title: Adenosine A1 receptor agonists inhibit trigeminovascular nociceptive transmission.
abstract: There is a considerable literature to suggest that adenosine A1 receptor agonists may have anti-nociceptive effects, and we sought to explore the role of adenosine A1 receptors in a model of trigeminovascular nociceptive transmission. Cats were anaesthetized (alpha-chloralose 60 mg/kg, intraperitoneally), and prepared for physiological monitoring. The superior sagittal sinus (SSS) was stimulated electrically, and linked units were recorded in the trigeminocervical complex. Post-stimulus histograms were constructed to analyse the responses and the effect of drug administration. Blood was sampled from the external jugular vein to determine levels of calcitonin gene-related peptide (CGRP) release before and after drug administration. Intravenous administration of the highly selective adenosine A1 receptor agonist, GR79236 (3-100 microg/kg) had a dose-dependent inhibitory effect on SSS-evoked trigeminal activity. The maximal effect (80 +/- 6% reduction in probability of firing) was seen at 100 microg/kg. The neuronal inhibitory effect of GR79236 could be inhibited by the selective adenosine A1 receptor antagonist DPCPX (300 microg/kg; P < 0.05). SSS stimulation increased cranial CGRP levels from 33 +/- 2 pmol/l (n = 6) to 64 +/- 3 pmol/l, an effect substantially reduced by pre-treatment with GR79236 (30 microg/kg; P < 0.01). The selective low efficacy adenosine A1 receptor agonist, GR190178 (30-1000 microg/kg i.v.), also inhibited SSS-evoked neuronal activity in a dose-dependent fashion. In this model of trigeminovascular nociception, adenosine A1 receptor activation leads to neuronal inhibition without concomitant vasoconstriction, suggesting a novel avenue for the treatment of migraine and cluster headache.
authors.affiliation: Headache Group, Institute of Neurology, Queen Square, London, UK. peterg@ion.ucl.ac.uk
authors.forename: P J
authors.initials: PJ
authors.lastname: Goadsby
authors.forename: K L
authors.initials: KL
authors.lastname: Hoskin
authors.forename: R J
authors.initials: RJ
authors.lastname: Storer
authors.forename: L
authors.initials: L
authors.lastname: Edvinsson
authors.forename: H E
authors.initials: HE
authors.lastname: Connor
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D002415:Cats; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects*; D010147:Pain Measurement / Q000706:statistics & numerical data*; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1 / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects*; D014278:Trigeminal Nuclei / Q000187:drug effects* / Q000502:physiology; D014970:Xanthines / Q000494:pharmacology
chemical_list: D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D014970:Xanthines; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine; C082299:N-((1S,trans)-2-hydroxycyclopentyl)adenosine