Functional Analysis of TRPA1, TRPM3, and TRPV1 Channels in Human Dermal Arteries and Their Role in Vascular Modulation.

Transient receptor potential (TRP) channels are pivotal in modulating vascular functions. In fact, topical application of cinnamaldehyde or capsaicin (TRPA1 and TRPV1 channel agonists, respectively) induces "local" changes in blood flow by releasing vasodilator neuropeptides. We investigated TRP channels' contributions and the pharmacological mechanisms driving vasodilation in human isolated dermal arteries. Ex vivo studies assessed the vascular function of artery segments and analyzed the effects of different compounds. Concentration-response curves to cinnamaldehyde, pregnenolone sulfate (PregS, TRPM3 agonist), and capsaicin were constructed to evaluate the effect of the antagonists HC030031 (TRPA1); isosakuranetin (TRPM3); and capsazepine (TRPV1). Additionally, the antagonists/inhibitors olcegepant (CGRP receptor); L-NAME (nitric oxide synthase); indomethacin (cyclooxygenase); TRAM-34 plus apamin (K+ channels); and MK-801 (NMDA receptors, only for PregS) were used. Moreover, CGRP release was assessed in the organ bath fluid post-agonist-exposure. In dermal arteries, cinnamaldehyde- and capsaicin-induced relaxation remained unchanged after the aforementioned antagonists, while PregS-induced relaxation was significantly inhibited by isosakuranetin, L-NAME and MK-801. Furthermore, there was a significant increase in CGRP levels post-agonist-exposure. In our experimental model, TRPA1 and TRPV1 channels seem not to be involved in cinnamaldehyde- or capsaicin-induced relaxation, respectively, whereas TRPM3 channels contribute to PregS-induced relaxation, possibly via CGRP-independent mechanisms.

Pharmacological Nature of the Purinergic P2Y Receptor Subtypes That Participate in the Blood Pressure Changes Produced by ADPßS in Rats.

Purine nucleosides (adenosine) and nucleotides such as adenosine mono/di/triphosphate (AMP/ADP/ATP) may produce complex cardiovascular responses. For example, adenosine-5'-(ß-thio)-diphosphate (ADPßS; a stable synthetic analogue of ADP) can induce vasodilatation/vasodepressor responses by endothelium-dependent and independent mechanisms involving purinergic P2Y receptors; however, the specific subtypes participating in these responses remain unknown. Therefore, this study investigated the receptor subtypes mediating the blood pressure changes induced by intravenous bolus of ADPßS in male Wistar rats in the absence and presence of central mechanisms with the antagonists MRS2500 (P2Y1), PSB0739 (P2Y12), and MRS2211 (P2Y13). For this purpose, 120 rats were divided into 60 anaesthetised rats and 60 pithed rats, and further subdivided into four groups (n = 30 each), namely: (a) anaesthetised rats, (b) anaesthetised rats with bilateral vagotomy, (c) pithed rats, and (d) pithed rats continuously infused (intravenously) with methoxamine (an α1-adrenergic agonist that restores systemic vascular tone). We observed, in all four groups, that the immediate decreases in diastolic blood pressure produced by ADPßS were exclusively mediated by peripheral activation of P2Y1 receptors. Nevertheless, the subsequent increases in systolic blood pressure elicited by ADPßS in pithed rats infused with methoxamine probably involved peripheral activation of P2Y1, P2Y12, and P2Y13 receptors.

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.

Pharmacological Profile of the Purinergic P2Y Receptors That Modulate, in Response to ADPßS, the Vasodepressor Sensory CGRPergic Outflow in Pithed Rats.

