Distinctive Neurophysiological Signatures of Analgesia after Inflammatory Pain in the ACC of Freely Moving Mice.

Preclinical assessments of pain have often relied upon behavioral measurements and anesthetized neurophysiological recordings. Current technologies enabling large-scale neural recordings, however, have the potential to unveil quantifiable pain signals in conscious animals for preclinical studies. Although pain processing is distributed across many brain regions, the anterior cingulate cortex (ACC) is of particular interest in isolating these signals given its suggested role in the affective ("unpleasant") component of pain. Here, we explored the utility of the ACC toward preclinical pain research using head-mounted miniaturized microscopes to record calcium transients in freely moving male mice expressing genetically encoded calcium indicator 6f (GCaMP6f) under the Thy1 promoter. We verified the expression of GCaMP6f in excitatory neurons and found no intrinsic behavioral differences in this model. Using a multimodal stimulation paradigm across naive, pain, and analgesic conditions, we found that while ACC population activity roughly scaled with stimulus intensity, single-cell representations were highly flexible. We found only low-magnitude increases in population activity after complete Freund's adjuvant (CFA) and insufficient evidence for the existence of a robust nociceptive ensemble in the ACC. However, we found a temporal sharpening of response durations and generalized increases in pairwise neural correlations in the presence of the mechanistically distinct analgesics gabapentin or ibuprofen after (but not before) CFA-induced inflammatory pain. This increase was not explainable by changes in locomotion alone. Taken together, these results highlight challenges in isolating distinct pain signals among flexible representations in the ACC but suggest a neurophysiological hallmark of analgesia after pain that generalizes to at least two analgesics.

Nitrogen isotopes reveal independent origins of N2-fixing symbiosis in extant cycad lineages.

Cycads are ancient seed plants (gymnosperms) that emerged by the early Permian. Although they were common understory flora and food for dinosaurs in the Mesozoic, their abundance declined markedly in the Cenozoic. Extant cycads persist in restricted populations in tropical and subtropical habitats and, with their conserved morphology, are often called 'living fossils.' All surviving taxa receive nitrogen from symbiotic N2-fixing cyanobacteria living in modified roots, suggesting an ancestral origin of this symbiosis. However, such an ancient acquisition is discordant with the abundance of cycads in Mesozoic fossil assemblages, as modern N2-fixing symbioses typically occur only in nutrient-poor habitats where advantageous for survival. Here, we use foliar nitrogen isotope ratios-a proxy for N2 fixation in modern plants-to probe the antiquity of the cycad-cyanobacterial symbiosis. We find that fossilized cycad leaves from two Cenozoic representatives of extant genera have nitrogen isotopic compositions consistent with microbial N2 fixation. In contrast, all extinct cycad genera have nitrogen isotope ratios that are indistinguishable from co-existing non-cycad plants and generally inconsistent with microbial N2 fixation, pointing to nitrogen assimilation from soils and not through symbiosis. This pattern indicates that, rather than being ancestral within cycads, N2-fixing symbiosis arose independently in the lineages leading to living cycads during or after the Jurassic. The preferential survival of these lineages may therefore reflect the effects of competition with angiosperms and Cenozoic climatic change.

Plasma calcitonin gene-related peptide and nerve growth factor as headache and pain biomarkers in recently deployed soldiers with and without a recent concussion.

