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Abstract

Objective

To systematically review clinical studies investigating the involvement of adenosine and its receptors in migraine pathophysiology.

Background

Adenosine is a purinergic signaling molecule, clinically used in cardiac imaging during stress tests. Headache is a frequent adverse event after intravenous adenosine administration. Migraine headache relief is reported after intake of adenosine receptor antagonist, caffeine. These findings suggest a possible involvement of adenosine signaling in migraine pathophysiology and its potential as a drug target.

Methods

A search through PubMed and EMBASE was undertaken for clinical studies investigating the role of adenosine and its receptors in migraine, published until September 2021.

Results

A total of 2510 studies were screened by title and abstract. Of these, seven clinical studies were included. The main findings were that adenosine infusion induced headache, and plasma adenosine levels were elevated during ictal compared to interictal periods in migraine patients.

Conclusion

The present systematic review emphasizes a potentially important role of adenosine signaling in migraine pathogenesis. Further randomized and placebo-controlled clinical investigations applying adenosine receptors modulators in migraine patients are needed to further understand the adenosine involvement in migraine.

Keywords

Headache migraine adenosine receptor humans

Introduction

Signaling pathways underlying migraine pathophysiology are complex and may include interplay between several vasoactive amines and peptides released in the trigeminovascular system (1). Adenosine, a by-product of hydrolysis of adenosine monophosphate (AMP) or S-adenosylhomocysteine (SAH) (2), is a vasoactive amine involved in inflammatory response and metabolic stress including hypoxia and ischemic damage (2). Adenosine binds to four G-protein coupled receptors (A₁, A_2A, A_2B and A₃ receptors) with a unique profile of tissue distribution, signaling pathways (Figure 1 and 2) and function (Table 1) (3,4). Due to functional diversity, adenosine receptors are therapeutic targets for a wide spectrum of disorders including inflammatory diseases, cancer, myocardial perfusions scintigraphy (3 –5) and for termination of paroxysmal supraventricular arrythmias (5). The most common adverse reaction related to adenosine administration is headache (6 –8). Similar adverse events were reported upon administration of adenosine reuptake and deaminase inhibitors (9 –12). In addition, adenosine receptor antagonist, caffeine, is known to relieve headache (9,13), and is a useful monotherapy against some headache types (14). These observations and the finding that serum adenosine level is elevated during migraine attacks (15,16) indicate a possible implication of adenosine and its receptors in migraine pathophysiology. In this systematic review, we present clinical studies on the role of adenosine signaling pathway in headache and migraine and discuss whether targeting adenosine may represent a novel strategy for the treatment of migraine.

Figure 1.

Adenosine signaling pathway through protein kinase A.

Figure 2.

Adenosine signaling pathway through protein kinase C.

Table 1.

Adenosine receptors and their functions.

Receptor	Subunit	Signaling pathway
Adenosine A₁ receptor	Gα_i-subunit	Inhibits adenylate cyclase and decreases cAMP formation (4,5), leading to activation of KATP channels (44 –47) and inactivation of BKCa channels (48).
Adenosine A₁ receptor	G_βγ subunits	Activates PLC and upregulates IP₃ (4,5).
Adenosine A_2A receptor	Gα_s-subunit	Activates adenylate cyclase and increases cAMP formation (4,5), leading to activation of K_ATP channels (49).
Adenosine A_2A receptor	Pertussis toxin insensitive Gα15 and Gα16 proteins	Activates PLC and upregulates IP₃ (4).
Adenosine A_2B receptor	Gα_s-subunit	Activates adenylate cyclase and increases cAMP formation (5), leading to activation of K_ATP channels (49).
Adenosine A_2B receptor	G_q subunit	Activates PLC and upregulates IP₃ (5).
Adenosine A₃ receptor	Gα_i -subunit	Inhibits adenylate cyclase and decreases cAMP formation (4,9).
Adenosine A₃ receptor	G_βγ subunits	Activates PLC and PLD (5).
All		Modulates MAPK (4).

cAMP, cyclic adenosine monophosphate; IP₃, inositol 1,4,5-triphosphate; MAPK, mitogen-activated protein kinase; PLC, phospholipase C; PLD, phospholipase D.

Table 2.

Presented molecules targeting adenosine receptors. Only caffeine is currently approved for treatment.

Name	Target	Clinical use
Adenosine receptor agonists
GR190178	Low efficacy (partial) adenosine A₁ receptor agonist (35)	Cluster headache (35).
GR79236	Highly potent and selective adenosine A₁ receptor agonist (18)	Ischemic heart disease (50,51), sleep apnea (52), modulation of lipolysis and insulin sensitivity (53).
Adenosine receptor antagonists
Caffeine	Non-selective adenosine A₁ and A_2A antagonist (31)	Pain management, headache treatment, apnea in premature children and neurodegenerative diseases (32)
CSC	Adenosine A_2A receptor antagonist (16)	Ischemic heart disease (54), Parkinson’s disease (55,56) and epilepsy (57)
SCH58261	Potent and highly selective A_2A receptor antagonist (38)	Spinal cord injury (58), epilepsy (57) and preeclampsia (59).

