The Role of Adenosine Signaling in Headache a Review

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• Published: 05 April 2022

Interest of adenosine signaling pathway in migraine pathophysiology: a systematic review of preclinical studies

The Journal of Headache and Hurting volume 23, Commodity number:43 (2022) Cite this article

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Abstract

Background

Adenosine is a purinergic signaling molecule with a wide range of physiological functions including anti- and pronociceptive properties. Adenosine receptors are expressed in the trigeminovascular system, and adenosine receptor antagonist, caffeine, relieves migraine headache. We performed a systematic review of the literature of preclinical data addressing the part of adenosine in migraine pathophysiology.

Methods

PubMed and EMBASE were searched for pre-clinical studies on the office of adenosine in migraine pathophysiology on September 5^th, 2021.

Results

A total of 2510 studies were screened by title and abstract. Of these, thirteen pre-clinical studies evaluating adenosine, adenosine A1, A2A and A3 receptors were included.

These studies showed that adenosine signaling pathway is involved in controlling vascular tone. Furthermore, electric stimulation of the trigeminal ganglion modulates the expression of adenosine A_one and A_2A receptors in the trigeminal ganglion and trigeminal nucleus caudalis implicating adenosine signaling pathway in pain transmission.

Conclusion

Preclinical studies showed that adenosine has a dual effect on vasodilation and trigeminal pain pathway due to unlike receptor activation, suggesting a possible role of adenosine in migraine pathophysiology. Studies investigating pharmacological characteristics of subtypes of adenosine receptors are needed to farther elucidate their role as a potential target for migraine treatment.

Introduction

Adenosine, a vasoactive amine produced by the hydrolysis of adenosine monophosphate (AMP) or S-adenosylhomocysteine (SAH) [43], is involved in numerous physiological processes such as metabolism, inflammation, respiration and pain [39]. Adenosine binds to iv Thou-poly peptide coupled receptors (GPCR), A_i, A_2A, A_2B and A_3, with a unique contour of tissue distribution, signaling pathways and office (Tabular array 1 & Fig. ane) [20, 21]. Adenosine receptors activate the mitogen-activated poly peptide kinase (MAPK), leading to survival, jail cell growth, and differentiation [xx], and modulate the activeness of adenylate cyclase [eleven, 20], the enzyme that regulates intracellular concentration of cyclic adenosine monophosphate (army camp) [38]. Adenosine A₁ and A₃ receptors are coupled to a Gα_i subunit that downregulates camp by inhibiting adenylate cyclase [20, 38], while A_2A and A_2B receptors are coupled to a Gα_s subunit which stimulates adenylate cyclase to upregulate cAMP [twenty, 38]. A₁ and A₃ receptors are considered to have anti-nociceptive effects, whereas, activation of A_2A and A_2B receptors induces nociception [eleven]. Adenosine A_i receptors are expressed at the trigeminovascular system (TVS), including the trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC) [6, 32], which is considered to be the anatomical and physiological substrate of migraine hurting [two]. Stimulation of this receptor causes inhibition of the TVS by reducing neuronal firing from the trigeminal nucleus and decreasing the release of calcitonin gene-related peptide (CGRP) [6, xiii]. A_2A and A_2B receptors are located in vascular smooth muscle cells [20, 38] and in pre- and postsynaptic nerve terminals [38], and stimulation of these receptors causes dural vasodilation [16], leading to stimulation of the TVS. Collectively, adenosine signaling pathways are complex and might be involved in headache and migraine pathophysiology.

Table 1 Adenosine receptors and their functions

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Fig. 1

Adenosine signaling pathway. Adenosine binds to G-protein coupled receptors (GPCR) resulting in either activation (adenosine A_2A and A_2B receptors) or inactivation (adenosine A₁ and A₃ receptors) of adenylyl cyclase (Air-conditioning). Activation of Ac increases the formation of cyclic adenosine monophosphate (military camp) which binds to protein kinase A (PKA). Active PKA then phosphorylates and thereby modulates cellular responses. ATP: adenosine triphosphate

Full size paradigm

Here, we systematically review preclinical studies on the involvement of adenosine in trigeminal hurting pathway, to make the instance that adenosine signaling pathways may play a part in migraine and discuss adenosine receptors as potential target for hereafter treatment of migraine (Table 2).

