title: Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states.
abstract: Chronic pain is a global burden that promotes disability and unnecessary suffering. To date, efficacious treatment of chronic pain has not been achieved. Thus, new therapeutic targets are needed. Here, we demonstrate that increasing endogenous adenosine levels through selective adenosine kinase inhibition produces powerful analgesic effects in rodent models of experimental neuropathic pain through the A3 adenosine receptor (A3AR, now known as ADORA3) signalling pathway. Similar results were obtained by the administration of a novel and highly selective A3AR agonist. These effects were prevented by blockade of spinal and supraspinal A3AR, lost in A3AR knock-out mice, and independent of opioid and endocannabinoid mechanisms. A3AR activation also relieved non-evoked spontaneous pain behaviours without promoting analgesic tolerance or inherent reward. Further examination revealed that A3AR activation reduced spinal cord pain processing by decreasing the excitability of spinal wide dynamic range neurons and producing supraspinal inhibition of spinal nociception through activation of serotonergic and noradrenergic bulbospinal circuits. Critically, engaging the A3AR mechanism did not alter nociceptive thresholds in non-neuropathy animals and therefore produced selective alleviation of persistent neuropathic pain states. These studies reveal A3AR activation by adenosine as an endogenous anti-nociceptive pathway and support the development of A3AR agonists as novel therapeutics to treat chronic pain.
authors.affiliation: 1 Saint Louis University School of Medicine, Saint Louis, MO USA.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Little
authors.affiliation: 1 Saint Louis University School of Medicine, Saint Louis, MO USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Ford
authors.affiliation: 2 University of Arizona, Department of Pharmacology and Anesthesiology, Tucson, AZ USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Symons-Liguori
authors.affiliation: 1 Saint Louis University School of Medicine, Saint Louis, MO USA.
authors.forename: Zhoumou
authors.initials: Z
authors.lastname: Chen
authors.affiliation: 1 Saint Louis University School of Medicine, Saint Louis, MO USA.
authors.forename: Kali
authors.initials: K
authors.lastname: Janes
authors.affiliation: 1 Saint Louis University School of Medicine, Saint Louis, MO USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Doyle
authors.affiliation: 2 University of Arizona, Department of Pharmacology and Anesthesiology, Tucson, AZ USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Xie
authors.affiliation: 3 Department of Experimental Medicine, Division of Pharmacology, Second University of Naples, Naples, Italy.
authors.forename: Livio
authors.initials: L
authors.lastname: Luongo
authors.affiliation: 4 National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD USA.
authors.forename: Dillip K
authors.initials: DK
authors.lastname: Tosh
authors.affiliation: 3 Department of Experimental Medicine, Division of Pharmacology, Second University of Naples, Naples, Italy.
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.affiliation: 5 University College London, Department of Neuroscience, Physiology and Pharmacology, London, UK.
authors.forename: Kirsty
authors.initials: K
authors.lastname: Bannister
authors.affiliation: 5 University College London, Department of Neuroscience, Physiology and Pharmacology, London, UK.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Dickenson
authors.affiliation: 2 University of Arizona, Department of Pharmacology and Anesthesiology, Tucson, AZ USA.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
authors.affiliation: 2 University of Arizona, Department of Pharmacology and Anesthesiology, Tucson, AZ USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.affiliation: 4 National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD USA.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.affiliation: 1 Saint Louis University School of Medicine, Saint Louis, MO USA salvemd@slu.edu.
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006930:Hyperalgesia / Q000175:diagnosis / Q000503:physiopathology; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use; D009270:Naloxone / Q000008:administration & dosage; D009437:Neuralgia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D058915:Purinergic P1 Receptor Antagonists / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D043684:Receptor, Adenosine A3 / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
chemical_list: C419146:2,3-diethyl-4,5-dipropyl-6-phenylpyridine-3-thiocarboxylate-5-carboxylate; D009025:Morpholines; D058915:Purinergic P1 Receptor Antagonists; D011725:Pyridines; D011743:Pyrimidines; D043684:Receptor, Adenosine A3; C416933:ABT 702; D009270:Naloxone; D000241:Adenosine
keywords: A3AR; adenosine; chronic pain; rostral ventromedial medulla; spontaneous pain