Method

Data source

We searched PubMed and Embase for clinical articles on adenosine in relation to headache and migraine. The search was conducted on 5 September 2021. The first search string was “(“adenosine”[MeSH Terms] OR “adenosine”[All Fields] OR “adenosin”[All Fields] OR “adenosine s”[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 s”[All Fields] OR “migraineous”[All Fields] OR “migrainers”[All Fields] OR “migrainous”[All Fields])”. The second search string was “(“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 s”[All Fields])”.

Selection criteria and study inclusion

Articles were restricted to English language and screened by two investigators (J.T. and L.K.) independently, first by title and abstract and then full text to confirm eligibility for this review. References of the included studies were screened to include studies missed by the search. Any disagreements were resolved through discussion by the two investigators (J.T. and L.K.). If the conflict remained, a third investigator (M.M.K) made the final decision. We included clinical studies investigating the involvement of adenosine, adenosine agonist, adenosine antagonist, adenosine deaminase, adenosine deaminase inhibitor and adenosine reuptake inhibitors in headache and migraine pathophysiology. We excluded reviews, meta-analysis, conference proceedings and case reports. For each included study, aim, method, main outcome, conclusion, and limitations were extracted by two investigators (J.T. and L.K.)

Results

The database search identified 3209 citations of which 701 were duplicates (Figure 3). An additional two studies were included through a manual search of identified primary articles. A total of 2510 studies were screened by title and abstract. Of these, 20 studies were included: 13 preclinical studies and 7 clinical studies (Table 3). Pre-clinical findings are reported in a separate article.

Figure 3.

Flow chart of search strategy.

Table 3.

Summary of the clinical studies.