Table 2 Molecules presented hither that target adenosine receptors. None are approved for handling

Total size table

Method

Information source

Nosotros conducted two searches on PubMed and Embase on September 5^th, 2021. Firstly, we searched "("adenosine"[MeSH Terms] OR "adenosine"[All Fields] OR "adenosin"[All Fields] OR "adenosine southward"[All Fields] OR "adenosines"[All Fields]) AND ("migrain"[All Fields] OR "migraine disorders"[MeSH Terms] OR ("migraine"[All Fields] AND "disorders"[All Fields]) OR "migraine disorders"[All Fields] OR "migraine"[All Fields] OR "migraines"[All Fields] OR "migraine southward"[All Fields] OR "migraineous"[All Fields] OR "migrainers"[All Fields] OR "migrainous"[All Fields])". Secondly, nosotros searched for "("adenosine"[MeSH Terms] OR "adenosine"[All Fields] OR "adenosin"[All Fields] OR "adenosine s"[All Fields] OR "adenosines"[All Fields]) AND ("headache"[MeSH Terms] OR "headache"[All Fields] OR "headaches"[All Fields] OR "headache southward"[All Fields])". Both searches were restricted to English language.

Pick criteria and study inclusion

Studies were restricted to pre-clinical or clinical studies that investigated adenosine, adenosine agonist, adenosine adversary, adenosine deaminase, adenosine deaminase inhibitor and adenosine reuptake inhibitors in headache and migraine pathophysiology. We excluded reviews, meta-analysis, briefing proceedings and case reports.

Two investigators (J.T. and 50.Thousand.) screened all studies past title and abstract, followed by full text screening to confirm eligibility. References of the included studies were screened to discover studies that were missed past the search. For each included study, both investigators (J.T. and Fifty.K.) extracted hypothesis or purpose of the study, method, sample size, principal consequence, determination, and limitations. Whatever disagreements were resolved through discussion by the two investigators (J.T. and L.K.). If the conflict remained, a third investigator (K.M.K) made the final conclusion.

Results

The database search identified 3209 citations of which 701 were duplicates (Fig. ii). An additional two studies were included through a manual search of identified primary articles. A total of 2510 studies were screened by title and abstruse and 44 were full text screened. Of these, 20 studies were included – 13 preclinical (Table 3) and vii clinical studies. Data for clinical studies has been published recently [45].

Fig. 2

Flow chart of search strategy

Total size image

Table 3 Summary of preclinical studies

Total size table

Narrative summaries

Arulmani et al. [1]. In pigs, intravenous infusion of adenosine A_one receptor agonist, GR79236, was compared to vehicle prior to capsaicin infusion. Total carotid blood menstruum, conductance, and plasma CGRP concentrations in jugular vein were assessed at baseline and after the infusions. GR79236 dose-dependently adulterate the capsaicin-induced carotid hemodynamic changes but not the CGRP release, compared to vehicle infusion.

Carruthers et al. [6]. In rats, adenosine agonists and antagonist (A₁ receptor agonist GR79236X, adenosine A₁ receptor antagonist, DPCPX, adenosine A_2A agonist, CGS21680, and A_three receptor agonist, 2-CI-IB-MECA) were applied to cultured trigeminal neurons in combination with forskolin or vehicle to induce release CGRP. Immunocytochemical studies and Western analysis assessed whether these pharmacological agents could modulate the forskolin induced CGRP release. GR79236X concentration-dependently inhibited forskolin-stimulated CGRP release, while DPCPX abolished GR79236X´s event. CGS21680 and two-CI-IB-MECA were unable to attenuate forskolin-induced CGRP secretion.

Faraci et al. [9]. Intravenous infusion of adenosine was administered to anesthetized dogs. Claret flow was measured with labelled, radioactive microspheres. Adenosine decreased aortic pressure forth with claret menstruum and vascular resistance in the dura. Adenosine infusion did not alter cerebral blood period.

Goadsby et al. [13]. Intravenous infusion of adenosine A₁ receptor agonists were administered in anesthetized dogs, following electrical stimulation of the superior sagittal sinus (SSS). Jugular vein blood samples were taken at baseline, immediately afterwards the SSS stimulation and post-obit the A₁ agonist infusion, for detection of CGRP levels. Both A₁ receptor agonists, GR79236 and GR190178, inhibited SSS-induced activation in TNC and CGRP release in cranial circulation, in a dose-dependent style. Moreover, adenosine A_one receptor antagonist, DPCPX, was able to reverse GR79236's inhibitory result on TNC activation.

Haanes et al. [xv]. Adenosine was applied to pre-contracted middle meningeal avenue (MMA) segments isolated from rats. RT-PCR was used to narrate the expression of purinergic receptor and myography to access the vascular effects. Notably, all purinergic receptor mRNAs were detected in the trigeminal ganglion and MMA. Adenosine caused dilation of MMA, which was reversed by SCH58261 (A_2A receptor antagonist) and caffeine (adenosine receptor antagonist).

