RT Journal Article
SR Electronic
T1 A Positive Allosteric Modulator of the Adenosine A1 Receptor Selectively Inhibits Primary Afferent Synaptic Transmission in a Neuropathic Pain Model
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.115.099499
DO 10.1124/mol.115.099499
A1 Wendy L Imlach
A1 Rebecca F Bhola
A1 Lauren Therese May
A1 Arthur Christopoulos
A1 Macdonald J Christie
YR 2015
UL http://molpharm.aspetjournals.org/content/early/2015/06/23/mol.115.099499.abstract
AB 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 signalling, together with the actions of a novel A1R positive allosteric modulator (PAM), VCP171, 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, DPCPX (1 μM), produced a significantly greater increase in electrically evoked AMPAR-mediated synaptic current (eEPSC) amplitude in both lamina I and II neurons from nerve-injured 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 following nerve-injury. The A1R agonist, N6-Cyclopentyladenosine (CPA), produced greater inhibition of eEPSC amplitude in lamina II but not lamina I of the spinal cord dorsal horn in nerve-injured versus controls, 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.