Both acute glyphosate and the aminomethylphosphonic acid intoxication decreased the acetylcholinesterase activity in rat hippocampus, prefrontal cortex and gastrocnemius muscle.

It has been reported that glyphosate, one of the most common herbicides used in agriculture, impairs locomotion and cognition. Glyphosate has a variable half-life in soil up to biotic and/or abiotic factors transform the molecule in metabolites such as the aminomethylphosphonic acid (AMPA) that has a longer half-life. In this study, female Sprague Dawley rats were acutely exposed to different doses of glyphosate or AMPA (i.e. 10, 56 or 100 mg/kg) and, subsequently, the acetylcholinesterase (AChE) activity was measured in the hippocampus, prefrontal cortex (PFC) and the gastrocnemius muscle. Both glyphosate and AMPA produced a similar decrease in the AChE activity in all the tissues tested. These results suggest that interference with normal cholinergic neurotransmission may be one of the mechanisms involved in glyphosate-induced motor alterations in rats. Moreover, our results highlight the biological importance of AMPA as a molecule with anticholinesterase action in brain and skeletal muscle. To our knowledge, this is the first report showing in vivo that AMPA, the major metabolite of glyphosate, behaves as an organophosphate.

1-Boc-Piperidine-4-Carboxaldehyde Prevents Binge-Eating Behaviour and Anxiety in Rats.

BACKGROUND: Piperidines are biogenic amines studied mainly in toxicology because they were initially found as alkaloids from peppers and insect venoms. Piperidines are also produced in the human body, and their actions seem to be related to wakefulness/sleep and other cognitive phenomena. Piperidines have been minimally characterized for therapeutic applications. In this context, 1-Boc-piperidine-4-carboxaldehyde (1-Boc-piperidine) is a piperidine-derivative molecule with no mechanism of action reported, although its uses include the synthesis of GPR119 selective agonists that have been patented as anti-obesity drugs. OBJECTIVES: The aim of this work was to study the effects of 1-Boc-piperidine on binge-eating behaviour and anxiety in Wistar rats. METHODS: In experimental protocol 1, binge-eating behaviour was induced in animals that received pre-treatment (i.p.) with (i) vehicle (methanol 10%; 1 mL/kg), (ii) 1-Boc-piperidine (1 µmol kg-1), or (iii) 1-Boc-piperidine (10 µmol kg-1). In experimental protocol 2, mildly stressed animals were evaluated in the elevated plus maze under the acute effects of the pre-treatments applied in experimental protocol 1. RESULTS AND CONCLUSIONS: 1-Boc-piperidine decreased, in a dose-dependent manner, the intake of calories from a succulent hyper-caloric food in a binge-eating protocol in female rats, whereas the acute exposition to this piperidine exerted an anxiolytic effect in the male rat. In both effects, the mechanism of action remains to be characterized.

Potential Mechanisms Involved in Palmitoylethanolamide-Induced Vasodepressor Effects in Rats.

Palmitoylethanolamide is an endogenous lipid that exerts complex vascular effects, enhances the effects of endocannabinoids and induces a direct hypotension, but the mechanisms involved have been poorly explored. Hence, this study investigated in Wistar pithed rats the role of CB1, CB2, TRPV1 and GPR55 receptors in the inhibition by palmitoylethanolamide of the vasopressor responses produced by sympathetic stimulation or exogenous noradrenaline. Frequency- and dose-dependent vasopressor responses were analysed before and during intravenous (i.v.) continuous infusions of palmitoylethanolamide in animals receiving i.v. bolus of the antagonists NIDA41020 (CB1), AM630 (CB2), capsazepine (TRPV1), and/or cannabidiol (GPR55). Palmitoyletha-nolamide (0.1-3.1 µg/kg/min) dose-dependently inhibited the sympathetically induced and noradrenaline-induced vasopressor responses. Both inhibitions were: (i) partially blocked by 100 µg/kg NIDA41020, 100 µg/kg capsazepine, or 31 µg/kg cannabidiol; (ii) unaffected by 310 µg/kg AM630; and (iii) abolished by the combination NIDA41020 + capsazepine + cannabidiol (100, 100, and 31 µg/kg, respectively). The resting blood pressure was decreased by palmitoylethanolamide (effect prevented by NIDA41020, capsazepine or cannabidiol, but not by AM630). These results suggest that: (i) palmitoylethanolamide inhibits the vasopressor responses to sympathetic stimulation and exogenous noradrenaline and that it induces hypotension; and (ii) all these effects are mediated by prejunctional and vascular CB1, TRPV1 and probably GPR55, but not by CB2, receptors.