Haanes et al. [16]. Adenosine and caffeine were administered intravenously to half dozen rats. Adenosine resulted in dural vasodilation and subtract in blood pressure. However, pre-handling with caffeine inhibited adenosine´southward effect. Caffeine caused an increase in claret pressure level and a not-meaning dilation of dural arteries. Secondly, intravenous infusions of dissimilar adenosine A_2A receptor antagonists (JNJ compounds) were given following intravenous administration of adenosine A_2A receptor agonist, CGS21680, or periarterial electric stimulation (mode of CGRP-release), in rats. The closed cranial window was used to evaluate the antagonists´ effect on the CGS21680 and CGRP -induced dural dilation. CGS21680 caused vasodilation and decrease in arterial blood pressure level. All A_2A receptor antagonists blocked CGS21680-induced dural vasodilation with a more potent respond with A_2A over A₁ selectivity, while they did not impact electrical stimulated neurogenic vasodilation.

Hardebo et al. [17]. Adenosine, cAMP, ADP and ATP were practical in segments of middle cerebral avenue and extracranial arteries of feline and humans. The dissected vessels were pre-constricted by prostaglandin F_2a (PGF_2a) or 5-hydroxytryptamine (v-HT). The tension was measured with force deportation transducers and recorded on a Grass polygraph. All adenine compounds dilated feline pial arteries, all the same the dilatory response was less pronounced when extracellular K⁺ concentration increased. Adenine compounds did non influence the diameter of human and feline extracranial arteries.

Honey et al. [19]. In rats, intravenous infusion of adenosine A₁-receptor agonist, GR79236, was compared to saline infusion in models of neurogenic dural vasodilation. Vasodilation was induced by either electrical stimulation of perivascular trigeminal fretfulness or intravenous CGRP. Cranial window was used to evaluate the vascular responses. GR79236 inhibited electrically induced neurogenic vasodilation in a dose-dependent mode but had no effect on vasodilation acquired by CGRP. Selective A_ane receptor antagonist, DPCPX, inhibited the effect of GR79236 on electrically evoked vasodilation, compared to vehicle.

Jenkins et al. [22]. Adenosine deaminase was applied in cultured rat trigeminal neurons. Application of prostaglandin Due east₂ (PGE_two) led to CGRP release from the cultured cells. Adenosine deaminase did not alter baseline or PGE2-evoked CGRP levels.

Lindquist et al. [31]. Accumulation of adenosine post-obit spreading depolarization (SD) was investigated in brain slices of mice and in vivo. Amperometric recordings from adenosine-sensitive enzyme-linked electrochemical were made in brain slices and applied in vivo. SD generated transient adenosine aggregating in vivo which could reliably report underlying metabolic status in encephalon slices.

Lu et al. [32]. Εlectrical stimulation of the trigeminal ganglion (ESTG) or sham operation was performed in rats to investigate its upshot on CGRP, adenosine A_one receptor and adenosine A_2A receptor expression. RT-qPCR and Western analysis was used for detection and quantification of the proteins. In the trigeminal nucleus caudalis (TNC) and ipsilateral trigeminal ganglion (TG), CGRP and A_2A expression increased post-obit ESTG, while A₁ decreased. Interestingly, pretreatment with hinese medicine Tianshu capsule (TSC) decreased CGRP and A_2A expression and increased A₁ receptor expression.

Wei et al. [46]. In cats, the event of topical application of adenosine and adenosine diphosphate was investigated before and post-obit application of CGRP receptor antagonist, CGRP8-37. Cranial window was used to evaluate the vascular responses. CGRP8-37 was non able to reverse vasodilating issue of adenosine and adenosine diphosphate. Moreover, guanylate cyclase inhibitor, LY83583, had no result on adenosine-induced vasodilation.

Yegutkin et al. [48]. The furnishings of adenine nucleotides were assessed in meninges of rats and cultured trigeminal cells following application of CGRP or placebo. Bioluminescent and fluorometric techniques were used to measure out purine levels in trigeminal ganglion cells, and electrophysiology to tape the nociceptive spikes in the meningeal trigeminal nerves, before and after pre-treatment with CGRP. CGRP decreased adenosine levels in cultured cells but not in the meninges, while adenosine was not able to activate nociceptive firing in the meningeal nerves. Moreover, basal levels of adenosine and AMP where higher compared to ATP and ADP in trigeminal cells.

