nerve responses revealed that ADM enhanced responses to sugars but not to artificial sweeteners and other tastants. Moreover, ADM increased the apical uptake of a fluorescent D-glucose derivative into taste cells and SGLT1 mRNA expression in taste buds. These results suggest that the T1R-independent sweet taste pathway in mouse taste cells is a peripheral target of ADM, and the specific enhancement of gustatory nerve responses to sugars by ADM may contribute to caloric sensing and food intake.

A Scoping Review and Meta-Analysis of Anti-CGRP Monoclonal Antibodies: Predicting Response.

Calcitonin gene-related peptide-targeted monoclonal antibodies (CGRP mAbs) are increasingly being used as preventive treatments for migraine. Their effectiveness and safety were established through numerous randomized placebo-controlled trials and real-world studies, yet a significant proportion of patients do not respond to this treatment, and currently, there is a lack of accepted predictors of response to guide expectations, as data from studies so far are lacking and inconsistent. We searched Embase and MEDLINE databases for studies reporting on predictors of response to CGRP and/or CGRP-receptor (CGRP-R) mAbs, defined as a 30% or 50% reduction in monthly headache or migraine days at varying durations of follow-up. Quantitative synthesis was performed where applicable. We found 38 real-world studies that investigated the association between various predictors and response rates. Based on these studies, good response to triptans and unilateral pain with or without unilateral autonomic symptoms are predictors of a good response to CGRP(-R) mAbs. Conversely, obesity, interictal allodynia, the presence of daily headaches, a higher number of non-successful previous prophylactic medications, and psychiatric comorbidities including depression are predictive of a poor response to CGRP(-R) mAbs. Future studies should confirm these results and help to generate more tailored treatment strategies in patients with migraine.

Treatment of Persistent Posttraumatic Headache with the Anti-CGRP Receptor Antibody Erenumab: a Case Report

Calcitonin gene-related peptide (CGRP) has only recently emerged as a potential target in posttraumatic headache. To our knowledge, this is the first description of a patient with persistent posttraumatic headache following severe traumatic head injury who has been treated with the CGRP receptor monoclonal antibody erenumab. A 56-year-old man presented with a 30-year history of frequent migraine-like posttraumatic headaches following a high-voltage head injury that he treated with an excessive intake of peripheral analgesics. Although amitriptyline was reasonably effective, it had to be discontinued when the patient developed restless legs syndrome in the second year of treatment. Under therapy with erenumab, he achieved a rapid and stable reduction in his symptoms down to only 2–3 headache days per month without adverse events. This case demonstrates that the inhibition of the CGRP-receptor with erenumab could be an effective treatment option in migraine-like posttraumatic headache even decades after the traumatic event.

Migraine and cardiovascular disease: what cardiologists should know.

Migraine is a chronic neurovascular disease with a complex, not fully understood pathophysiology with multiple causes. People with migraine suffer from recurrent moderate to severe headache attacks varying from 4 to 72 h. The prevalence of migraine is two to three times higher in women compared with men. Importantly, it is the most disabling disease in women <50 years of age due to a high number of years lived with disability, resulting in a very high global socioeconomic burden. Robust evidence exists on the association between migraine with aura and increased incidence of cardiovascular disease (CVD), in particular ischaemic stroke. People with migraine with aura have an increased risk of atrial fibrillation, myocardial infarction, and cardiovascular death compared with those without migraine. Ongoing studies investigate the relation between migraine and angina with non-obstructive coronary arteries and migraine patients with patent foramen ovale. Medication for the treatment of migraine can be preventative medication, such as beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, antiepileptics, antidepressants, some of the long-acting calcitonin gene-related peptide receptor antagonists, or monoclonal antibodies against calcitonin gene-related peptide or its receptor, or acute medication, such as triptans and calcitonin gene-related peptide receptor antagonists. However, these medications might raise concerns when migraine patients also have CVD due to possible (coronary) side effects. Specifically, knowledge gaps remain for the contraindication to newer treatments for migraine. All cardiologists will encounter patients with CVD and migraine. This state-of-the-art review will outline the basic pathophysiology of migraine and the associations between migraine and CVD, discuss current therapies, and propose future directions for research.