ß-Adrenoceptor Blockade for Infantile Hemangioma Therapy: Do ß3-Adrenoceptors Play a Role?

Infantile hemangiomas (IH) are frequent (4-5% of the childhood population) benign vascular tumors that involve accumulation, proliferation, and differentiation of aberrant vascular cells. Typically, IH are innocuous and spontaneously disappear, but they represent a potential risk for harmful effects in the body (e.g., permanent disfigurement) and health (e.g., ulcerations) in some patients. From a serendipitous discovery, the nonselective ß-adrenoceptor blocker propranolol (which blocks ß1-adrenoceptors, ß2-adrenoceptors, and ß3-adrenoceptors) emerged as an alternative therapy to treat this pathology and it quickly became a first-line treatment for IH. Nevertheless, its specific mechanisms of action remain thus far unknown. In this respect, several studies have suggested that ß1-adrenoceptors and ß2-adrenoceptors play a role in proliferative and angiogenic mechanisms. However, current basic research studies suggest that ß3-adrenoceptors could be also involved. Notably, ß3-adrenoceptors stimulate multiple intracellular pathways related to vascular function (e.g., blood flow, angiogenesis, etc.). This review compiles some lines of evidence suggesting that ß3-adrenoceptors may: (1) play a role in the pathophysiology of IH and (2) represent a potential therapeutic target for IH treatment. Hence, clinical evidence is mandatory to decide whether incorporation of ß3-adrenoceptor blockers into the therapeutic armamentarium may increase effectiveness in the treatment of IH and other vascular anomalies.

Dihydroergotamine inhibits the vasodepressor sensory CGRPergic outflow by prejunctional activation of α2-adrenoceptors and 5-HT1 receptors.

BACKGROUND: Dihydroergotamine (DHE) is an antimigraine drug that produces cranial vasoconstriction and inhibits trigeminal CGRP release; furthermore, it inhibits the vasodepressor sensory CGRPergic outflow, but the receptors involved remain unknown. Prejunctional activation of α2A/2C-adrenergic, serotonin 5-HT1B/1F, or dopamine D2-like receptors results in inhibition of this CGRPergic outflow. Since DHE displays affinity for these receptors, this study investigated the pharmacological profile of DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow. METHODS: Pithed rats were pretreated i.v. with hexamethonium (2 mg/kg·min) followed by continuous infusions of methoxamine (20 µg/kg·min) and DHE (3.1 µg/kg·min). Then, stimulus-response curves (spinal electrical stimulation; T9-T12) or dose-response curves (i.v. injections of α-CGRP) resulted in frequency-dependent or dose-dependent decreases in diastolic blood pressure. RESULTS: DHE inhibited the vasodepressor responses to electrical stimulation (0.56-5.6 Hz), without affecting those to i.v. α-CGRP (0.1-1 µg/kg). This inhibition by DHE (not produced by the methoxamine infusions): (i) was abolished by pretreatment with the combination of the antagonists rauwolscine (α2-adrenoceptor; 310 µg/kg) plus GR127935 (5-HT1B/1D; 31 µg/kg); and (ii) remained unaffected after rauwolscine (310 µg/kg), GR127935 (31 µg/kg) or haloperidol (D2-like; 310 µg/kg) given alone, or after the combination of rauwolscine plus haloperidol or GR127935 plus haloperidol at the aforementioned doses. CONCLUSION: DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow is mainly mediated by prejunctional rauwolscine-sensitive α2-adrenoceptors and GR127935-sensitive 5-HT1B/1D receptors, which correlate with α2A/2C-adrenoceptors and 5-HT1B receptors, respectively. These findings suggest that DHE-induced inhibition of the perivascular sensory CGRPergic outflow may facilitate DHE's vasoconstrictor properties resulting in an increased vascular resistance.