Calcitonin gene-related peptide (CGRP), an endogenous neuropeptide released from perivascular sensory nerves, exerts a powerful vasodilatation. Interestingly, adenosine triphosphate (ATP) stimulates the release of CGRP by activation of prejunctional P2X2/3 receptors, and adenosine 5'-O-2-thiodiphosphate (ADPßS), a stable adenosine diphosphate (ADP) analogue, produces vasodilator/vasodepressor responses by endothelial P2Y1 receptors. Since the role of ADP in the prejunctional modulation of the vasodepressor sensory CGRPergic drive and the receptors involved remain unknown, this study investigated whether ADPßS inhibits this CGRPergic drive. Accordingly, 132 male Wistar rats were pithed and subsequently divided into two sets. In set 1, ADPßS (5.6 and 10 µg/kg·min) inhibited the vasodepressor CGRPergic responses by electrical stimulation of the spinal T9-T12 segment. This inhibition by ADPßS (5.6 µg/kg·min) was reverted after i.v. administration of the purinergic antagonists MRS2500 (300 µg/kg; P2Y1) or MRS2211 (3000 µg/kg; P2Y13), but not by PSB0739 (300 µg/kg; P2Y12), MRS2211 (1000 µg/kg; P2Y13) or the KATP blocker glibenclamide (20 mg/kg). In set 2, ADPßS (5.6 µg/kg·min) failed to modify the vasodepressor responses to exogenous α-CGRP. These results suggest that ADPßS inhibits CGRP release in perivascular sensory nerves. This inhibition, apparently unrelated to activation of ATP-sensitive K+ channels, involves P2Y1 and probably P2Y13, but not P2Y12 receptors.

Trigeminovascular effects of propranolol in men and women, role for sex steroids.

OBJECTIVE: Assess whether propranolol modulates the trigeminovascular system in both men and women. METHODS: We investigated the effect of propranolol (80 mg, 90 min after oral administration, corresponding to Tmax ) on the increase in dermal blood flow of the forehead skin (innervated by the trigeminal nerve) by capsaicin application (0.6 mg/mL) and electrical stimulation (0.2-1.0 mA) before and after placebo (grapefruit juice) or propranolol (oral solution diluted in grapefruit juice) in a randomized, double-blind, placebo-controlled cross-over study, including healthy males (n = 10) and females on contraceptives (n = 11). Additionally, we compared our results with data from the Dutch IADB.nl prescription database by analyzing the change in triptan use after propranolol prescription in a population similar to our dermal blood flow study subjects (males and females, 20-39 years old). RESULTS: Dermal blood flow responses to capsaicin were significantly attenuated after propranolol, but not after placebo. When stratifying by sex, no significant changes in the capsaicin-induced dermal blood flow were observed in females after propranolol, whereas they remained significant in males. Dermal blood flow responses to electrical stimulation were not modified in any case. In our prescription database study, after propranolol, a more pronounced decrease in triptan use was observed in male patients than in female patients. INTERPRETATION: Propranolol (80 mg) inhibits capsaicin-induced increases in dermal blood flow in a sex-dependent manner. In patients, a more pronounced decrease in triptan use is observed in males when compared with females, suggesting an interaction between propranolol and sex steroids in the modulation of the trigeminovascular system.

Streptozotocin-induced diabetes in rats modifies the role D2 , D3 and D4 dopamine receptors play in cardiac sympathetic inhibition.

BACKGROUND: Diabetes mellitus is associated with abnormalities in peripheral/central catecholaminergic systems, including changes in catecholamine levels and receptor expression. OBJECTIVE: Since quinpirole-induced cardiac sympathetic inhibition is greater in diabetic than in normoglycemic rats, this study pharmacologically investigated the dopamine D2 -like receptor subtypes that mediate cardiac sympathetic inhibition in diabetic (streptozotocin [STZ]-pretreated) pithed rats. METHODS: Fifty male Wistar rats were pretreated with STZ, pithed and conditioned for spinal stimulation (C7 -T1 ) of the tachycardic sympathetic tone. The resulting increases in heart rate were evaluated following i.v. blocking doses of antagonists at D2 , D3 and D4 receptors during a continuous i.v. infusion of quinpirole (an agonist at D2 -like receptors) or saline (vehicle). RESULTS: With this experimental approach, the cardiac sympathetic inhibition produced by quinpirole in diabetic rats was: (i) unchanged after administration of vehicles and; (ii) abolished by the antagonists L-741,626 (D2 ), SB-277011-A (D3 ) or L-745,870 (D4 ). CONCLUSION: These findings in diabetic pithed rats imply that: (i) the cardiac sympathetic inhibition by quinpirole involves activation of D2/3/4 dopamine receptors; and (ii) there is a differential stimulation of these receptors compared to normoglycemic rats. These D2/3/4 receptor subtypes could be a novel drug target for the therapy of typical cardiac complications of diabetes.