Discussion

The main findings of the present systematic review are that adenosine receptors attune pain manual through the TVS. While A_i receptor has an inhibitory effect, stimulation of A_2A receptor causes vasodilation and activation of trigeminal pain pathway.

In rats, electrical stimulation of the TG decreased adenosine A₁ receptor expression and increased adenosine A_2A receptor expression in ipsilateral TG and TNC [32]. The sometime is suggested to be involved in migraine assail initiation, while upregulation of adenosine A₁ receptors or activation of this receptor might block migraine attacks [32]. In back up, ane study found that treatment with adenosine A₁ receptor agonists, GR79236 and GR190178, inhibited TVS activation after electrical stimulation of the superior sagittal sinus in cats [13]. Upregulation of both adenosine A_2A and CGRP receptors following electrical stimulation implies that when combined, the 2 receptors activate trigeminal pain transmission and cause migraine [32]. Overall, these findings implicate both adenosine A₁ and A_2A receptors in pain regulation and manual during migraine [xiii, 32].

Iii studies showed that adenosine caused prominent dilation of pre-contracted middle meningeal artery, dural and pial arteries in vitro [15,16,17]. Another report showed that adenosine caused dural vasodilation in dogs [9]. Pretreatment with caffeine or adenosine A_2A receptor antagonist, SCH58261, was able to block adenosine-induced dilation in vitro [15, 16], suggesting that adenosine-induced vasodilation might exist mainly dependent on adenosine A_2A receptor [15].

Adenosine A_ane receptor agonist, GR79236, inhibited electrically-induced vasodilation and capsaicin-induced hemodynamic changes in carotid artery [1, 19]. Pretreatment with DPCPX prevented the inhibition following GR79236, indicating that its inhibitory or vasoconstricting result is mediated through adenosine A₁ receptor [19]. The same agonist, GR79236, inhibited CGRP release induced past adenylate cyclase activator, forskolin [half-dozen] without whatsoever outcome on CGRP-induced vasodilation in rats [xix]. These data point that GR79236 inhibits CGRP release via a pre-junctional inhibition, and that adenosine A₁ receptors are present on CGRP-positive neurons [6, xiii, 19]. Together with its vasoconstricting ability, information technology is suggested that GR79236 and adenosine A_ane receptors concur anti-migraine potential [1, 6, 19].

In contrast to GR79236, adenosine A_2A receptor agonist, CGS21680, had no effect on forskolin-induced CGRP release [6]. However, CGS21680 caused dural vasodilation that was blocked by adenosine A_2A receptor antagonists (JNJ-compounds) [16]. The report showed that the lower the selectivity for A_2A receptor over A₁ receptors, the higher the potential to attenuate the CGS21680 induced vasodilation. Information technology was suggested that blocking both A₁ and A_2A receptors might be necessary to completely attenuate dural vasodilation [16].

Of note, ii-CI-IB-MECA, an adenosine A₃ receptor agonist, had no issue on forskolin-induced CGRP secretion in rats [six]. The interest of adenosine A_three receptor in migraine has not been further investigated, nonetheless, adenosine A₃ receptor agonist exhibited anti-nociceptive properties in models of chronic pain in rats and mice [24].

While CGRP antagonist, CGRP(8–37), and guanylate cyclase inhibitor, LY83583, inhibited CGRP and nitroglycerine induced vasodilation, both compounds did not alter adenosine-induced vasodilation [46]. This finding demonstrates that adenosine induced dilation is not dependent on activation of CGRP receptors or an increment in cyclic guanosine monophosphate. Another written report showed that pretreatment of trigeminal ganglion cells with CGRP is followed past decreased adenosine levels compared to baseline [48]. Information technology is suggested that the finding might exist a office of migraine sensitization but due to other contradicting findings (i.e., no change in nociceptive firing), further investigation on adenosine's mechanisms was recommended [48].

Collectively, studies showed adenosine receptors expression in the trigeminal pain pathway and indicated that adenosine-induced pronociceptive effect is mediated through A_2A receptor activation, whilst A₁ receptor mediates antinociception. A₁ receptor agonist, GR79236, inhibits activation of the TVS and vasodilation, while A_2A receptor antagonist, SCH58261, attenuated adenosine-induced vasodilation [13, 15, 19], designating adenosine A₁ and A_2A receptors every bit possible targets in the treatment of migraine.