Zavegepant Nasal Spray for Treatment of Acute Migraine: A Systematic Review

Background: Migraine is a widespread neurological disorder that can impair quality of life. Current treatments are often insufficient, with side effects causing some patients to seek alternative options. Zavegepant nasal spray, a new treatment being developed for acute migraine, shows promise in blocking the CGRP receptor and providing several potential advantages, such as faster onset of action and higher bioavailability. This systematic review aimed to assess the efficacy and safety of Zavegepant nasal spray in treating acute migraine attacks and identify adverse events.&#x0D; Methods: Adult patients diagnosed with acute migraine who were treated with Zavegepant nasal spray in randomized controlled trials (RCTs) or non-randomized clinical trials were included. A comprehensive search was conducted in PubMed, Embase, Cochrane Library, and ClinicalTrials.gov until March 2023. The following keywords were employed: "Zavegepant nasal spray", "migraine", "calcitonin gene-related peptide receptor antagonist." A narrative synthesis was conducted to summarize and analyze the extracted data from the included studies, with a focus on the efficacy and safety of Zavegepant nasal spray for the treatment of acute migraine.&#x0D; Results: This systematic review included three clinical trials, of which two were RCTs, and one was an open-label trial. The total number of participants was 3681, and all of them were in phase 2/3 of testing. The inclusion criteria for these trials were broadly based on individuals who had a history of migraines with or without aura lasting for over a year, which is consistent with the third edition of the International Classification of Headache Disorder. The findings were tabulated and discussed.&#x0D; Conclusion: Zavegepant nasal spray is an effective and well-tolerated treatment for acute migraines. Further research is needed to confirm its safety and efficacy, optimal dosing and administration, and effectiveness in different populations. The cost-effectiveness, patient satisfaction, and long-term effects on migraine burden ought to be investigated.

Drugs for migraine.

Drugs for acute and preventive treatment of migraine, including analgesics, triptans, CGRP receptor antagonists. As well as nonpharmacologic acute and preventive treatment options (devices, other interventions).

Asymmetric Hydrogenation of Indazole-Containing Enamides Relevant to the Synthesis of Zavegepant Using Neutral and Cationic Cobalt Precatalysts.

The cobalt-catalyzed asymmetric hydrogenation of indazole-containing enamides relevant to the synthesis of the calcitonin gene-related peptide (CGRP) receptor antagonist, zavegepant (1), approved for the treatment of migraines, is described. Both neutral bis(phosphine)cobalt(II) and cationic bis(phosphine)cobalt(I) complexes served as efficient precatalysts for the enamide hydrogenation reactions, providing excellent yield and enantioselectivities (up to >99.9%) for a range of related substrates, though key reactivity differences were observed. Hydrogenation of indazole-containing enamide, methyl (Z)-2-acetamido-3-(7-methyl-1H-indazol-5-yl)acrylate, was performed on a 20 g scale.

RWD65 Novel Adverse Events of CGRP Receptor Antagonists: A Disproportionality Analysis in USFDA Adverse Event Reporting System Database

Signal detection is a promising technique used for prompt detection of novel reactions. It is a modern method of detecting new reaction of a drug. Ubrogepant and Rimegepant are calcitonin gene-related peptide (CGRP) receptor antagonists were approved by US Food and Drug Administration (USFDA) in December 2019 and February 2020 respectively for acute treatment of Migraine. This study was to identify the signal strength for Ubrogepant and Rimegepant associated ADRs using data mining technique in USFDA adverse event reporting system (AERS) database.

Nasal spray (Zavegepant) for migraines: a mini-review.