Prospective role of α2A/2B/2C-adrenoceptor subtypes in the modulation of cardioaccelerator sympathetic tone in an experimental model of diabetes.

Abnormalities in the cardiac sympathetic innervation and tone, as well as in the noradrenergic system are associated, among other peripheral complications, with diabetes mellitus. Furthermore, B-HT 933, an agonist at α2-adrenoceptors, induces a greater cardiac sympathetic inhibition in diabetic rats than in normoglycaemic rats. Accordingly, this pharmacological study analysed the specific involvement of the α2A/2B/2C adrenoceptor subtypes mediating inhibition of the cardioaccelerator sympathetic tone (i.e. cardiac sympathetic inhibition) in an experimental model of diabetes induced by streptozotocin (STZ). Fifty male Wistar rats were consecutively: injected i.p. with STZ to cause diabetes; pithed after four weeks; and primed for electrical preganglionic stimulation (spinal C7-T1 segment) to selectively produce increases in heart rate. These responses were evaluated after i.v. bolus injections of relatively selective α2A-, α2B- and α2C-adrenoceptor antagonists (or vehicles) during an i.v. continuous infusion of B-HT 933 or vehicle. B-HT 933 produced a significant inhibition of the sympathetic tachycardic responses, which was: (i) unaffected after the vehicles saline or dimethyl sulfoxide (DMSO); (ii) partially attenuated after blocking doses of the antagonists BRL44408 (α2A) or JP-1302 (α2C); and (iii) abolished after blocking doses of the antagonist imiloxan (α2B). These findings in diabetic pithed rats indicate that the modulation of the cardioaccelerator sympathetic tone predominantly involves the α2B-adrenoceptor subtype and, to a lesser degree, the α2A- and α2C-adrenoceptor subtypes. Hence, blockade of the sympatho-inhibitory α2B-adrenoceptor subtype (absent in normoglycaemic rats) could denote a novel pharmacological strategy for the therapy of some cardiac disorders during the early stages of diabetes.

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.

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.

Metabolic Aspects of Migraine: Association With Obesity and Diabetes Mellitus.

Migraine is a disabling neurovascular disorder, characterized by moderate to severe unilateral headaches, nausea, photophobia, and/or phonophobia, with a higher prevalence in women than in men, which can drastically affect the quality of life of migraine patients. In addition, this chronic disorder is related with metabolic comorbidities associated with the patient's lifestyle, including obesity and diabetes mellitus (DM). Beyond the personal and socioeconomic impact caused by migraine, obesity and DM, it has been suggested that these metabolic disorders seem to be related to migraine since: (i) they are a risk factor for developing cardiovascular disorders or chronic diseases; (ii) they can be influenced by genetic and environmental risk factors; and (iii) while clinical and epidemiological studies suggest that obesity is a risk factor for migraine, DM (i.e., type 1 and type 2 DM) have been reported to be either a protective or a risk factor in migraine. On this basis, and given the high worldwide prevalence of migraine, obesity, and DM, this article provides a narrative review of the current literature related to the association between the etiology and pathophysiology of migraine and these metabolic disorders, considering lifestyle aspects, as well as the possible involvement of neurotransmitters, neuropeptides, and/or sex hormones. While a link between migraine and metabolic disorders has been suggested, many studies are contradictory and the mechanisms involved in this association are not yet sufficiently established. Therefore, further research should be focused on understanding the possible mechanisms involved.

Susceptibility for Some Infectious Diseases in Patients With Diabetes: The Key Role of Glycemia.