Blockade of GPR55 in the dorsolateral striatum impairs performance of rats in a T-maze paradigm.

To investigate the role of GPR55 receptors, which are expressed in human and rat striatum (a structure that regulates procedural memory), Wistar rats received five training sessions (10 trials/session, 1 session/day) to solve a T-maze paradigm. From these data, we constructed learning curves following pharmacological manipulation of GPR55. Five minutes before each session, animals received bilateral intradorsolateral striatum injections of noladin-ether (3.1 nmol/l; endogenous agonist of GPR55 and CB1 receptors), CID16020036 (5.6 nmol/l; GPR55 antagonist), AM251 (5.6 nmol/l; CB1 antagonist), or a combination of noladin-ether with each antagonist. Noladin-ether by itself induced no significant changes in the learning curve. Nevertheless, while simultaneously blocking CB1 receptors (with AM251), noladin-ether improved acquisition. In contrast, while simultaneously blocking GPR55 (with CID16020036), noladin-ether weakened acquisition. CID16020036 by itself impaired learning, whereas AM251 by itself reduced the efficiency in the task. There were no differences between groups in the latency to reach the arms from the starting point; thus, no motor coordination impairments interfered with this task. These results strongly suggest a role of GPR55 in procedural memory and constitute the first evidence indicating that this receptor regulates cognitive processes.

Neurotoxicity of glyphosate: Focus on molecular mechanisms probably associated with alterations in cognition and behavior.

In recent decades, glyphosate and glyphosate-based herbicides (GBH) have been extensively used in agriculture all over the world. Initially, they were considered safe, but rising evidence suggests that these molecules reach the central nervous system producing metabolic, functional, and permanent alterations that impact cognition and behavior. This theoretical and non-systematic review involved searching, integrating, and analyzing preclinical evidence regarding the effects of acute, sub-chronic, and chronic exposure to glyphosate and GBH on cognition, behavior, neural activity, and development in adult and juvenile rodents following perinatal exposition. In addition, this review gathers the mechanisms underlying the neurotoxicity of glyphosate mediating cognitive and behavioral alterations. Furthermore, clinical evidence of the effects of exposition to GBH on human health and its possible link with several neurological disorders was revised.

Aminomethylphosphonic Acid (AMPA), a Glyphosate Metabolite, Decreases Plasma Cholinesterase Activity in Rats.

Glyphosate, a widely used herbicide, is linked to a plethora of deleterious effects in both clinical and preclinical studies. Nevertheless, the effects of its main metabolite, aminomethylphosphonic acid (AMPA), whose half-life in soil is even longer than that of glyphosate, have been little explored. On this basis, as a first approach, in this work, we report that intraperitoneal (i.p.) administration of AMPA or glyphosate (at 10, 56, and 100 mg/kg) decreased, to a similar extent, plasma cholinesterase (ChE) activity in acutely exposed rats. Moreover, we designed an experimental protocol to analyze and compare the effects of AMPA and glyphosate on human plasma ChE activity; this protocol consisted of adding these compounds to human plasma to subsequently test the effects of this plasma on the contraction to acetylcholine (ACh) in the frog rectus abdominis muscle (an indirect estimate of ChE activity). Accordingly, this muscular contraction to ACh was evaluated before and after pre-incubation of ACh with (i) plasma alone, (ii) plasma with AMPA, and (iii) plasma with glyphosate. Our results indicate that AMPA, like glyphosate, decreased ChE activity in the plasma of rats (when given i.p.) and humans (when added in vitro), suggesting that both xenobiotics may exert similar toxicological effects.

Rapid liver self-recovery: A challenge for rat models of tissue damage.

