title: A Positive Allosteric Modulator of the Adenosine A1 Receptor Selectively Inhibits Primary Afferent Synaptic Transmission in a Neuropathic Pain Model.
abstract: In the spinal cord and periphery, adenosine inhibits neuronal activity through activation of the adenosine A1 receptor (A1R), resulting in antinociception and highlighting the potential of therapeutically targeting the receptor in the treatment of neuropathic pain. This study investigated the changes in adenosine tone and A1R signaling, together with the actions of a novel A1R positive allosteric modulator (PAM), VCP171 [(2-amino-4-(3-(trifluoromethyl)phenyl)thiophen-3-yl)(phenyl)methanone], on excitatory and inhibitory neurotransmission at spinal cord superficial dorsal horn synapses in a rat partial nerve-injury model of neuropathic pain. In the absence of A1R agonists, superfusion of the A1R antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 1 μM), produced a significantly greater increase in electrically evoked α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated synaptic current (eEPSC) amplitude in both lamina I and II neurons from nerve-injured animals than in controls, suggesting that endogenous adenosine tone is increased in the dorsal horn. Inhibitory GABAergic and glycinergic synaptic currents were also significantly increased by DPCPX in controls but there was no difference after nerve injury. The A1R agonist, N6-cyclopentyladenosine, produced greater inhibition of eEPSC amplitude in lamina II but not lamina I of the spinal cord dorsal horn in nerve-injured versus control animals, suggesting a functional increase in A1R sensitivity in lamina II neurons after nerve injury. The A1R PAM, VCP171, produced a greater inhibition of eEPSC amplitude of nerve-injury versus control animals in both lamina I and lamina II neurons. Enhanced adenosine tone and A1R sensitivity at excitatory synapses in the dorsal horn after nerve injury suggest that new generation PAMs of the A1R can be effective treatments for neuropathic pain.
authors.affiliation: Discipline of Pharmacology, The University of Sydney, Sydney, Australia (W.L.I., R.F.B., M.J.C.); and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Victoria, Australia (L.T.M., A.C.) wendy.imlach@sydney.edu.au.
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Imlach
authors.affiliation: Discipline of Pharmacology, The University of Sydney, Sydney, Australia (W.L.I., R.F.B., M.J.C.); and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Victoria, Australia (L.T.M., A.C.).
authors.forename: Rebecca F
authors.initials: RF
authors.lastname: Bhola
authors.affiliation: Discipline of Pharmacology, The University of Sydney, Sydney, Australia (W.L.I., R.F.B., M.J.C.); and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Victoria, Australia (L.T.M., A.C.).
authors.forename: Lauren T
authors.initials: LT
authors.lastname: May
authors.affiliation: Discipline of Pharmacology, The University of Sydney, Sydney, Australia (W.L.I., R.F.B., M.J.C.); and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Victoria, Australia (L.T.M., A.C.).
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.affiliation: Discipline of Pharmacology, The University of Sydney, Sydney, Australia (W.L.I., R.F.B., M.J.C.); and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Victoria, Australia (L.T.M., A.C.).
authors.forename: Macdonald J
authors.initials: MJ
authors.lastname: Christie
mesh_terms: D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D000494:Allosteric Regulation; D000818:Animals; D019706:Excitatory Postsynaptic Potentials; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D009437:Neuralgia / Q000188:drug therapy*; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use; D014970:Xanthines / Q000494:pharmacology
chemical_list: C573296:(2-amino-5-methyl-4-(3-(trifluoromethyl)phenyl)thiophen-3-yl)(phenyl)methanone; D058907:Adenosine A1 Receptor Agonists; D043682:Receptor, Adenosine A1; D013876:Thiophenes; D014970:Xanthines; C051360:1,3-dipropyl-8-cyclopentylxanthine