Neurological disorders, especially migraines, pose a significant global burden. This has driven the recent innovative research being conducted in the field of anti-migraine therapies, including the discovery of Zavegepant for the treatment of acute migraine attacks. Zavegepant is a novel, first-in-class, intranasally administered calcitonin gene-related peptide (CGRP) receptor antagonist that has recently been approved for use in acute migraine attacks. Recent randomized controlled trials comparing Zavegepant with a placebo have demonstrated favorable results with respect to primary endpoints, as well as a desirable safety profile. The current first-line therapy consists of oral triptans, which are associated with lower efficacy, weaker safety profile, and an unsatisfactory preference rate among patients. Moreover, the intranasal method of administration is a characteristic advantage of Zavegepant, as patients suffering from acute migraine attacks cannot easily ingest oral medication, due to severe nausea and vomiting. In this mini-review, the efficacy and safety of Zavegepant will be compared with those of alternative treatments available for migraines, including oral triptans, intranasal triptans, and other CGRP antagonists currently available in the market. With currently available research, Zavegepant holds superiority over other forms of treatment and can be included in the current treatment guidelines for migraine attacks. However, further research is necessary to effectively assess Zavegepant's long-term efficacy, safety, tolerability, and drug-drug interactions.

Reassessing the adrenomedullin scavenging function of ACKR3 in lymphatic endothelial cells.

Atypical chemokine receptor 3 (ACKR3) is a scavenger of the chemokines CXCL11 and CXCL12 and of several opioid peptides. Additional evidence indicates that ACKR3 binds two other non-chemokine ligands, namely the peptide hormone adrenomedullin (AM) and derivatives of the proadrenomedullin N-terminal 20 peptide (PAMP). AM exhibits multiple functions in the cardiovascular system and is essential for embryonic lymphangiogenesis in mice. Interestingly, AM-overexpressing and ACKR3-deficient mouse embryos both display lymphatic hyperplasia. Moreover, in vitro evidence suggested that lymphatic endothelial cells (LECs), which express ACKR3, scavenge AM and thereby reduce AM-induced lymphangiogenic responses. Together, these observations have led to the conclusion that ACKR3-mediated AM scavenging by LECs serves to prevent overshooting AM-induced lymphangiogenesis and lymphatic hyperplasia. Here, we further investigated AM scavenging by ACKR3 in HEK293 cells and in human primary dermal LECs obtained from three different sources in vitro. LECs efficiently bound and scavenged fluorescent CXCL12 or a CXCL11/12 chimeric chemokine in an ACKR3-dependent manner. Conversely, addition of AM induced LEC proliferation but AM internalization was found to be independent of ACKR3. Similarly, ectopic expression of ACKR3 in HEK293 cells did not result in AM internalization, but the latter was avidly induced upon co-transfecting HEK293 cells with the canonical AM receptors, consisting of calcitonin receptor-like receptor (CALCRL) and receptor activity-modifying protein (RAMP)2 or RAMP3. Together, these findings indicate that ACKR3-dependent scavenging of AM by human LECs does not occur at ligand concentrations sufficient to trigger AM-induced responses mediated by canonical AM receptors.

Zavegepant: First Approval.

Zavegepant is a third generation, small-molecule, calcitonin gene-related peptide (CGRP) receptor antagonist being developed by Pfizer, under a license from Bristol-Myers Squibb, for the prevention and treatment of chronic and episodic migraine. In March 2023, zavegepant nasal spray (ZAVZPRET™) received its first approval in the USA for the acute treatment of migraine with or without aura in adults. Clinical development of an oral formulation of zavegepant is currently underway. This article summarizes the milestones in the development of zavegepant leading to this first approval for the acute treatment of migraine with or without aura in adults.

Drug therapy of the acute migraine attack and prophylaxis ofmigraine

Migraine has a prevalence of 10 % in Germany, making it the most common neurological disorder. Migraine is a prevalent disorder not only for neurologist, it's an everyday topic for general physicians and internal medicine as well. Acute migraine attacks are treated with analgesics or triptans. In case of frequent migraine attacks, there is an indication for medicinal and non-pharmacological migraine prophylaxis. Medications include beta-blockers, flunarizine, anticonvulsants, amitriptyline or, in the case of chronic migraine, onabotulinumtoxinA. If these drugs are not effective, are not tolerated or contraindicated, monoclonal antibodies against calcitonin gene-related peptide (CGRP) or the CGRP receptor can be used.