Animal models, mainly murine, stay as a fundamental resource in diverse research pursuits, notably contributing to significant strides in discovering novel treatments for therapeutic applications. Preclinical assays must consider the existence of self-recovery mechanisms in the murine species to achieve a well-designed control group. This study focuses on unveiling the innate rapid regenerative capacity of rat liver by utilizing the thioacetamide-induced sub-chronic liver injury model. Employing histopathological, biochemical, and molecular liver function tests, we assessed the recovery of liver tissue functionality. Moreover, animals were housed with voluntary running wheels and locomotory activity was recorded and employed as an indirect index of overall animal recuperation. Remarkably, basal locomotory activity reestablished to normal levels only two weeks post-thioacetamide exposure. Our results raise vital considerations about the importance of temporal synchronicity in comparative assays to validate the real action of treatments, emphasizing the role of the rapid rat liver endogenous self-recovery.

Neuroglycome alterations of hippocampus and prefrontal cortex of juvenile rats chronically exposed to glyphosate-based herbicide.

Introduction: Glyphosate-based herbicides (GBHs) have been shown to have significant neurotoxic effects, affecting both the structure and function of the brain, and potentially contributing to the development of neurodegenerative disorders. Despite the known importance of glycosylation in disease progression, the glycome profile of systems exposed to GBH has not been thoroughly investigated. Methods: In this study, we conducted a comprehensive glycomic profiling using LC-MS/MS, on the hippocampus and prefrontal cortex (PFC) of juvenile rats exposed to GBH orally, aiming to identify glyco-signature aberrations after herbicide exposure. Results: We observed changes in the glycome profile, particularly in fucosylated, high mannose, and sialofucosylated N-glycans, which may be triggered by GBH exposure. Moreover, we found major significant differences in the N-glycan profiles between the GBH-exposed group and the control group when analyzing each gender independently, in contrast to the analysis that included both genders. Notably, gender differences in the behavioral test of object recognition showed a decreased performance in female animals exposed to GBH compared to controls (p < 0.05), while normal behavior was recorded in GBH-exposed male rats (p > 0.05). Conclusion: These findings suggest that glycans may play a role in the neurotoxic effect caused by GBH. The result suggests that gender variation may influence the response to GBH exposure, with potential implications for disease progression and specifically the neurotoxic effects of GBHs. Understanding these gender-specific responses could enhance knowledge of the mechanisms underlying GBH-induced toxicity and its impact on brain health. Overall, our study represents the first detailed analysis of N-glycome profiles in the hippocampus and PFC of rats chronically exposed to GBH. The observed alterations in the expression of N-glycan structures suggest a potential neurotoxic effect associated with chronic GBH exposure, highlighting the importance of further research in this area.

Metabolomic Changes in Rat Serum after Chronic Exposure to Glyphosate-Based Herbicide.

Glyphosate-based herbicides (GBHs) have gained extensive popularity in recent decades. For many years, glyphosate has been regarded as harmless or minimally toxic to mammals due to the absence of its primary target, the shikimic acid pathway in humans. Nonetheless, mounting evidence suggests that glyphosate may cause adverse health effects in humans via other mechanisms. In this study, we described the metabolomic changes in the serum of experimental rats exposed to chronic GBH using the highly sensitive LC-MS/MS technique. We investigated the possible relationship between chronic exposure to GBH and neurological disorders. Our findings suggest that chronic exposure to GBH can alter spatial learning memory and the expression of some important metabolites that are linked to neurophysiological disorders in young rats, with the female rats showing higher susceptibility compared to the males. This indicates that female rats are more likely to show early symptoms of the disorder on exposure to chronic GBH compared to male rats. We observed that four important metabolites (paraxanthine, epinephrine, L-(+)-arginine, and D-arginine) showed significant changes and involvement in neurological changes as suggested by ingenuity pathway analysis. In conclusion, our results indicate that chronic exposure to GBH can increase the risk of developing neurological disorders.

Serum N-Glycan Changes in Rats Chronically Exposed to Glyphosate-Based Herbicides.