Uncontrolled diabetes results in several metabolic alterations including hyperglycemia. Indeed, several preclinical and clinical studies have suggested that this condition may induce susceptibility and the development of more aggressive infectious diseases, especially those caused by some bacteria (including Chlamydophila pneumoniae, Haemophilus influenzae, and Streptococcus pneumoniae, among others) and viruses [such as coronavirus 2 (CoV2), Influenza A virus, Hepatitis B, etc.]. Although the precise mechanisms that link glycemia to the exacerbated infections remain elusive, hyperglycemia is known to induce a wide array of changes in the immune system activity, including alterations in: (i) the microenvironment of immune cells (e.g., pH, blood viscosity and other biochemical parameters); (ii) the supply of energy to infectious bacteria; (iii) the inflammatory response; and (iv) oxidative stress as a result of bacterial proliferative metabolism. Consistent with this evidence, some bacterial infections are typical (and/or have a worse prognosis) in patients with hypercaloric diets and a stressful lifestyle (conditions that promote hyperglycemic episodes). On this basis, the present review is particularly focused on: (i) the role of diabetes in the development of some bacterial and viral infections by analyzing preclinical and clinical findings; (ii) discussing the possible mechanisms by which hyperglycemia may increase the susceptibility for developing infections; and (iii) further understanding the impact of hyperglycemia on the immune system.

An outlook on the trigeminovascular mechanisms of action and side effects concerns of some potential neuropeptidergic antimigraine therapies.

Introduction: In addition to serotonin (5-hydroxytryptamine; 5-HT) and other (neuro)mediators, the role of neuropeptides in migraine pathophysiology is relevant. Indeed, while some molecules interfering with calcitonin gene-related peptide (CGRP) transmission have recently been approved for clinical antimigraine use, other neuropeptides with translational use are in the pipeline. Among others, hypothalamic neuropeptides such as pituitary adenylate cyclase-activating peptide (PACAP), oxytocin (OT), and orexins stand out as potential novel targets to treat this neurovascular disorder. Areas covered: Based on the aforementioned findings, the present review: (i) summarizes the current knowledge on the role of the above neuropeptides in the trigeminovascular system, and migraine pathophysiology; and (ii) discusses some issues related with the mechanisms of action and side effects concerns that could be elicited when targeting the CGRPergic, PACAPergic, oxytocinergic and orexinergic systems. Expert opinion: Specific antimigraine pharmacotherapies have evolved from the enhancement of serotonergic 5-HT1B/1D/1F transmission to the use of compounds interacting with neuropeptidergic systems. Canonically, neuropeptides cause an array of complex intracellular mechanisms that, after modifying neuronal and/or vascular transmission, result in antimigraine action and also potential side effects. Furthermore, due to the chemical nature of some molecules targeting the above neuropeptidergic transmission (e.g., monoclonal antibodies, peptides), there are some limiting pharmacokinetics issues.

International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function.

5-HT receptors expressed throughout the human body are targets for established therapeutics and various drugs in development. Their diversity of structure and function reflects the important role 5-HT receptors play in physiologic and pathophysiological processes. The present review offers a framework for the official receptor nomenclature and a detailed understanding of each of the 14 5-HT receptor subtypes, their roles in the systems of the body, and, where appropriate, the (potential) utility of therapeutics targeting these receptors. SIGNIFICANCE STATEMENT: This review provides a comprehensive account of the classification and function of 5-hydroxytryptamine receptors, including how they are targeted for therapeutic benefit.

Role of peripheral 5-HT5A receptors in 5-HT-induced cardiac sympatho-inhibition in type 1 diabetic rats.

5-HT inhibits cardiac sympathetic neurotransmission in normoglycaemic rats, via 5-HT1B, 5-HT1D and 5-HT5A receptor activation. Since type 1 diabetes impairs the cardiac sympathetic innervation leading to cardiopathies, this study aimed to investigate whether the serotonergic influence on cardiac noradrenergic control is altered in type 1 diabetic rats. Diabetes was induced in male Wistar rats by streptozotocin (50 mg/kg, i.p.). Four weeks later, the rats were anaesthetized, pithed and prepared for producing tachycardic responses by electrical preganglionic stimulation (C7-T1) of the cardioaccelerator sympathetic outflow or i.v. noradrenaline bolus injections. Immunohistochemistry was performed to study 5-HT1B, 5-HT1D and 5-HT5A receptor expression in the stellate ganglion from normoglycaemic and diabetic rats. In the diabetic group, i) i.v. continuous infusions of 5-HT induced a cardiac sympatho-inhibition that was mimicked by the 5-HT1/5A agonist 5-carboxamidotryptamine (without modifying noradrenaline-induced tachycardia), but not by the agonists indorenate (5-HT1A), CP 93,129 (5-HT1B), PNU 142633 (5-HT1D), or LY344864 (5-HT1F); ii) SB 699551 (5-HT5A antagonist; i.v.) completely reversed 5-CT-induced cardiac sympatho-inhibition; and iii) 5-HT5A receptors were more expressed in the stellate ganglion compared to normoglycaemic rats. These results show the prominent role of the peripheral 5-HT5A receptors prejunctionally inhibiting the cardiac sympathetic drive in type 1 diabetic rats.