TRPV1 activation in human Langerhans cells and T cells inhibits mucosal HIV-1 infection via CGRP-dependent and independent mechanisms

Upon its mucosal transmission, HIV type 1 (HIV-1) rapidly targets genital antigen-presenting Langerhans cells (LCs), which subsequently transfer infectious virus to CD4+ Tcells. We previously described an inhibitory neuroimmune cross talk, whereby calcitonin gene-related peptide (CGRP), a neuropeptide secreted by peripheral pain-sensing nociceptor neurons innervating all mucosal epithelia and associating with LCs, strongly inhibits HIV-1 transfer. As nociceptors secret CGRP following the activation of their Ca2+ ion channel transient receptor potential vanilloid 1 (TRPV1), and as we reported that LCs secret low levels of CGRP, we investigated whether LCs express functional TRPV1. We found that human LCs expressed mRNA and protein of TRPV1, which was functional and induced Ca2+ influx following activation with TRPV1 agonists, including capsaicin (CP). The treatment of LCs with TRPV1 agonists also increased CGRP secretion, reaching its anti-HIV-1 inhibitory concentrations. Accordingly, CP pretreatment significantly inhibited LCs-mediated HIV-1 transfer to CD4+ Tcells, which was abrogated by both TRPV1 and CGRP receptor antagonists. Like CGRP, CP-induced inhibition of HIV-1 transfer was mediated via increased CCL3 secretion and HIV-1 degradation. CP also inhibited direct CD4+ Tcells HIV-1 infection, but in CGRP-independent manners. Finally, pretreatment of inner foreskin tissue explants with CP markedly increased CGRP and CCL3 secretion, and upon subsequent polarized exposure to HIV-1, inhibited an increase in LC-Tcell conjugate formation and consequently Tcell infection. Our results reveal that TRPV1 activation in human LCs and CD4+ Tcells inhibits mucosal HIV-1 infection, via CGRP-dependent/independent mechanisms. Formulations containing TRPV1 agonists, already approved for pain relief, could hence be useful against HIV-1.

Rimegepant for migraine: acute efficacy beyond the USA

The safety and efficacy of rimegepant, a synthetic molecule that competes with calcitonin gene-related peptide (CGRP) for binding to its receptor, have been shown in two phase 3 studies on symptomatic treatment 1 Lipton RB Croop R Stock EG et al. Rimegepant, an oral calcitonin gene-related peptide receptor antagonist, for migraine. N Engl J Med. 2019; 381: 142-149 Crossref PubMed Scopus (177) Google Scholar , 2 Croop R Goadsby PJ Stock DA et al. Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial. Lancet. 2019; 394: 737-745 Summary Full Text Full Text PDF PubMed Scopus (172) Google Scholar and one on prophylactic treatment 3 Croop R Lipton RB Kudrow D et al. Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial. Lancet. 2021; 397: 51-60 Summary Full Text Full Text PDF PubMed Scopus (106) Google Scholar of migraine, all done in the USA. On the basis of these data, rimegepant was the first CGRP antagonist (gepant) to be approved by the US Food and Drug Administration and European Medicines Agency for both symptomatic and prophylactic treatment of migraine, giving it a unique and innovative role in the treatment of headaches. Rimegepant is available as a pill for oral administration as needed by people with migraine (ie, whenever they have a migraine attack 4 Mitsikostas DD Belesioti I Arvaniti C et al. Patients' preferences for headache acute and preventive treatment. J Headache Pain. 2017; 18: 102 Crossref PubMed Scopus (26) Google Scholar ), possibly without the risk of developing medication overuse headache, and without the need to take another medication for migraine prophylaxis. Until the development of the anti-CGRP treatments, all prophylactic anti-migraine medications had been repurposed from other diseases; these older treatments have little evidence of efficacy in migraine prophylaxis and have well known side-effects, which increases the likelihood that individuals have adverse events, reducing adherence and benefit. 5 Charles A Pozo-Rosich P Targeting calcitonin gene-related peptide: a new era in migraine therapy. Lancet. 2019; 394: 1765-1774 Summary Full Text Full Text PDF PubMed Scopus (157) Google Scholar By contrast, CGRP-pathway-targeting drugs are mechanism-based, are migraine-specific, and have very good evidence of tolerability and safety. 6 Hepp Z Dodick DW Varon SF Gillard P Hansen RN Devine EB Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015; 35: 478-488 Crossref PubMed Scopus (254) Google Scholar Safety and efficacy of rimegepant orally disintegrating tablet for the acute treatment of migraine in China and South Korea: a phase 3, double-blind, randomised, placebo-controlled trialAmong adults living in China or South Korea, a single dose of 75 mg rimegepant was effective for the acute treatment of migraine. Safety and tolerability were similar to placebo. Our findings suggest that rimegepant might be a useful new addition to the range of medications for the acute treatment of migraine in China and South Korea, but further studies are needed to support long-term efficacy and safety and to compare rimegepant with other medications for the acute treatment of migraine in this population. Full-Text PDF