Glyphosate, the active ingredient in many herbicides, has been widely used in agriculture since the 1970s. Despite initial beliefs in its safety for humans and animals due to the absence of the shikimate pathway, recent studies have raised concerns about its potential health effects. This study aimed to identify glycomic changes indicative of glyphosate-induced toxicity. Specifically, the study focused on profiling N-glycosylation, a protein post-translational modification increasingly recognized for its involvement in various disorders, including neurological conditions. A comprehensive analysis of rat serum N-glycomics following chronic exposure to glyphosate-based herbicides (GBH) was conducted using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results revealed significant changes in the N-glycan profile, particularly in sialylated and sialofucosylated N-glycans. The analysis of N-glycans across gender subgroups provided insights into gender-specific responses to GBH exposure, with the male rats exhibiting a higher susceptibility to these N-glycan changes compared to females. The validation of significantly altered N-glycans using parallel reaction monitoring (PRM) confirmed their expression patterns. This study provides novel insights into the impact of chronic GBH exposure on serum N-glycan composition, with implications for assessing glyphosate toxicity and its potential neurological implications.

Serotonergic Modulation of Neurovascular Transmission: A Focus on Prejunctional 5-HT Receptors/Mechanisms.

5-Hydroxytryptamine (5-HT), or serotonin, plays a crucial role as a neuromodulator and/or neurotransmitter of several nervous system functions. Its actions are complex, and depend on multiple factors, including the type of effector or receptor activated. Briefly, 5-HT can activate: (i) metabotropic (G-protein-coupled) receptors to promote inhibition (5-HT1, 5-HT5) or activation (5-HT4, 5-HT6, 5-HT7) of adenylate cyclase, as well as activation (5-HT2) of phospholipase C; and (ii) ionotropic receptor (5-HT3), a ligand-gated Na+/K+ channel. Regarding blood pressure regulation (and beyond the intricacy of central 5-HT effects), this monoamine also exerts direct postjunctional (on vascular smooth muscle and endothelium) or indirect prejunctional (on autonomic and sensory perivascular nerves) effects. At the prejunctional level, 5-HT can facilitate or preclude the release of autonomic (e.g., noradrenaline and acetylcholine) or sensory (e.g., calcitonin gene-related peptide) neurotransmitters facilitating hypertensive or hypotensive effects. Hence, we cannot formulate a specific impact of 5-HT on blood pressure level, since an increase or decrease in neurotransmitter release would be favoured, depending on the type of prejunctional receptor involved. This review summarizes and discusses the current knowledge on the prejunctional mechanisms involved in blood pressure regulation by 5-HT and its impact on some vascular-related diseases.

Pharmacologic hyperreactivity of kappa opioid receptors in periaqueductal gray matter during alcohol withdrawal syndrome in rats.

BACKGROUND: Periaqueductal gray matter (PAG) is a brain region rich in kappa-opioid receptors (KOR). KOR in PAG mediates behavioral responses related to pain integration, and panic response, among others. Its participation in the addiction phenomena has been poorly studied. Hence, this preliminary study explored the pharmacological effects of KOR stimulation/blockade in dorsal-PAG (D-PAG) during alcohol withdrawal on anxiety-type behaviors and alcohol intake/preference. METHODS: Juvenile male Wistar rats were unexposed (A-naïve group) or exposed to alcohol for 5 weeks and then restricted (A-withdrawal group). Posteriorly, animals received intra D-PAG injections of vehicle (10% DMSO), salvinorin A (SAL-A; a selective KOR agonist), or 2-Methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF-04455242; a highly selective KOR-antagonist). Subsequently, the defensive burying behavior (DBB) and alcohol intake/preference paradigms were evaluated. RESULTS: SAL-A markedly increased burying time, the height of bedding, and alcohol consumption/preference in A-withdrawal, while slightly increased the height of bedding in A-näive rats. PF-04455242 decreased both burying and immobility duration, whereas increases latency to burying, frequency of rearing, and the number of stretches attempts with no action on alcohol intake/preference in A-withdrawal rats. CONCLUSIONS: In general, stimulation/blockade of KOR in A-withdrawal animals exert higher responses compared to A-naïve ones. SAL-A produced anxiety-like behaviors and increased alcohol consumption/preference, especially/solely in the alcohol-withdrawal condition, while PF-04455242 augmented exploration with no effects on alcohol intake/preference. Our findings suggest a possible pharmacologic hyperreactivity of the KOR in PAG during alcohol withdrawal.

The oncogenic lysophosphatidylinositol (LPI)/GPR55 signaling.

