Background:The G protein-coupled receptor 55 (GPR55) is a mammalian orphan receptor that awaits a formal classification. There are an increasing number of reports directed to know the physiology and pathophysiology of this receptor. Lamentably, its functions in the central nervous system (CNS) have been scarcely elucidated.Methods:A bibliographic search in PubMed database about GPR55 actions in the CNS was made. The information was grouped for brain structures to facilitate the interpretation. Finally, we constructed a schematic representation of the current knowledge about the potential participation of GPR55 in some physiological and pathophysiological events.Results:Seventy nine papers were included in the review. Only few of them showed data about GPR55 (mRNA/protein) expression in multiple brain areas. The rest showed findings in different preparations both in vitro and in vivo conditions that allowed us to speculate a potential activity of GPR55 in the different brain areas.Conclusion:GPR55 mRNA is expressed in several brain areas as the hippocampus, hypothalamus, frontal cortex and cerebellum; but due to the lack of information, only some speculative information about its function in these regions has been suggested. Therefore, this review provide relevant information to motivate further research about GPR55 physiology/pathophysiology in the CNS.

Migraine is a neurovascular disorder. Current acute specific antimigraine pharmacotherapies target trigeminovascular 5-HT, 5-HT and CGRP receptors but, unfortunately, they induce some cardiovascular and central side effects that lead to poor treatment adherence/compliance. Therefore, new antimigraine drugs are being explored. Areas covered: This review considers the adverse (or potential) side effects produced by current and prospective antimigraine drugs, including medication overuse headache (MOH) produced by ergots and triptans, the side effects observed in clinical trials for the new gepants and CGRP antibodies, and a section discussing the potential effects resulting from disruption of the cardiovascular CGRPergic neurotransmission. Expert opinion: The last decades have witnessed remarkable developments in antimigraine therapy, which includes acute (e.g. triptans) and prophylactic (e.g. β-adrenoceptor blockers) antimigraine drugs. Indeed, the triptans represent a considerable advance, but their side effects (including nausea, dizziness and coronary vasoconstriction) preclude some patients from using triptans. This has led to the development of the ditans (5-HT receptor agonists), the gepants (CGRP receptor antagonists) and the monoclonal antibodies against CGRP or its receptor. The latter drugs represent a new hope in the antimigraine armamentarium, but as CGRP plays a role in cardiovascular homeostasis, the potential for adverse cardiovascular side effects remains latent.

Background: Marijuana extracts (cannabinoids) have been used for several millennia for pain treatment. Regarding the site of action, cannabinoids are highly promiscuous molecules, but only two cannabinoid receptors (CB1 and CB2) have been deeply studied and classified. Thus, therapeutic actions, side effects and pharmacological targets for cannabinoids have been explained based on the pharmacology of cannabinoid CB1/CB2 receptors. However, the accumulation of confusing and sometimes contradictory results suggests the existence of other cannabinoid receptors. Different orphan proteins (e.g., GPR18, GPR55, GPR119, etc.) have been proposed as putative cannabinoid receptors. According to their expression, GPR18 and GPR55 could be involved in sensory transmission and pain integration.Methods: This article reviews select relevant information about the potential role of GPR18 and GPR55 in the pathophysiology of pain.Results: This work summarized novel data supporting that, besides cannabinoid CB1 and CB2 receptors, GPR18 and GPR55 may be useful for pain treatment.Conclusion: There is evidence to support an antinociceptive role for GPR18 and GPR55.

Calcitonin gene-related peptide (CGRP) released from perivascular sensory nerves plays a role in the regulation of vascular tone. Indeed, electrical stimulation of the perivascular sensory out-flow in pithed rats produces vasodepressor responses, which are mainly mediated by CGRP release. This study investigated the potential role of dopamine D 1 -like and D 2 -like receptors in the inhibition of these vasodepressor responses. For this purpose, male Wistar pithed rats (pre-treated i.v. with 25 mg/kg gallamine and 2 mg/kg min. hexamethonium) received i.v. continuous infusions of methoxamine (20 lg/kg min.) followed by physiological saline (0.02 ml/min.), the D 1 -like receptor agonist SKF-38393 (0.1-1 lg/kg min.) or the D 2 -like receptor agonist quinpirole (0.03-10 lg/kg min.). Under these conditions, electrical stimulation (0.56-5.6 Hz; 50 V and 2 ms) of the thoracic spinal cord (T 9 -T 12 ) resulted in frequency-dependent vasodepressor responses which were (i) unchanged during the infusions of saline or SKF-38393 and (ii) inhibited during the infusions of quinpirole (except at 0.03 lg/kg min.). Moreover, the inhibition induced by 0.1 lg/kg min. quinpirole (which failed to inhibit the vasodepressor responses elicited by i.v. bolus injections of exogenous a-CGRP; 0.1-1 lg/kg) was (i) unaltered after i.v. treatment with 1 ml/kg of either saline or 5% ascorbic acid and (ii) abolished after 300 lg/kg (i.v.) of the D 2 -like receptor antagonists haloperidol or raclopride. These doses of antagonists (enough to completely block D 2 -like receptors) essentially failed to modify per se the electrically induced vasodepressor responses. In conclusion, our results suggest that quinpirole-induced inhibition of the vasodepressor sensory CGRPergic out-flow is mainly mediated by pre-junctional D 2 -like receptors.It has been widely documented that dopamine regulates a broad range of physiological functions (including cardiovascular homeostasis), and it contributes to blood pressure control due to its peripheral action on the kidney, adrenal glands and vascular tone [1][2][3][4][5][6][7]. With the conjunction of structural, transductional and operational (pharmacological) criteria, dopamine receptors can be classified into Regarding resistance blood vessels, these are mainly innervated by sympathetic [8] and primary sensory [9] nerves which modulate the vascular tone. The perivascular sensory nerves are mainly C-fibres originating from the spinal cord and, upon stimulation, cause a non-adrenergic, non-cholinergic (NANC) vasodilatation via the release of neuropeptides, primarily calcitonin gene-related peptide (CGRP) [9]. CGRP is predominantly located in sensory neurons (including perivascular nerves), where it is colocalized with other neuropeptides, such as substance P and neurokinin A [10].Interestingly, Taguchi et al.[9] have shown that electrical stimulation of the thoracic (T 9 -T 12 ) spinal cord in pithed rats receiving i.v. infusions of hexamethonium and methoxamine caused vasodepressor responses, which are ma...

Olcegepant (i.v.) selectively blocked the neurogenic and non-neurogenic CGRPergic vasodepressor responses. This blockade by olcegepant potentiated the neurogenic and non-neurogenic noradrenergic vasopressor responses in pithed rats, an effect that might result in an increased vascular resistance and, consequently, in a prohypertensive action.