Assessment of Functional Characteristics of Small Arterioles and Capillaries Using an Intact Dura Mater Preparation

The dura mater, a protective layer surrounding the brain and spinal cord, plays a crucial role in maintaining homeostatic function of the central nervous system. The large arteries and veins of the dura mater are relatively sparse and have been extensively studied with respect to their contribution to pain sensation, with unclear and controversial contributions to headache and migraine pathology. Small arterioles and capillaries exhibit nearly ubiquitous coverage of the entire dura, yet their physiological and pathophysiological functions remain largely unexplored. Here, using ex vivo mouse dura, we examined the electrical (membrane potential recordings), Ca2+ signaling properties (GCaMP or Cal-520 AM imaging), and vasomotor behavior (pressurized dura vessels with diameter measurement) of these exquisitely small vessels. Furthermore, we show electrical and Ca2+ responses in smooth muscle and pericytes in response to calcitonin gene-related peptide (CGRP) receptor and transient receptor potential V1 (TRPV1) channel activation, which are two principal targets in headache and migraine pathology. Last, we highlight unique anatomical interactions between nerves and arterioles in the dura mater using immunostaining techniques. In conclusion, we hypothesize that microvessels consisting of arterioles and capillaries are a logical and unexplored region for studying homeostatic and pathological roles of the dura mater. Funding Provided by the Totman Medical Trust This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of rimegepant 75 mg daily on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate in healthy female participants.

To assess the effect of single and multiple doses of rimegepant 75 mg dose on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol (EE)/norgestimate (NGM) in healthy females of childbearing potential or non-menopausal females with tubal ligation. Females of childbearing age experience the highest prevalence of migraine and frequently inquire about the concomitant use of anti-migraine medications and contraceptives. Rimegepant, a calcitonin gene-related peptide receptor antagonist, demonstrated efficacy and safety for treating an acute migraine attack and preventing migraine. This open-label, single-center, phase 1, drug-drug interaction study explored the effects of rimegepant 75 mg daily dose on the pharmacokinetics of an oral contraceptive containing EE/NGM 0.035 mg/0.25 mg in healthy females of childbearing potential or non-menopausal females with tubal ligation. During cycles 1 and 2, participants received EE/NGM once daily for 21 days followed by placebo tablets with inactive ingredients for 7 days. Rimegepant was administered during only cycle 2 for 8 days, from days 12 through 19. The primary endpoint was the effect of single and multiple doses of rimegepant on the pharmacokinetics of EE and norelgestromin (NGMN), an active metabolite of NGM, at steady state, including area under the concentration-time curve for 1 dosing interval (AUC0-τ,ss ) and maximum observed concentration (Css[max] ). The study enrolled 25 participants, with pharmacokinetic data assessed for 20 participants. A single 75 mg dose of rimegepant co-administered with EE/NGM increased exposures of EE and NGMN by ≤16% (geometric mean ratio [GMR], 1.03; 90% confidence interval [CI], 1.01-1.06; and GMR, 1.16; 90% CI, 1.13-1.20, respectively). After 8 days of co-administering EE/NGM with rimegepant, EE pharmacokinetic parameters, AUC0-τ,ss and Css(max) , increased by 20% (GMR, 1.20; 90% CI, 1.16-1.25) and 34% (GMR, 1.34; 90% CI, 1.23-1.46), respectively, and NGMN pharmacokinetic parameters increased by 46% (GMR, 1.46; 90% CI, 1.39-1.52) and 40% (GMR, 1.40; 90% CI, 1.30-1.51), respectively. The study identified modest elevations in overall EE and NGMN exposures after multiple doses of rimegepant, but these elevations are unlikely to be clinically relevant in healthy females with migraine.