Author	Hypothesis/purpose of the study	Study design	Sample size	Method	Main outcomes	Conclusion	Limitation
Adenosine
Guieu et al. (15)	To measure the variations of blood adenosine levels in the course of a migraine crisis.	Case-control study	10 migraine patients +8 healthy subjects	Venous blood sampling twice - one was taken 1 hour after headache onset and before any treatment. Second was taken at least 72 hours after a crisis period.	Adenosine levels:Interictally: no significant difference between patients and controls. Ictally: significantly increased compared to interictally.	It is probable that excess adenosine participates in maintaining the headache as a result of its vasodilating effects and could partially explain the beneficial effect of caffeine in the treatment of migraine.	1. The origin of the adenosine thus released during the common migraine crisis is difficult to define 2. Considerable interindividual variations in the measured levelsin the different groups.
Guieu et al. (16)	1) To measure the level of circulating adenosine in patients suffering from migraine without aura during crisis and in migraine-free periods, and to compare the data with controls. 2) Examine the effect of adenosine and antagonists on the calcium-dependence uptake and the release of (14C) serotonin by platelets.	Observational, parallel-group, cross sectional study	12 migraine patients (MO) + 10 healthy subjects	Venous blood sampling three times - 1 hour after headache onset and before any treatment, 72 h after the end of the attacks and during a crisis free period. Serotonin incorporation into platelet rich plasma was investigated in vitro.	1) Adenosine levels: Interictally: No significant difference between patients and controls. Ictally: Significantly increased compared to interictally. 2) When adenosine concentration was less than or equal to 0.5 µM, serotonin incorporation by platelets were significantly lower in patients than in controls. 3) Adenosine inhibited serotonin uptake by platelets in both migraine patients and in controls. 4) In the presence of both adenosine and an A₂ receptor blocker, CSC: Serotonin uptake by platelets did not differ from spontaneous levels in both patients and in controls.	Inhibition of (serotonin) uptake could participate in the rapid elimination of serotonin in migraine suffers. As a result of this, the use of A₂ adenosine antagonists could be an effective complementary treatment for migraine.	Not reported
Birk et al. (17)	To investigate the effect of two different doses of infused adenosine on headache and MCA caliber changes in healthy subjects.	Randomized, double-blind, placebo-controlled, three-way, cross-over study	12 healthy subjects	Infusion of placebo, 80µg/kg/min adenosine and 120 µg/kg/min adenosine for 20 min each intravenously in randomized order on the same day. Measurements were done at baseline and until 60 min. after each dose.	Headache induction:Placebo: No one experienced headache.80 µg/kg/min: sixexperienced immediate headaches. 120 µg/kg/min: six experienced immediate headaches, and six experience delayed headache.Cerebral blood flow: No changes in rCBF or V_MCA were found between treatments, but the superficial temporal artery was seen dilated.	Circulating adenosine has no effect on rCBF or V_MCA, while it dilates the STA and causes very mild headache. It is likewise possible that adenosine released from perivascular nerve terminals or from the brain itself may cause headache.	Lack of a control group
Adenosine agonist
Giffin et al. (18)	To assess the response of GR79236 on human trigeminal nociception as measured by the blink reflex.	Randomized, double-blind, placebo-controlled, cross-over study	12 healthy, female subjects	Blink reflexes were elicited with SE and NE before and 30 min after intravenous infusion or GR79236 (10 µg/kg) or placebo.	Comparison of the two treatment groups demonstrated a greater reduction of the R2 response after GR79236 compared with placebo.	Adenosine A₁-receptor agonists, such as GR79236, inhibit trigeminal nociceptive pathways in humans as well as in animals. By inhibiting trigeminal nociception, adenosine A₁-receptor agonists may be effective as novel therapeutic agents in migraine and other primary headache disorders.	Too small of a sample size
Adenosine reuptake inhibitor, dipyridamole
Hawkes et al. (19)	Platelet aggregability is abnormal in patients with migraine, either chronically or in relation to an attack.	Randomized, double-blind, placebo-controlled, cross-over study	9 migraine patients	Dipyridamole (100 mg x 4 daily) or placebo (lactose pill) were given for 12 weeks.	Trial was abandoned due to: 1) One patient defaulted.2) Four patients experienced more severe headaches compared to previously within the first four days of treatment.3) Two patients abandoned dipyridamole within the first 5 weeks and one at 10 weeks because of increased headache intensity. 4) An unknown number of patients completed the study but reported a doubling in headache frequency. 5) Only four patients took the placebo, and none reported any adverse effects.	Dipyridamole is being tested in cardiac and cerebral ischemia, so investigators should be alert to the aggravation of pre-existing migraine.	Not reported
Kruuse et al. (20)	To examine the effects of dipyridamole on regional cerebral blood flow (rCBF) in the middle cerebral artery territory (rCBF_MCA) by 133-Xenon single photon emission computed tomography and the effects on mean blood flow velocity in the middle cerebral artery (V_MCA) and furthermore, to quantify, characterize, and time any headache caused by dipyridamole, and relate it to the observed hemodynamic changes.	Single-blinded, placebo-controlled study	12 healthy subjects	4 min infusion of placebo followed y 4-min infusion of dipyridamole (0.142 mg/kg/min).	Induction of headache: 1) Eight reported mild to severe headache after dipyridamole of which one subject fulfilled the migraine criteria.2) Five reported a second delayed headache.3) Four reported a mild headache after placebo. Cerebral flow: 1) No significant change over time compared with baseline in rCBF_MCA or global CBF when values were corrected for the change in pC0₂ induced by dipyridamole. 2) V_MCA decreased significantly after start of dipyridamole infusion and remained decreased until at least 1 hour after endof infusion.	Dipyridamole causes a modest pCO₂ independent dilatation of the MCA, which is time-linked to the onset, but not to the cessation, of headache.	Subjects’ knowledge of active treatment
Kruuse et al. (12)	To test the hypothesis that dipyridamole is able to induce symptoms of migraine in migraine patients and headache in healthy subjects.	Single-blind study	10 migraine patients (MO) + 10 healthy subjects	4 min infusion of dipyridamole (0.142 mg/kg/min).	Induction of headache: 1) Headache was induced in all migraine patients and in eight of 10 healthy subjects. 2) Headache in five patients and one healthy subject fulfilled the ICHD-criteria for migraine without aura within 12 h. Blood flow: 1) No significant side difference in V_MCA.2) No overall differences in systolic and diastolic blood pressure or mean blood pressure.	Dipyridamole is a less potent migraine-inducing compound than GTN or sildenafil. The dual actions of dipyridamole may explain this difference in migraine frequency since the cGMP effects through PDE5 inhibition may be counteracted by the adenosine effects on A₁ receptors.	1) Dipyridamole was not as potent as other cGMP elevating compounds. 2) Environmental factors affecting the subjects after discharge might also influence the induction of delayed headache.

CBF, cerebral blood flow; cGMP, cyclic guanosine monophosphate; GTN, glyceryl trinitrate; ICHD, International Classification of Headache Disorders; MCA, middle cerebral artery; MO, migraine without aura; PDE5, phosphodiesterase type 5; SE, standard electrode; NE, nociception-specific electrode; rCBF, regional cerebral blood flow; STA, superficial temporal artery; V_MCA, velocity in the middle cerebral artery.