OBJECTIVE: The objective of this study was to characterize the utility of calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF) as potential biomarkers for headache and pain disorders in the post-military deployment setting. BACKGROUND: The need to improve recognition, assessment, and prognoses of individuals with posttraumatic headache or other pain has increased interest in the potential of CGRP and NGF as biomarkers. METHODS: The Warrior Strong Study (NCT01847040) is an observational longitudinal study of United States-based soldiers who had recently returned from deployment to Afghanistan or Iraq from 2009 to 2014. The present nested cross-sectional analysis uses baseline data collected from soldiers returning to Fort Bragg, North Carolina. RESULTS: In total, 264 soldiers (mean (standard deviation [SD] age 28.1 [6.4] years, 230/264 [87.1%] men, 171/263 [65.0%] White) were analyzed. Mean (SD) plasma levels of CGRP were 1.3 (1.1) pg/mL and mean levels of NGF were 1.4 (0.4) pg/mL. Age was negatively correlated with NGF (-0.01 pg/mL per year, p = 0.007) but was not associated with CGRP. Men had higher mean (SD) CGRP plasma levels than women (1.4 95% confidence interval [CI; 1.2] vs. 0.9 95% CI [0.5] pg/mL, p < 0.002, Kruskal-Wallis test). CGRP levels were lower in participants who had a headache at the time of the blood draw (1.0 [0.6] pg/mL vs. 1.4 [1.2] pg/mL, p = 0.024). NGF was lower in participants with continuous pain (all types; 1.2 [0.4] vs. 1.4 [0.4] pg/mL, p = 0.027) and was lower in participants with traumatic brain injury (TBI) + posttraumatic headache (PTH) versus TBI without PTH (1.3 [0.3] vs. 1.4 [0.4] pg/mL, p = 0.021). Otherwise, CGRP and NGF were not associated with migraine-like headache, TBI status, or headache burden as measured by the number of medical encounters in crude or adjusted models. CONCLUSION: In this exploratory study, plasma levels of NGF and CGRP showed promise as biomarkers for headache and other types of pain. These findings need to be replicated in other cohorts.

TRPA1 Antagonist LY3526318 Inhibits the Cinnamaldehyde-Evoked Dermal Blood Flow Increase: Translational Proof of Pharmacology.

Transient receptor potential Ankyrin 1 (TRPA1) is an ion channel expressed by sensory neurons, where it mediates pain signaling. Consequently, it has emerged as a promising target for novel analgesics, yet, to date, no TRPA1 antagonists have been approved for clinical use. In the present translational study, we utilized dermal blood flow changes evoked by TRPA1 agonist cinnamaldehyde as a target engagement biomarker to investigate the in vivo pharmacology of LY3526318, a novel TRPA1 antagonist. In rats, LY3526318 (1, 3, and 10 mg/kg, p.o.) dose-dependently reduced the cutaneous vasodilation typically observed following topical application of 10% v/v cinnamaldehyde. The inhibition was significant at the site of cinnamaldehyde application and also when including an adjacent area of skin. Similarly, in a cohort of 16 healthy human volunteers, LY3526318 administration (10, 30, and 100 mg, p.o.) dose-dependently reduced the elevated blood flow surrounding the site of 10% v/v cinnamaldehyde application, with a trend toward inhibition at the site of application. Comparisons between both species reveal that the effects of LY3526318 on the cinnamaldehyde-induced dermal blood flow are greater in rats relative to humans, even when adjusting for cross-species differences in potency of the compound at TRPA1. Exposure-response relationships suggest that a greater magnitude response may be observed in humans if higher antagonist concentrations could be achieved. Taken together, these results demonstrate that cinnamaldehyde-evoked changes in dermal blood flow can be utilized as a target engagement biomarker for TRPA1 activity and that LY3526318 antagonizes the ion channel both in rats and humans.

Evaluation of Plasma Calcitonin Gene-Related Peptide as a Biomarker for Painful Temporomandibular Disorder and Migraine.

Objective: To assess associations of plasma calcitonin gene-related peptide (CGRP) with chronic temporomandibular disorder (TMD) myalgia/arthralgia or frequent/chronic migraine, alone and in combination, and to evaluate relations between the CGRP concentration and clinical, psychological, and somatosensory characteristics of participants. Methods: The cross-sectional study selected four groups of adult volunteers: healthy controls (HCs), TMD without migraine, migraine without TMD, and TMD with migraine. Each group comprised 20 participants, providing 94% power to detect statistically significant associations with CGRP concentration for either TMD or migraine. TMD and headache were classified according to the Diagnostic Criteria for TMD and the International Classification for Headache Disorders, 3rd edition, respectively. Plasma CGRP was quantified with a validated high-sensitivity electrochemiluminescent Meso Scale Discovery assay. Questionnaires and clinical examinations were used to evaluate characteristics of TMD, headache, psychological distress, and pressure pain sensitivity. Univariate regression models quantified associations of the CGRP concentration with TMD, migraine, and their interaction. Univariate associations of the CGRP concentration with clinical, psychological, and pressure pain characteristics were also assessed. Results: Among 80 participants enrolled, neither TMD nor migraine was associated with plasma CGRP concentration (P = 0.761 and P = 0.972, respectively). The CGRP concentration (mean ± SD) was similar in all 4 groups: HCs 2.0 ± 0.7 pg/mL, TMD 2.1 ± 0.8 pg/mL, migraine 2.1 ± 0.9 pg/mL, and TMD with migraine 2.2 ± 0.7 pg/mL. CGRP concentration was positively associated with age (P = 0.034) and marginally with body mass index (P = 0.080) but was unrelated to other participant characteristics. Conclusion: In this well-powered study, interictal plasma concentration of CGRP was a poor biomarker for TMD and migraine.