CGRP inhibitors for migraine prophylaxis: a safety review.

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

Dopamine D4 receptor subtype activation reduces the rat cardiac parasympathetic discharge.

The dopaminergic system influences the heart rhythm by inhibiting the rat cardiac sympathetic and parasympathetic neurotransmissions through activation of D2-like receptors (encompassing the D2, D3, and D4 subtypes). Whereas D2 receptor subtype activation results in cardiac sympatho-inhibition, the dopamine receptor subtypes involved in rat cardiac vago-inhibition remain unknown. Hence, this study investigated the specific functional role of the D2-like receptor subtypes (D2, D3, and/or D4) inhibiting the rat heart cholinergic drive. For this purpose, male Wistar rats were pithed and prepared for cardiac vagal stimulation. Bradycardic responses were obtained by electrical stimulation of vagal fibres (3, 6, 9 Hz; n = 100) or i.v. acetylcholine (ACh; 1, 5, 10 µg/kg; n = 15). Expression of D2, D3, and D4 receptors was studied in left and right atrium samples by PCR (n = 4). Intravenous injections of quinpirole (D2-like agonist; 1-30 µg/kg), but not of SFK-38393 (D1-like agonist; 1-30 µg/kg), dose-dependently inhibited the vagally induced bradycardia. The vago-inhibition induced by quinpirole (which failed to affect the bradycardia to i.v. ACh) was unchanged after i.v. injections of the antagonists L-741,626 (D2; 100 µg/kg) or SB-277011-A (D3; 100 µg/kg), but it was abolished by L-745,870 (D4; 100 µg/kg). mRNA levels of D2, D3, and D4 receptor subtype were detected in the left and right rat atria. Our results suggest that the quinpirole-induced vagolytic effect involves prejunctional D4 receptor subtypes, located in the left and right atria. This provides new evidence on the relevance of D4 receptor modulating the heart parasympathetic control.

The activation of D2 and D3 receptor subtypes inhibits pathways mediating primary afferent depolarization (PAD) in the mouse spinal cord.

Somatosensory information can be modulated at the spinal cord level by primary afferent depolarization (PAD), known to produce presynaptic inhibition (PSI) by decreasing neurotransmitter release through the activation of presynaptic ionotropic receptors. Descending monoaminergic systems also modulate somatosensory processing. We investigated the role of D1-like and D2-like receptors on pathways mediating PAD in the hemisected spinal cord of neonatal mice. We recorded low-threshold evoked dorsal root potentials (DRPs) and population monosynaptic responses as extracellular field potentials (EFPs). We used a paired-pulse conditioning-test protocol to assess homosynaptic and heterosynaptic depression of evoked EFPs to discriminate between dopaminergic effects on afferent synaptic efficacy and/or on pathways mediating PAD, respectively. DA (10 µM) depressed low-threshold evoked DRPs by 43 %, with no effect on EFPs. These depressant effects on DRPs were mimicked by the D2-like receptor agonist quinpirole (35 %). Moreover, by using selective antagonists at D2-like receptors (encompassing the D2, D3, and D4 subtypes), we found that the D2 and D3 receptor subtypes participate in the quinpirole depressant inhibitory effects of pathways mediating PAD.

The locus of Action of CGRPergic Monoclonal Antibodies Against Migraine: Peripheral Over Central Mechanisms.