Narrative Summary

Guieu et al. (15) assessed levels of circulating adenosine in migraine patients and healthy participants. Blood samples were drawn within 1 hour of migraine attack onset and 72 hours following a migraine attack. Adenosine was significantly increased ictally compared to interictally in migraine patients, while no difference was reported between migraine patients (interictally) and healthy controls.

Guieu et al. (16) investigated a possible interaction between adenosine and serotonin in migraine patients and healthy participants. The effect of adenosine and adenosine agonists on the uptake and release of serotonin were assessed in platelet-rich plasma solutions in vitro. Adenosine A₂ receptor agonist led to a dose-dependent inhibition of serotonin uptake by platelets in both migraine patients and healthy controls. Furthermore, adenosine was elevated ictally compared to interictally in migraine patients, while no difference was reported between migraine patients (interictally) and healthy controls.

Birk et al. (17) compared intravenous infusion of adenosine over 20 minutes to saline in healthy participants. Single-photon emission computed tomography (SPECT) and transcranial doppler were used to measure regional cerebral blood flow (rCBF) and velocity in the middle cerebral artery (V_MCA), respectively. Headache was rated on a verbal scale (1 –10). Headache induction and dilation of the superficial temporal artery (STA) was significantly higher after adenosine infusion compared to saline. No difference was observed on rCBF and V_MCA between the two study days.

Giffin et al. (18) compared intravenous infusion of adenosine A₁-receptor agonist, GR79236 (Table 2), to placebo in healthy female volunteers. Blink reflexes were elicited with standard (SE) and nociception specific electrodes (NE) before and 30 minutes after the infusion (GR79236 or placebo) to evaluate trigeminal nociception. GR79236 partially attenuated the blink reflex when meased by NE. The reduction was significant contralaterally but not ipsilaterally.

Hawkes et al. (19) compared the effect of daily dipyridamole to placebo in migraine patients over 12 weeks. The trial was abandoned, as patients on dipyridamole experienced severe headaches, while no patient on placebo reported any adverse event.

Kruuse et al. (20) compared intravenous infusion of dipyridamole over four minutes to saline in healthy subjects. SPECT and transcranial doppler were used to measure cerebral blood flow and V_MCA respectively. Headache was rated on a verbal scale (1 –10). Dipyridamole infusion decreased V_MCA significantly and caused more headache compared to placebo infusion. No difference was observed in global and region cerebral blood flow between the two study arms.

Kruuse et al. (12) used intravenous infusion of dipyridamole over four minutes in migraine patients and healthy subjects. Transcranial doppler was used to measure V_MCA. Headache was rated on a verbal scale (1 –10). There was no difference in headache and migraine induction rate between the two study groups. V_MCA decreased significantly following dipyridamole infusion and no difference was observed between healthy participants and migraine patients.

Discussion

The present systematic review implicates adenosine and its signaling pathways in the pathophysiology of headache and migraine (Table 3).

Adenosine

Increased adenosine levels during a migraine attack compared to interictally, and to healthy participants suggest that adenosine is involved in triggering and maintaining migraine headache due to its vasodilating properties (15,16). Adenosine levels did not differ between migraine patients interictally compared to healthy volunteers, suggesting that the increase seen during an attack was related to migraine attack as seen with other substances (15,16). It is hypothesized that adenosine is a bi-product to an increase in adenosine triphosphate (ATP) levels during the first few hours of an attack (21). Another explanation is that increased adenosine levels were due to a possible hypoperfusion (16). Finally, it has been proposed that mitochondrial dysfunction causes an increase in extracellular adenosine in migraine patients, which activates AMP-activated protein kinase that affects pain processing (9). It has been difficult to define the origin of adenosine released during an attack (15), and it remains unclear whether the increase appears prior to the headache or secondarily to the migraine attack (16).

Considerable interindividual variations in adenosine levels were reported, possibly due to changes related to circadian rhythm (15,22).

Dipyridamole

Three studies included in the current review concern dipyridamole (12,19,20). Dipyridamole is an adenosine reuptake inhibitor causing accumulation of adenosine. Furthermore, dipyridamole is a phosphodiesterase inhibitor that increases cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP) (23). Clinical studies have shown that substances (e.g. calcitonin gene related peptide, pituitary adenylate cyclase-activation peptide and glyceryl trinitrate) that increase cAMP and cGMP have the potential to induce migraine in migraine patients, implicating them in migraine pathophysiology (1). Presented data suggest that dipyridamole causes headache in healthy volunteers and migraine in patients with migraine (12,19,20). At present, it is unknown whether the headache and migraine induction is a direct result of adenosine elevation, or cAMP and cGMP elevation. Intravenous infusion of dipyridamole increases adenosine and cAMP acutely in humans and rabbits (24,25). In rats, the increase in adenosine was biphasic with an increase during infusion and secondly, 20 minutes after the dipyridamole injection. Meanwhile, cAMP reached its highest level 20 minutes after the injection (25), questioning a direct adenosine mediated headache induction in both studies with intravenous dipyridamole (12,20). Adenosine is also increased following oral administration of dipyridamole over two days (26), which could be the cause of exacerbated headache intensity following daily intake of dipyridamole (19). A study has shown that continuous intake of oral dipyridamole leads to increased headache frequency followed by a decrease in headache frequency, severity and duration (27), The finding was suggested to be related to tolerance to dipyridamole induced headache (27), which questions dipyridamole’s role in the exacerbation of headache intensity (19).