Airway soluble CSF1R predicts progression in patients with idiopathic pulmonary fibrosis.

This study provides the first evidence for a role of airway sCSF1R in IPF https://bit.ly/3KTBrCA.

A global approach for natural history museum collections.

Integration of the world's natural history collections can provide a resource for decision-makers.

Semi-field and surveillance data define the natural diapause timeline for Culex pipiens across the United States.

Reproductive diapause serves as biological mechanism for many insects, including the mosquito Culex pipiens, to overwinter in temperate climates. While Cx. pipiens diapause has been well-studied in the laboratory, the timing and environmental signals that promote diapause under natural conditions are less understood. In this study, we examine laboratory, semi-field, and mosquito surveillance data to define the approximate timeline and seasonal conditions that contribute to Cx. pipiens diapause across the United States. While confirming integral roles of temperature and photoperiod in diapause induction, we also demonstrate the influence of latitude, elevation, and mosquito population genetics in shaping Cx. pipiens diapause incidence across the country. Coinciding with the cessation of WNV activity, these data can have important implications for mosquito control, where targeted efforts prior to diapause induction can decrease mosquito populations and WNV overwintering to reduce mosquito-borne disease incidence the following season.

Correction: Insect herbivory on Catula gettyi gen. et sp. nov. (Lauraceae) from the Kaiparowits Formation (Late Cretaceous, Utah, USA).

[This corrects the article DOI: 10.1371/journal.pone.0261397.].

No Consistent Shift in Leaf Dry Mass per Area Across the Cretaceous-Paleogene Boundary.

The Chicxulub bolide impact has been linked to a mass extinction of plants at the Cretaceous-Paleogene boundary (KPB; ∼66 Ma), but how this extinction affected plant ecological strategies remains understudied. Previous work in the Williston Basin, North Dakota, indicates that plants pursuing strategies with a slow return-on-investment of nutrients abruptly vanished after the KPB, consistent with a hypothesis of selection against evergreen species during the globally cold and dark impact winter that followed the bolide impact. To test whether this was a widespread pattern we studied 1,303 fossil leaves from KPB-spanning sediments in the Denver Basin, Colorado. We used the relationship between petiole width and leaf mass to estimate leaf dry mass per area (LMA), a leaf functional trait negatively correlated with rate of return-on-investment. We found no evidence for a shift in this leaf-economic trait across the KPB: LMA remained consistent in both its median and overall distribution from approximately 67 to 65 Ma. However, we did find spatio-temporal patterns in LMA, where fossil localities with low LMA occurred more frequently near the western margin of the basin. These western margin localities are proximal to the Colorado Front Range of the Rocky Mountains, where an orographically driven high precipitation regime is thought to have developed during the early Paleocene. Among these western Denver Basin localities, LMA and estimated mean annual precipitation were inversely correlated, a pattern consistent with observations of both fossil and extant plants. In the Denver Basin, local environmental conditions over time appeared to play a larger role in determining viable leaf-economic strategies than any potential global signal associated with the Chicxulub bolide impact.

Characterization of transit rates in the large intestine of mice following treatment with a CGRP antibody, CGRP receptor antibody, and small molecule CGRP receptor antagonists.