GPR55 is a class A orphan G protein-coupled receptor that has drawn important therapeutic attention in the last decade because of its role in pathophysiological processes including vascular functions, metabolic dysfunction, neurodegenerative disorders, or bone turnover among others. Several cannabinoids of phytogenic, endogenous, and synthetic nature have shown to modulate this receptor leading to propose it as a member of the endocannabinoid system. The putative endogenous GPR55 ligand is L-α-lysophosphatidylinositol (LPI) and it has been associated with several processes that control cell survival and tumor progression. The relevance of GPR55 in cancer is currently being extensively studied in vitro and in vivo using diverse cancer models. The LPI/GPR55 axis has been reported to participate in pro-oncogenic processes including cellular proliferation, differentiation, migration, invasion, and metastasis being altered in several cancer cells via G12/13 and Gq signaling. Moreover, GRP55 and its bioactive lipid have been proposed as potential biomarkers for cancer diagnosis. Indeed, GPR55 overexpression or high expression has been shown to correlate with cancer aggressiveness in specific tumors including acute myeloid leukemia, uveal melanoma, low grade glioma and renal cancer. This review aims to analyze and summarize current evidence on the cancerogenic role of the LPI/GPR55 axis providing a critical view of the therapeutic prospects of this promising target.

Central GPR55 may prevent nicotine reinforcing actions: a preliminary study.

GPR55 is an orphan receptor whose endogenous agonists include lysophosphatidylinositol (LPI) and N­acetylethanolamides (NAEs), such as palmitoylethanolamide (PEA) and anandamide. Furthermore, its physiology in the central nervous system involves motor coordination, procedural and spatial memory, pain, and anxiety, among others. Recent reports indicate that systemic injections of O­1602 (a GPR55 and GPR18 agonist) blocked the reinforcing effects of morphine and nicotine in the conditioned place preference (CPP) paradigm, suggesting a possible participation of peripheral and/or central GPR55/GPR18 in brain reward/anti­reward systems. In this pilot study, the endogenous GPR55 agonists LPI and PEA, the highly selective GPR55 synthetic agonist ML184 or the selective GPR55 antagonist ML193 were injected to examine their pharmacological effects on the reinforcing actions of nicotine in the CPP paradigm. Our preliminary study shows that injections of LPI, PEA, ML184 and ML193 interfered with the change in place preference induced by nicotine via mechanisms that remain to be identified (which probably include central GPR55).

Experimental protocol for detecting higher alcohol consumers from a conventional rat line based on basal anxiety.

Predisposition for a high alcohol intake and the impact of alcohol-abstinence-relapse may be reliable experimentally performed in conventional adult rat lines if animals received juvenile exposure to alcohol (e.g., by forced consumption) and selecting those individuals with high basal anxiety levels during juvenile periods. Importantly, a forced alcohol consumption phase must be followed by an imposed withdrawal period to form an exposure-abstinence cycle (at least two cycles are required) which allow to obtain animals with notorious alcohol relapses. The easier way to test alcohol relapses is through voluntary ethanol intake models. On the other hand, the anxiety classification may be performance by classical paradigms such as an elevated plus maze test, defensive burying behavior test or any other. Here, we provide a step-by-step protocol description to detect higher alcohol consumers animals from male Wistar rats. This protocol should be especially useful for those interested in studying the participation of specific brain nucleus [e.g., periaqueductal gray (PAG)] and/or the neurotransmitters involved [e.g., neuropeptide Y (NPY)] in the alcohol intake phenomena if it is combined with stereotaxic surgery. However, every administration route of treatments or experimental design is appropriate; the limit is the own imagination, and the resources.

The impact of CGRPergic monoclonal antibodies on prophylactic antimigraine therapy and potential adverse events.