Adenosine receptors as a pharmacological target for migraine

Adenosine has four G-protein coupled receptors (A₁, A_2A, A_2B and A₃ receptors) mainly expressed at cerebrum (A₁) (5), hippocampus and cerebellum (A₁ and A₃) (5), pre- and postsynaptic nerve terminals (A_2A) (5,28) and some internal organs (A_2B) (5). Preclinical studies report expression of adenosine A₁ and A_2A receptors in the trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC) in the trigeminal pain pathway (29,30). In contrast to A₁ and A₃ receptors which are considered to have anti-nociceptive effects, activation of A_2A and A_2B receptors induces nociception (9) due to different signaling pathways (Table 1, Figure 1 and Figure 2).

The role of adenosine receptors in migraine pathophysiology has previously been questioned due to the effect of caffeine on headache. Caffeine is a non-selective adenosine A₁ and A_2A antagonist (31) that is used in combination with other analgesics for treating pain including migraine attack (31,32). The analgetic effect is mainly mediated by inhibiting adenosine A_2A receptors (32). Caffeine withdrawal can result in caffeine withdrawal headache, and caffeine overuse is a risk factor for migraine chronification, while coffee consumption can be a migraine trigger in some migraine patients (31,33). Interestingly, caffeine overuse upregulates adenosine levels and sudden withdrawal results in increased sensitivity to adenosine, which potentially causes caffeine withdrawal headache (9,34). It is suggested that caffeine may trigger migraine attacks due to dehydration, inhibition of adenosine A₁ receptors, which leads to increased nitric oxide and/or decreased magnesium levels (31). Although the effect of caffeine on headache is ambiguous, it is suggested that the role of caffeine in headache is mediated through adenosine A₁ and A_2A receptors (34).

In human models of pain (trigeminal nociception with blink reflex), GR79236, an adenosine A₁ receptors agonist, partially inhibited the trigeminal nociceptive pathway (18). Similarly, adenosine A₁ receptors agonist, GR79236 and GR190178, inhibited activation of the trigeminovascular system induced by pain stimuli in cats (35). In rats, electrical stimulation of the TG caused a reduction of adenosine A₁ receptors in the TG and TNC (30), while intrathecal administration of adenosine A₁ agonist decreased nonevoked pain behavior and evoked mechanical hyperalgesia following surgical paw incision (36). The findings suggest that adenosine A₁ receptor agonists plays a role in pain modulation and might be effective for pain management (18,37).

Application of adenosine inhibited serotonin uptake by platelets in vitro. The inhibition was eliminated in the presence of adenosine A₂ receptor antagonist, CSC, and therefore adenosine A₂ receptor antagonists were suggested as a potential complementary migraine treatment (16). In rats, a highly selective A_2A receptor antagonist, SCH58261, blocked adenosine-induced dilation of the middle meningeal artery (38). An increased in adenosine A_2A receptors in TG and TNC was seen following electrical stimulation of TG in rats (30) implicating the role of the receptor in pain transmission.

To further implicate adenosine in headache and migraine pathophysiology, a case report described that infusion of regadenoson, a selective adenosine A_2A receptor agonist, triggered a hemiplegic migraine attack in a patient with a known history of hemiplegic migraine (39). The attack started eight minutes after start of infusion with left sided numbness and weakness, and after 20 minutes a typical, pulsating migraine headache had followed. The attack subsided within 24 hours. Interestingly, pre-clinical studies suggest that adenosine contributes to cortical spreading depression (40,41).

Limitations and future perspective

The major limitations of studies included were the small sample sizes, the different study designs and that almost half of the studies included investigated dipyridamole which increases adenosine concentration (12,19,20). Only a few studies on headache and migraine inducing abilities of adenosine are currently available (15 –19), and no new studies have been conducted in the last 15 years.

A case report showed that adenosine administration triggered migraine attack (42). Furthermore, preclinical studies indicate that accumulation of adenosine and an adenosine A_2A receptor haplotype may contribute to migraine aura (40,41,43). These findings should be further investigated in future clinical and pre-clinical studies. To further elucidate the role of adenosine in migraine pathophysiology, investigating the effect of intravenous adenosine infusion in migraine patients and clinically differentiating the receptor subtypes would be of great interest.