OBJECTIVE: To characterize the effects of blocking calcitonin gene-related peptide (CGRP) activity in a mouse model of gastrointestinal transport. BACKGROUND: Migraine management using CGRP modulating therapies can cause constipation of varying frequency and severity. This variation might be due to the different mechanisms through which therapies block CGRP activity (e.g., blocking CGRP, or the CGRP receptor) with antibodies or receptor antagonists. The charcoal meal gastrointestinal transit assay was used to characterize constipation produced by these modes of therapy in transgenic mice expressing the human receptor activity-modifying protein 1 (hRAMP1) subunit of the CGRP receptor complex. METHODS: Male and female hRAMP1 mice were dosed with compound or vehicle and challenged with a charcoal meal suspension via oral gavage. The mice were then humanely euthanized and the proportion of the length of the large intestine that the charcoal meal had traveled indicated gastrointestinal transit. RESULTS: Antibody to the CGRP receptor produced % distance traveled (mean ± standard deviation) of 31.8 ± 8.2 (4 mg/kg; p = 0.001) and 33.2 ± 6.0 (30 mg/kg; p < 0.001) compared to 49.7 ± 8.3 (control) in female mice (n = 6-8), and 35.6 ± 13.5 (30 mg/kg, p = 0.019) compared to 50.2 ± 14.0 (control) in male mice (n = 10). Telcagepant (5 mg/kg, n = 8) resulted in % travel of 30.6 ± 14.7 versus 41.2 ± 8.3 (vehicle; p = 0.013) in male mice. Atogepant (3 mg/kg, n = 9) resulted in % travel of 30.6 ± 12.0, versus 41.2 ± 3.7 (control; p = 0.030) in female mice. The CGRP antibody galcanezumab (n = 7-10; p = 0.958 and p = 0.929) did not have a statistically significant effect. CONCLUSIONS: These results are consistent with reported clinical data. Selectively blocking the CGRP receptor may have a greater impact on gastrointestinal transit than attenuating the activity of the ligand CGRP. This differential effect may be related to physiologically opposing mechanisms between the CGRP and AMY1 receptors, as the CGRP ligand antibody could inhibit the effects of CGRP at both the CGRP and AMY1 receptors.

Insect herbivory on Catula gettyi gen. et sp. nov. (Lauraceae) from the Kaiparowits Formation (Late Cretaceous, Utah, USA).

The Upper Cretaceous (Campanian Stage) Kaiparowits Formation of southern Utah, USA, preserves abundant plant, invertebrate, and vertebrate fossil taxa. Taken together, these fossils indicate that the ecosystems preserved in the Kaiparowits Formation were characterized by high biodiversity. Hundreds of vertebrate and invertebrate species and over 80 plant morphotypes are recognized from the formation, but insects and their associations with plants are largely undocumented. Here, we describe a new fossil leaf taxon, Catula gettyi gen et. sp. nov. in the family Lauraceae from the Kaiparowits Formation. Catula gettyi occurs at numerous localities in this deposit that represent ponded and distal floodplain environments. The type locality for C. gettyi has yielded 1,564 fossil leaf specimens of this species, which provides the opportunity to circumscribe this new plant species. By erecting this new genus and species, we are able to describe ecological associations on C. gettyi and place these interactions within a taxonomic context. We describe an extensive archive of feeding damage on C. gettyi caused by herbivorous insects, including more than 800 occurrences of insect damage belonging to five functional feeding groups indicating that insect-mediated damage on this taxon is both rich and abundant. Catula gettyi is one of the best-sampled host plant taxa from the Mesozoic Era, a poorly sampled time interval, and its insect damage is comparable to other Lauraceae taxa from the younger Late Cretaceous Hell Creek Flora of North Dakota, USA.

The selective 5-HT1F receptor agonist lasmiditan inhibits trigeminal nociceptive processing: Implications for migraine and cluster headache.

BACKGROUND AND PURPOSE: Lasmiditan is a novel selective 5-HT1F receptor agonist, recently approved for acute treatment of migraine. 5-HT1F receptors are widely expressed in the CNS and trigeminovascular system. Here, we have explored the therapeutic effects of 5-HT1F receptor activation in preclinical models of migraine and cluster headache. EXPERIMENTAL APPROACH: Electrical stimulation of the dura mater or the superior salivatory nucleus in anaesthetised rats evoked trigeminovascular or trigeminal-autonomic reflex activation at the level of the trigeminocervical complex. Additionally, cranial autonomic manifestations in response to trigeminal-autonomic reflex activation were measured, via anterior choroidal blood flow alterations. These responses were then challenged with lasmiditan. We explored the tissue distribution of mRNA for 5-HT1F receptors in human post-mortem tissue and of several 5-HT1 receptor subtypes in specific tissue beds. KEY RESULTS: Lasmiditan dose-dependently reduced trigeminovascular activation in a preclinical model of migraine. Lasmiditan also reduced superior salivatory nucleus-evoked activation of the trigeminal-autonomic reflex, but had no effect on cranial autonomic activation. mRNA profiling in human tissue showed expression of the 5-HT1F receptor in several structures relevant for migraine and cluster headache. CONCLUSION AND IMPLICATIONS: Our data suggest that lasmiditan acts, at least in part, as an anti-migraine agent by reducing trigeminovascular activation. Furthermore, our results highlight a clear action for lasmiditan in a preclinical model of cluster headache. Given the proven translational efficacy of this model, our data support the potential utility of lasmiditan as a therapeutic option for the acute treatment of cluster headache attacks. LINKED ARTICLES: This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc.