Acetaldehyde via CGRP receptor and TRPA1 in Schwann cells mediates ethanol-evoked periorbital mechanical allodynia in mice: relevance for migraine

BackgroundIngestion of alcoholic beverages is a known trigger of migraine attacks. However, whether and how ethanol exerts its pro-migraine action remains poorly known. Ethanol stimulates the transient receptor potential vanilloid 1 (TRPV1) channel, and its dehydrogenized metabolite, acetaldehyde, is a known TRP ankyrin 1 (TRPA1) agonist.MethodsPeriorbital mechanical allodynia following systemic ethanol and acetaldehyde was investigated in mice after TRPA1 and TRPV1 pharmacological antagonism and global genetic deletion. Mice with selective silencing of the receptor activated modifying protein 1 (RAMP1), a component of the calcitonin gene-related peptide (CGRP) receptor, in Schwann cells or TRPA1 in dorsal root ganglion (DRG) neurons or Schwann cells, were used after systemic ethanol and acetaldehyde.ResultsWe show in mice that intragastric ethanol administration evokes a sustained periorbital mechanical allodynia that is attenuated by systemic or local alcohol dehydrogenase inhibition, and TRPA1, but not TRPV1, global deletion, thus indicating the implication of acetaldehyde. Systemic (intraperitoneal) acetaldehyde administration also evokes periorbital mechanical allodynia. Importantly, periorbital mechanical allodynia by both ethanol and acetaldehyde is abrogated by pretreatment with the CGRP receptor antagonist, olcegepant, and a selective silencing of RAMP1 in Schwann cells. Periorbital mechanical allodynia by ethanol and acetaldehyde is also attenuated by cyclic AMP, protein kinase A, and nitric oxide inhibition and pretreatment with an antioxidant. Moreover, selective genetic silencing of TRPA1 in Schwann cells or DRG neurons attenuated periorbital mechanical allodynia by ethanol or acetaldehyde.ConclusionsResults suggest that, in mice, periorbital mechanical allodynia, a response that mimics cutaneous allodynia reported during migraine attacks, is elicited by ethanol via the systemic production of acetaldehyde that, by releasing CGRP, engages the CGRP receptor in Schwann cells. The ensuing cascade of intracellular events results in a Schwann cell TRPA1-dependent oxidative stress generation that eventually targets neuronal TRPA1 to signal allodynia from the periorbital area.

Calcitonin receptors in GtoPdb v.2023.1

This receptor family comprises a group of receptors for the calcitonin/CGRP family of peptides. The calcitonin (CT), amylin (AMY), calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CGRP, AM, AMY, and CT receptors [131, 74, 71]) are generated by the genes CALCR (which codes for the CT receptor, CTR) and CALCRL (which codes for the calcitonin receptor-like receptor, CLR, previously known as CRLR). Their function and pharmacology are altered in the presence of RAMPs (receptor activity-modifying proteins), which are single TM domain proteins of ca. 150 amino acids, identified as a family of three members; RAMP1, RAMP2 and RAMP3. There are splice variants of the CTR; these in turn produce variants of AMY receptors [131], some of which can be potently activated by CGRP. The endogenous agonists are the peptides calcitonin, α-CGRP (formerly known as CGRP-I), β-CGRP (formerly known as CGRP-II), amylin (occasionally called islet-amyloid polypeptide, diabetes-associated polypeptide), adrenomedullin and adrenomedullin 2/intermedin. There are species differences in peptide sequences, particularly for the CTs. CTR-stimulating peptide (CRSP) is another member of the family with selectivity for the CTR but it is not expressed in humans [93]. CLR (calcitonin receptor-like receptor) by itself binds no known endogenous ligand, but in the presence of RAMPs it gives receptors for CGRP, adrenomedullin and adrenomedullin 2/intermedin. There are several approved drugs that target this receptor family, such as pramlintide, erenumab, and the "gepant" class of CGRP receptor antagonists. There are also species differences in agonist pharmacology; for example, CGRP displays potent activity at multiple rat and mouse receptors [58, 15]. The summary table only reflects human receptor pharmacology.