Conclusion

In conclusion, adenosine signaling might be involved in migraine pathogenesis, but current knowledge is limited by relatively low level of evidence in clinical studies. Plasma adenosine levels are elevated during migraine attacks (15,16) and administration of adenosine or positive modulators of adenosine signaling pathway induced headache in healthy volunteers and migraine patients (12,17,19,20). Adenosine A₁ receptor agonists and adenosine A₂ antagonist are potential strategies for future migraine treatments.

Clinical implications

Adenosine is a purinergic signaling molecule involved in a wide range of pathophysiological mechanisms including inflammation.

Adenosine infusion induced headache, and endogenous plasma adenosine levels were increased during ictal compared to interictal periods of migraine patients

Targeting adenosine A₁ and A₂ receptors might be a new potential strategy for the treatment of migraine.

Glossary

AC = adenylyl cyclase, AMP = adenosine monophosphate, ATP = adenosine triphosphate, cAMP = cyclic adenosine monophosphate, CBF = cerebral blood flow, cGMP = cyclic guanosine monophosphate, DAG = diacylglycerol, GPCR = G-protein coupled receptors, GTN = glyceryl trinitrate, ICHD = International Classification of Headache Disorders, IP₃ = inositol 1,4,5-triphosphate, MAPK = mitogen-activated protein kinase, MCA = middle cerebral artery, MO = migraine without aura, NE = nociception-specific electrode, NRS: numeric pain rating scale, PKA = protein kinase A, PDE5 = phosphodiesterase type 5, PGE₂ = prostaglandin E2, PIP₂ = phosphatidylinositol 4,5-biphosphate, PLC = phospholipase C, PLD = phospholipase D, SAH = S-adenosylhomocysteine, SE = standard electrode, STA = superficial temporal artery, TG = trigeminal ganglion, TNC = trigeminal nucleus caudalis, V_MCA = velocity in the middle cerebral artery.

Footnotes

Declaration of conflicting interests

The authors, JT, LK and MMK, declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. M.A. is a consultant, speaker, or scientific advisor for AbbVie, Amgen, Eli Lilly, Lundbeck, Novartis, and Teva and a primary investigator for ongoing AbbVie, Amgen and Lundbeck trials. M.A. has no ownership interest and does not own stocks of any pharmaceutical company. M.A. serves as associate editor of Cephalalgia, associate editor of the Journal of Headache and Pain, and associate editor of Brain.

Funding

M.A. was supported by the Lundbeck Foundation Professor Grant (R310-2018-3711).

ORCID iDs

Janu Thuraiaiyah

Lili Kokoti

Mohammad Al-Mahdi Al-Karagholi

References

Ashina

Migraine. N Engl J Med 2020; 383: 1866–1876.

Tabrizchi

Bedi

Pharmacology of adenosine receptors in the vasculature. Pharma Theraps 2001; 91: 133–147.

Jacobson

Tosh

Jain

, et al. Historical and current adenosine receptor agonists in preclinical and clinical development. Front Cell Neurosci 2019; 13: 1–17.

Jacobson

Gao

ZG.

Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 2006; 5: 247–264.

Sachdeva

Gupta

Adenosine and its receptors as therapeutic targets: An overview. Saudi Pharm J 2013; 21: 245–253.

Cerqueira

Nguyen

Staehr

, et al. Effects of age, gender, obesity, and diabetes on the efficacy and safety of the selective A_2A agonist regadenoson versus adenosine in myocardial perfusion imaging. Integrated ADVANCE-MPI trial results. JACC Cardiovasc Imaging 2008; 1: 307–316.

Iskandrian

Bateman

Belardinelli

, et al. Adenosine versus regadenoson comparative evaluation in myocardial perfusion imaging: Results of the ADVANCE phase 3 multicenter international trial. J Nucl Cardiol 2007; 14: 645–658.

Treuth

Reyes

, et al. Tolerance and diagnostic accuracy of an abbreviated adenosine infusion for myocardial scintigraphy: A randomized, prospective study. J Nucl Cardiol 2001; 8: 548–554.

Fried

Elliott

Oshinsky

ML.

The role of adenosine signaling in headache: A review. Brain Sci 2017; 7: 30.

10.

Kruuse

Thomsen

Jacobsen

, et al. The phosphodiesterase 5 inhibitor sildenafil has no effect on cerebral blood flow or blood velocity, but nevertheless induces headache in healthy subjects. J Cereb Blood Flow Metab 2002; 22: 1124–1131.

11.

Kruuse

Thomsen

Birk

, et al. Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain 2003; 126: 241–247.

12.

Kruuse

Lassen

Iversen

, et al. Dipyridamole may induce migraine in patients with migraine without aura. Cephalalgia 2006; 26: 925–933.