Migraine is a prevalent medical condition and the second most disabling neurological disorder. Regarding its pathophysiology, calcitonin gene-related peptide (CGRP) plays a key role, and, consequently, specific antimigraine pharmacotherapy has been designed to target this system. Hence, apart from the gepants, the recently developed monoclonal antibodies (mAbs) are a novel approach to treat this disorder. In this review we consider the current knowledge on the mechanisms of action, specificity, safety, and efficacy of the above mAbs as prophylactic antimigraine agents, and examine the possible adverse events that these agents may trigger. Antimigraine mAbs act as direct scavengers of CGRP (galcanezumab, fremanezumab, and eptinezumab) or against the CGRP receptor (erenumab). Due to their long half-lives, these molecules have revolutionized the prophylactic treatment of this neurovascular disorder. Moreover, because of their physicochemical properties, these agents are hepato-friendly and do not cross the blood-brain barrier (highlighting the relevance of peripheral mechanisms in migraine). Nevertheless, apart from potential cardiovascular side effects, the interaction with AMY1 receptors and immunogenicity induced by autoantibodies against mAbs could be a concern for the safety of long-term treatment with these molecules.

Blockade of GPR55 in dorsal periaqueductal gray produces anxiety-like behaviors and evocates defensive aggressive responses in alcohol-pre-exposed rats.

GPR55 is a receptor expressed in several central nervous system areas, including the periaqueductal gray (PAG). Current knowledge of GPR55 physiology in PAG only covers pain integration, but it is involved in other actions such as anxiety, panic, motivated behaviors, and alcohol intake. In the present study, juvenile male Wistar rats were unexposed (alcohol-naïve group; A-naïve) or exposed to alcohol for 5 weeks (alcohol-pre-exposed group; A-pre-exposed). Posteriorly, animals received intra dorsal-PAG (D-PAG) injections of vehicle (10% DMSO), LPI (1 nmol/0.5 µl) and ML-193 (1 nmol/0.5 µl, a selective GPR55 antagonist). Finally, defensive burying behavior (DBB) paradigm and alcohol preference were evaluated. Compared to the A-naïve group, the A-pre-exposed vehicle group had higher (p < 0.05): (i) time of immobility; (ii) latency to and duration of burying; and (iii) alcohol consumption. In both groups (i.e., A-naïve and A-pre-exposed) treatment with LPI: (i) decreased duration of burying (p < 0.05); (ii) suppressed time of immobility; and (iii) increased alcohol intake (p < 0.05). On the other hand, treatment with ML-193: (i) decreased duration of immobility in A-pre-exposed (but not in A-naïve rats); (ii) promoted an aggressive response against the shock-probe in A-pre-exposed rats (p < 0.05); and (iii) increased alcohol intake (p < 0.05). Our results suggest that blockade of GPR55 in D-PAG is associated with anxiety-like behaviors, defensive aggressive behaviors, and higher alcohol intake, whereas LPI in D-PAG produced anxiolytic-like effects (probably GPR55-mediated), but not prevention of alcohol intake.

A critical review of the neurovascular nature of migraine and the main mechanisms of action of prophylactic antimigraine medications.

INTRODUCTION: Migraine involves neurovascular, functional, and anatomical alterations. Migraineurs experience an intense unilateral and pulsatile headache frequently accompanied with vomiting, nausea, photophobia, etc. Although there is no ideal preventive medication, frequency in migraine days may be partially decreased by some prophylactics, including antihypertensives, antidepressants, antiepileptics, and CGRPergic inhibitors. However, the mechanisms of action involved in antimigraine prophylaxis remain elusive. AREAS COVERED: This review recaps some of the main neurovascular phenomena related to migraine and currently available preventive medications. Moreover, it discusses the major mechanisms of action of the recommended prophylactic medications. EXPERT OPINION: In the last three years, migraine prophylaxis has evolved from nonspecific to specific antimigraine treatments. Overall, nonspecific treatments  mainly involve neural actions, whereas specific pharmacotherapy (represented by CGRP receptor antagonists and CGRPergic monoclonal antibodies) is predominantly mediated by neurovascular mechanisms that may include, among others: (i) reduction in the cortical spreading depression (CSD)-associated events; (ii) inhibition of pain sensitization; (iii) blockade of neurogenic inflammation; and/or (iv) increase in cranial vascular tone. Accordingly, the novel antimigraine prophylaxis promises to be more effective, devoid of significant adverse effects (unlike nonspecific treatments), and more beneficial for the quality of life of migraineurs.