Levels of prolactin and testosterone and associated sexual dysfunction and breast abnormalities in men with schizophrenia treated with antipsychotic medications.

Sexual dysfunction is one of the most bothersome adverse drug effects seen in men and women taking antipsychotic medications and negatively impacts medication adherence. Antipsychotic medications are associated with hyperprolactinemia, which is known to contribute to sexual and hormonal side effects in men. However, testosterone also plays a key factor in male sexual function and may be affected by abnormal prolactin levels through gonadotropin-releasing hormone inhibition. This study was a pilot study undertaken to assess the prevalence of elevations in prolactin levels, related reductions in testosterone levels, associated symptoms of sexual dysfunction and breast abnormalities in male participants, and related distress to these symptoms in men taking prolactin-elevating antipsychotic medications. The study was conducted as a cross-sectional study. Our results showed a notably high prevalence of sexual side effects in this population, with gynecomastia occurring in 50% and penile-related symptoms in 73%. Additionally, we found elevated prolactin levels in 68% and low testosterone levels in 55% of our participants. This study was limited in its power due to a small sample size of 22 men and the lack of a control group. Still, even in our relatively small sample, we see a trend of hyperprolactinemia being associated with low testosterone and a significant correlation of low testosterone levels with penile-related symptoms. This suggests that testosterone plays a major role in the sexual side effects reported by men taking antipsychotics, although larger studies are needed to further categorize this relationship.

An image dataset of cleared, x-rayed, and fossil leaves vetted to plant family for human and machine learning.

Leaves are the most abundant and visible plant organ, both in the modern world and the fossil record. Identifying foliage to the correct plant family based on leaf architecture is a fundamental botanical skill that is also critical for isolated fossil leaves, which often, especially in the Cenozoic, represent extinct genera and species from extant families. Resources focused on leaf identification are remarkably scarce; however, the situation has improved due to the recent proliferation of digitized herbarium material, live-plant identification applications, and online collections of cleared and fossil leaf images. Nevertheless, the need remains for a specialized image dataset for comparative leaf architecture. We address this gap by assembling an open-access database of 30,252 images of vouchered leaf specimens vetted to family level, primarily of angiosperms, including 26,176 images of cleared and x-rayed leaves representing 354 families and 4,076 of fossil leaves from 48 families. The images maintain original resolution, have user-friendly filenames, and are vetted using APG and modern paleobotanical standards. The cleared and x-rayed leaves include the Jack A. Wolfe and Leo J. Hickey contributions to the National Cleared Leaf Collection and a collection of high-resolution scanned x-ray negatives, housed in the Division of Paleobotany, Department of Paleobiology, Smithsonian National Museum of Natural History, Washington D.C.; and the Daniel I. Axelrod Cleared Leaf Collection, housed at the University of California Museum of Paleontology, Berkeley. The fossil images include a sampling of Late Cretaceous to Eocene paleobotanical sites from the Western Hemisphere held at numerous institutions, especially from Florissant Fossil Beds National Monument (late Eocene, Colorado), as well as several other localities from the Late Cretaceous to Eocene of the Western USA and the early Paleogene of Colombia and southern Argentina. The dataset facilitates new research and education opportunities in paleobotany, comparative leaf architecture, systematics, and machine learning.

Lasmiditan mechanism of action - review of a selective 5-HT1F agonist.

Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second- and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT1B/1D receptors. The discovery that the serotonin 1F (5-HT1F) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine. The 5-HT1F receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT1B receptors, the activation of 5-HT1F receptors does not cause vasoconstriction.The potency of different serotonergic agonists towards 5-HT1F was correlated in an animal model of migraine (dural plasma protein extravasation model) leading to the development of lasmiditan. Lasmiditan is a newly approved acute treatment for migraine in the United States and is a lipophilic, highly selective 5-HT1F agonist that can cross the blood-brain barrier and act at peripheral nervous system (PNS) and central nervous system (CNS) sites.Lasmiditan activation of CNS-located 5-HT1F receptors (e.g., in the trigeminal nucleus caudalis) could potentially block the release of CGRP and the neurotransmitter glutamate, thus preventing and possibly reversing the development of central sensitization. Activation of 5-HT1F receptors in the thalamus can block secondary central sensitization of this region, which is associated with progression of migraine and extracephalic cutaneous allodynia. The 5-HT1F receptors are also elements of descending pain modulation, presenting another site where lasmiditan may alleviate migraine. There is emerging evidence that mitochondrial dysfunction might be implicated in the pathophysiology of migraine, and that 5-HT1F receptors can promote mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT1F agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways.

Evaluation of LY573144 (lasmiditan) in a preclinical model of medication overuse headache.

BACKGROUND: Medication overuse is a significant issue that complicates the treatment of headache disorders. The most effective medications for the acute treatment of migraine all have the capacity to induce medication overuse headache (MOH). Novel acute migraine-specific treatments are being developed. However, because the mechanism(s) underlying medication overuse headache are not well understood, it is difficult to predict whether any particular acute medication will induce MOH in susceptible individuals. LY573144 (lasmiditan), a 5-HT1F receptor agonist, has recently been shown to be effective in the acute treatment of migraine in phase 3 trials. The aim of this study is to determine whether frequent administration of lasmiditan induces behaviors consistent with MOH in a pre-clinical rat model. METHODS: Sprague Dawley rats were administered six doses of lasmiditan (10 mg/kg), sumatriptan (10 mg/kg), or sterile water orally over 2 weeks and cutaneous allodynia was evaluated regularly in the periorbital and hindpaw regions using von Frey filaments. Testing continued until mechanosensitivity returned to baseline levels. Rats were then submitted to bright light stress (BLS) or nitric oxide (NO) donor administration and were again evaluated for cutaneous allodynia in the periorbital and hindpaw regions hourly for 5 hours. RESULTS: Both lasmiditan and sumatriptan exhibited comparable levels of drug-induced cutaneous allodynia in both the periorbital and hindpaw regions, which resolved after cessation of drug administration. Both lasmiditan and sumatriptan pre-treatment resulted in cutaneous allodynia that was evoked by either BLS or NO donor. CONCLUSIONS: In a pre-clinical rat model of MOH, oral lasmiditan, like sumatriptan, induced acute transient cutaneous allodynia in the periorbital and hindpaw regions that after resolution could be re-evoked by putative migraine triggers. These results suggest that lasmiditan has the capacity to induce MOH through persistent latent peripheral and central sensitization mechanisms.

Lasmiditan inhibits calcitonin gene-related peptide release in the rodent trigeminovascular system.

Migraine headache pathophysiology involves trigeminovascular system activation, calcitonin gene-related peptide (CGRP) release, and dysfunctional nociceptive transmission. Triptans are 5-HT1B/1D/(1F) receptor agonists that prejunctionally inhibit trigeminal CGRP release, but their vasoconstrictor properties limit their use in migraine patients with cardiovascular disease. By contrast, lasmiditan is a novel antimigraine and selective 5-HT1F receptor agonist devoid of vasoconstrictor properties. On this basis, this study has investigated the modulation of trigeminal CGRP release by lasmiditan. For this purpose, we have comparatively analysed the inhibition of several components of the trigeminovascular system induced by lasmiditan and sumatriptan through: ex vivo KCl-induced CGRP release from isolated dura mater, trigeminal ganglion, and trigeminal nucleus caudalis of mice; and in vivo dural vasodilation in the rat closed-cranial window model induced by endogenous (electrical stimulation and capsaicin) and exogenous CGRP. The ex vivo release of CGRP was similarly inhibited by sumatriptan and lasmiditan in all trigeminovascular system components. In vivo, intravenous (i.v.) lasmiditan or higher doses of sumatriptan significantly attenuated the vasodilatory responses to endogenous CGRP release, but not exogenous CGRP effects. These data suggest that lasmiditan prejunctionally inhibits CGRP release in peripheral and central trigeminal nerve terminals. Because lasmiditan is a lipophilic drug that crosses the blood-brain barrier, additional central sites of action remain to be determined.