13.

Chen

Eltzschig

Fredholm

BB.

Adenosine receptors as drug targets-what are the challenges?

Nat Rev Drug Discov 2013; 12: 265–286.

14.

Lipton

Diener

H-C

Robbins

, et al. Caffeine in the management of patients with headache. J Headache Pain 2017; 18: 107.

15.

Guieu

Sampiéri

Bechis

, et al. Use of HPLC to measure circulating adenosine levels in migrainous patients. Clin Chim Acta 1994; 227: 185–194.

16.

Guieu

Devaux

Henry

, et al. Adenosine and migraine. Can J Neurol Sci 1998; 25: 55–58.

17.

Birk

Petersen

Kruuse

, et al. The effect of circulating adenosine on cerebral haemodynamics and headache generation in healthy subjects. Cephalalgia 2005; 25: 369–377.

18.

Giffin

Kowacs

Libri

, et al. Effect of the adenosine A₁ receptor agonist GR79236 on trigeminal nociception with blink reflex recordings in healthy human subjects. Cephalalgia 2003; 23: 287–292.

19.

Hawkes

CH.

Dipyridamole in migraine. Lancet 1978; 312: 153.

20.

Kruuse

Jacobsen

Lassen

, et al. Dipyridamole dilates large cerebral arteries concomitant to headache induction in healthy subjects. J Cereb Blood Flow Metab 2000; 20: 1372–1379.

21.

Burnstock

Pathophysiology of migraine: a new hypothesis. Lancet 1981; 317: 1397–1399.

22.

Luppi

P-H

Fort

Sleep-wake physiology. Handb Clin Neurol 2019; 160: 359–370.

23.

FitzGerald

Dipyridamole

N Engl J Med 1987; 316: 1051–1052.

24.

Sollevi

Östergren

Fagrell

, et al. Theophylline antagonizes cardiovascular responses to dipyridamole in man without affecting increases in plasma adenosine. Acta Physiol Scand 1984; 121: 165–171.

25.

Hegedüs

Keresztes

Fekete

, et al. Effect of i.v. dipyridamole on cerebral blood flow, blood pressure, plasma adenosine and cAMP levels in rabbits. J Neurol Sci 1997; 148: 153–161.

26.

German

Kredich

Bjornsson

TD.

Oral dipyridamole increases plasma adenosine levels in human beings. Clin Pharmacol Ther 1989; 45: 80–84.

27.

Theis

JGW

Deichsel

Marshall

Rapid development of tolerance to dipyridamole-associated headaches. Br J Clin Pharmacol 1999; 48: 750–755.

28.

Poulsen

Quinn

RJ.

Adenosine receptors: New opportunities for future drugs. Bioorganic Med Chem 1998; 6: 619–641.

29.

Carruthers

Sellers

Jenkins

, et al. Adenosine A₁ receptor-mediated inhibition of protein kinase A-induced calcitonin gene-related peptide release from rat trigeminal neurons. Mol Pharmacol 2001; 59: 1533–1541.

30.

Chen

, et al. Expression of calcitonin gene-related peptide, adenosine A₂a receptor and adenosine A₁ receptor in experiment rat migraine models. Biomed Reports 2016; 4: 379–383.

31.

Nowaczewska

Wiciński

Kaźmierczak

The ambiguous role of caffeine in migraine headache: from trigger to treatment. Nutrients 2020; 12: 1–16.

32.

Faudone

Arifi

Merk

The medicinal chemistry of caffeine. J Med Chem 2021; 64: 7156–7178.

33.

The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013; 33: 629–808.

34.

Alstadhaug

Andreou

AP.

Caffeine and primary (migraine) headaches-friend or foe?

Front Neurol 2019; 10: 1275.

35.

Goadsby

Hoskin

Storer

, et al. Adenosine A₁ receptor agonists inhibit trigeminovascular nociceptive transmission. Brain 2002; 125: 1392–1401.

36.

Zahn

Straub

Wenk

, et al. Adenosine A₁ but not A₂a receptor agonist reduces hyperalgesia caused by a surgical incision in rats: a pertussis toxin-sensitive G protein–dependent process. Anesthesiology 2007; 107: 797–806.

37.

Gordh

Karlsten

Kristensen

Intervention with spinal NMDA, adenosine, and NO systems for pain modulation. Ann Med 1995; 27: 229–234.

38.

Haanes

Edvinsson

Expression and characterization of purinergic receptors in rat middle meningeal artery-potential role in migraine. PLoS One 2014; 9: e108782–e108782.

39.

Elsadany

McMahon

Mehla

, et al . Hemiplegic migraine episode triggered by regadenoson. J Nucl Cardiol 2021; 1–5.

40.

Lindquist

Shuttleworth

CW.