Migraine is a complex neurovascular disorder characterized by attacks of moderate to severe unilateral headache, accompanied by photophobia among other neurological signs. Although an arsenal of antimigraine agents is currently available in the market, not all patients respond to them. As Calcitonin Gene-Related Peptide (CGRP) plays a key role in the pathophysiology of migraine, CGRP receptor antagonists (gepants) have been developed. Unfortunately, further pharmaceutical development (for olcegepant and telcagepant) was interrupted due to pharmacokinetic issues observed during the Randomized Clinical Trials (RCT). On this basis, the use of monoclonal antibodies (mAbs; immunoglobulins) against CGRP or its receptor has recently emerged as a novel pharmacotherapy to treat migraines. RCT showed that these mAbs are effective against migraines producing fewer adverse events. Presently, the U.S. Food and Drug Administration approved four mAbs, namely: (i) erenumab; (ii) fremanezumab; (iii) galcanezumab; and (iv) eptinezumab. In general, specific antimigraine compounds exert their action in the trigeminovascular system, but the locus of action (peripheral vs. central) of the mAbs remains elusive. Since these mAbs have a molecular weight of ∼150 kDa, some studies rule out the relevance of their central actions as they seem unlikely to cross the Blood-Brain Barrier (BBB). Considering the therapeutic relevance of this new class of antimigraine compounds, the present review has attempted to summarize and discuss the current evidence on the probable sites of action of these mAbs.

Monoaminergic Receptors as Modulators of the Perivascular Sympathetic and Sensory CGRPergic Outflows.

Blood pressure is a highly controlled cardiovascular parameter that normally guarantees an adequate blood supply to all body tissues. This parameter is mainly regulated by peripheral vascular resistance and is maintained by local mediators (i.e., autacoids), and by the nervous and endocrine systems. Regarding the nervous system, blood pressure can be modulated at the central level by regulating the autonomic output. However, at peripheral level, there exists a modulation by activation of prejunctional monoaminergic receptors in autonomic- or sensory-perivascular fibers. These modulatory mechanisms on resistance blood vessels exert an effect on the release of neuroactive substances from the autonomic or sensory fibers that modify blood pressure. Certainly, resistance blood vessels are innervated by perivascular: (i) autonomic sympathetic fibers (producing vasoconstriction mainly by noradrenaline release); and (ii) peptidergic sensory fibers [producing vasodilatation mainly by calcitonin gene-related peptide (CGRP) release]. In the last years, by using pithed rats, several monoaminergic mechanisms for controlling both the sympathetic and sensory perivascular outflows have been elucidated. Additionally, several studies have shown the functions of many monoaminergic auto-receptors and hetero-receptors expressed on perivascular fibers that modulate neurotransmitter release. On this basis, the present review: (i) summarizes the modulation of the peripheral vascular tone by adrenergic, serotoninergic, dopaminergic, and histaminergic receptors on perivascular autonomic (sympathetic) and sensory fibers, and (ii) highlights that these monoaminergic receptors are potential therapeutic targets for the development of novel medications to treat cardiovascular diseases (with some of them explored in clinical trials or already in clinical use).

Activation of α-adrenoceptors depresses synaptic transmission of myelinated afferents and inhibits pathways mediating primary afferent depolarization (PAD) in the in vitro mouse spinal cord.

Somatosensory afferent transmission strength is controlled by several presynaptic mechanisms that reduce transmitter release at the spinal cord level. We focused this investigation on the role of α-adrenoceptors in modulating sensory transmission in low-threshold myelinated afferents and in pathways mediating primary afferent depolarization (PAD) of neonatal mouse spinal cord. We hypothesized that the activation of α-adrenoceptors depresses low threshold-evoked synaptic transmission and inhibits pathways mediating PAD. Extracellular field potentials (EFPs) recorded in the deep dorsal horn assessed adrenergic modulation of population monosynaptic transmission, while dorsal root potentials (DRPs) recorded at root entry zone assessed adrenergic modulation of PAD. We found that noradrenaline (NA) and the α1-adrenoceptor agonists phenylephrine and cirazoline depressed synaptic transmission (by 15, 14 and 22%, respectively). DRPs were also depressed by NA, phenylephrine and cirazoline (by 62, 30, and 64%, respectively), and by the α2-adrenoceptor agonist clonidine, although to a lower extent (20%). We conclude that NA depresses monosynaptic transmission of myelinated afferents onto deep dorsal horn neurons via α1-adrenoceptors and inhibits interneuronal pathways mediating PAD through the activation of α1- and α2-adrenoceptors. The functional significance of these modulatory actions in shaping cutaneous and muscle sensory information during motor behaviors requires further study.