Limitations and time to come perspective

The major limitations of the studies included, were differences in methodological approaches including designs, subjects, substances, and sampling sources. Additionally, concentrations and types of adenosine A_i receptor agonists practical, differed across the studies [half dozen, xiii, 19]. Different CGRP releasing mechanisms were applied throughout the studies, potentially affecting the authorisation of adenosine receptor agonists and antagonists in modulating the CGRP release [1, 6, 13, 22].

Homo studies are needed to elucidate the headache inducing effect of adenosine in patients with migraine. A specific focus on adenosine A₁ receptor agonists and A_2A receptors antagonists would be of dandy interest considering of their potentially opposite furnishings based on current knowledge. Several adenosine receptor agonists and antagonist are currently available for research purpose merely, while only one adenosine receptor antagonist, istradefylline, is currently U.S. Food and Drug Administration (FDA) approved as treatment for Parkinson'due south disease (JF and RA 2020). To our best knowledge, no studies accept been conducted on the adenosine A_2B receptor in migraine and adenosine A₃ has just once been investigated in migraine [6]. This leaves a huge gap in our cognition that needs to be explored in both clinical and pre-clinical setting.

Conclusion

Preclinical data demonstrated that adenosine caused vasodilation and modulated CGRP release. We suggest that the adenosine A₁ receptor and adenosine A_2A receptor could exist potential targets for migraine treatment.

Availability of information and materials

Not applicable.

Abbreviations

A_aneR:

A_i receptor

A_2AR:

A_2A receptor

AC:

Adenylyl cyclase

AMP:

Adenosine monophosphate

ADP:

Adenosine five'-diphosphate

ATP:

Adenosine triphosphate

cAMP:

Cyclic adenosine monophosphate

CGRP:

Calcitonin gene related peptide

DAG:

Diacylglycerol

ES:

Electrical stimulation

ESTG:

Electrical stimulation of the trigeminal ganglion

FDA:

U.S. Food and Drug Administration

GPCR:

G-protein coupled receptors

ICHD:

International Nomenclature of Headache Disorders

IP_three :

Inositol one,4,5-triphosphate

MAPK:

Mitogen-activated protein kinase

MMA:

Meningeal media avenue

MO:

Migraine without aura

mRNA:

Messenger RNA

NR:

Not reported

PKA:

Protein kinase A

PCR:

Polymerase chain reaction

PGE₂ :

Prostaglandin Eastward₂

PGF_2a :

Prostaglandin F_2a

PIP₂ :

Phosphatidylinositol iv,five-biphosphate

PLC:

Phospholipase C

PLD:

Phospholipase D

SAH:

S-adenosylhomocysteine

SD:

Spreading depression

TG:

Trigeminal ganglion

TNC:

Trigeminal nucleus caudalis

TSC:

Tianshu capsule

TVS:

Trigeminovascular organisation

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Acknowledgements

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Funding

1000.A. was supported past the Lundbeck Foundation Professor Grant (R310-2018–3711).

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Affiliations

1. Danish Headache Center, Department of Neurology, Faculty of Health and Medical Sciences, Rigshospitalet – Glostrup, University of Copenhagen, Valdemar Hansen Vej 5, 2600, Glostrup, Kingdom of denmark

   Janu Thuraiaiyah, Lili Kokoti, Mohammad Al-Mahdi Al-Karagholi & Messoud Ashina

2. Danish Headache Knowledge Eye, Rigshospitalet – Glostrup, Valdemar Hansens Vej 5, 2600, Glostrup, Denmark

   Messoud Ashina

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JT did the search, screening of articles, data extraction and drafted showtime manuscript. LK did the screening of articles and data extraction. MMK and MA initiated, designed, supervised, and revised the paper. All authors reviewed and approved the final version.

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Correspondence to Messoud Ashina.

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JT, LK and MMK report no conflict of interest. MA has received consulting fees and honoraria for lectures/presentations from AbbVie, Allergan, Amgen, Eli Lily, Lundbeck, Novartis and Teva. MA has as well received personal payments for participating on data Condom Monitoring Board or Advisory Board for AbbVie, Amgen, Eli Lily, Lundbeck and Novartis.

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Thuraiaiyah, J., Kokoti, L., Al-Karagholi, M.AM. et al. Involvement of adenosine signaling pathway in migraine pathophysiology: a systematic review of preclinical studies. J Headache Hurting 23, 43 (2022). https://doi.org/10.1186/s10194-022-01412-0

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• Received: 29 Nov 2021

• Accepted: x March 2022

• Published: 05 April 2022

• DOI : https://doi.org/ten.1186/s10194-022-01412-0

Keywords

• Headache
• Adenosine receptor
• Pre-clinical
• Hurting

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