Evidence that adenosine contributes to Leao’s spreading depression in vivo. J Cereb Blood Flow Metab 2017; 37: 1656–1669.

41.

Lindquist

Shuttleworth

CW.

Adenosine receptor activation is responsible for prolonged depression of synaptic transmission after spreading depolarization in brain slices. Neuroscience 2012; 223: 365–376.

42.

Brown

SGA

Waterer

GW.

Migraine precipitated by adenosine. Med J Aust 1995; 162: 389–391.

43.

Hohoff

Marziniak

Lesch

, et al. An adenosine A_2A receptor gene haplotype is associated with migraine with aura. Cephalalgia 2007; 27: 177–181.

44.

Sawynok

Adenosine receptor targets for pain. Neuroscience 2016; 338: 1–18.

45.

Borea

Gessi

Merighi

, et al. Pharmacology of adenosine receptors: the state of the art. Physiol Rev 2018; 98: 1591–1625.

46.

Ocaña

Baeyens

JM.

Role of ATP-sensitive K+ channels in antinociception induced by R-PIA, an adenosine A₁ receptor agonist. Naunyn Schmiedebergs Arch Pharmacol 1994; 350: 57–62.

47.

Kirsch

Codina

Birnbaumer

, et al. Coupling of ATP-sensitive K+ channels to A₁ receptors by G proteins in rat ventricular myocytes. Am J Physiol 1990; 259: H820–6.

48.

Kunduri

Dick

Nayeem

, et al. Adenosine A(1) receptor signaling inhibits BK channels through a PKCα-dependent mechanism in mouse aortic smooth muscle. Physiol Rep 2013; 1: e00037.

49.

Kleppisch

Nelson

MT.

Adenosine activates ATP-sensitive potassium channels in arterial myocytes via A₂ receptors and cAMP-dependent protein kinase. Proc Natl Acad Sci USA 1995; 92: 12441–12445.

50.

Kelion

Webb

Gardner

, et al. Does a selective adenosine A₁ receptor agonist protect against exercise induced ischaemia in patients with coronary artery disease? Heart 2002; 87: 115–120.

51.

Baxter

Hale

Miki

, et al. Adenosine A₁ agonist at reperfusion trial (AART): Results of a three-center, blinded, randomized, controlled experimental infarct study. Cardiovasc Drugs Ther 2000; 14: 607–614.

52.

Carley

Hagan

Sheehan

, et al. Adenosine A₁ receptor agonist GR79236 suppresses apnea during all sleep stages in the rat. Sleep 1997; 20: 1093–1098.

53.

Heseltine

Webster

Taylor

Adenosine effects upon insulin action on lipolysis and glucose transport in human adipocytes. Mol Cell Biochem 1995; 144: 147–151.

54.

Norton

Woodiwiss

McGinn

, et al. Adenosine A₁receptor-mediated antiadrenergic effects are modulated by A₂a receptor activation in rat heart. Am J Physiol Circ Physiol 1999; 276: H341–H349.

55.

Aguiar

LMV

Macêdo

Vasconcelos

SMM

, et al. CSC, an adenosine A_2A receptor antagonist and MAO B inhibitor, reverses behavior, monoamine neurotransmission, and amino acid alterations in the 6-OHDA-lesioned rats. Brain Res 2008; 1191: 192–199.

56.

Nobre

de Andrade Cunha

de Vasconcelos

, et al. Caffeine and CSC, adenosine A_2A antagonists, offer neuroprotection against 6-OHDA-induced neurotoxicity in rat mesencephalic cells. Neurochem Int 2010; 56: 51–58.

57.

Kang

Shi

, et al. Anticonvulsant Activity of B2, an Adenosine Analog, on Chemical Convulsant-Induced Seizures. PLoS One 2013; 8: 67060.

58.

Paterniti

Melani

Cipriani

, et al. Selective adenosine A_2A receptor agonists and antagonists protect against spinal cord injury through peripheral and central effects. J Neuroinflammation 2011; 8: 1–14.

59.

Shen

Huang

Zhang

, et al. SCH58261, the antagonist of adenosine A_2A receptor, alleviates cadmium-induced preeclampsia via sirtiun-1/hypoxia-inducible factor-1a pathway in rats. Eur Rev Med Pharmacol Sci 2020; 24: 10941–10953.

Involvement of adenosine signaling pathway in migraine pathophysiology: A systematic review of clinical studies

Abstract

Objective

Background

Methods

Results

Conclusion

Keywords

Introduction

Method

Data source

Selection criteria and study inclusion

Results

Narrative Summary

Discussion

Adenosine

Dipyridamole

Adenosine receptors as a pharmacological target for migraine

Limitations and future perspective

Conclusion

Clinical implications

Glossary

Footnotes

Declaration of conflicting interests

Funding

ORCID iDs

References