RT Journal Article SR Electronic T1 Engagement of the GABA to KCC2 Signaling Pathway Contributes to the Analgesic Effects of A3AR Agonists in Neuropathic Pain JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 6057 OP 6067 DO 10.1523/JNEUROSCI.4495-14.2015 VO 35 IS 15 A1 Amanda Ford A1 Annie Castonguay A1 Martin Cottet A1 Joshua W. Little A1 Zhoumou Chen A1 Ashley M. Symons-Liguori A1 Timothy Doyle A1 Terrance M. Egan A1 Todd W. Vanderah A1 Yves De Koninck A1 Dilip K. Tosh A1 Kenneth A. Jacobson A1 Daniela Salvemini YR 2015 UL http://www.jneurosci.org/content/35/15/6057.abstract AB More than 1.5 billion people worldwide suffer from chronic pain, yet current treatment strategies often lack efficacy or have deleterious side effects in patients. Adenosine is an inhibitory neuromodulator that was previously thought to mediate antinociception through the A1 and A2A receptor subtypes. We have since demonstrated that A3AR agonists have potent analgesic actions in preclinical rodent models of neuropathic pain and that A3AR analgesia is independent of adenosine A1 or A2A unwanted effects. Herein, we explored the contribution of the GABA inhibitory system to A3AR-mediated analgesia using well-characterized mouse and rat models of chronic constriction injury (CCI)-induced neuropathic pain. The deregulation of GABA signaling in pathophysiological pain states is well established: GABA signaling can be hampered by a reduction in extracellular GABA synthesis by GAD65 and enhanced extracellular GABA reuptake via the GABA transporter, GAT-1. In neuropathic pain, GABAAR-mediated signaling can be further disrupted by the loss of the KCC2 chloride anion gradient. Here, we demonstrate that A3AR agonists (IB-MECA and MRS5698) reverse neuropathic pain via a spinal mechanism of action that modulates GABA activity. Spinal administration of the GABAA antagonist, bicuculline, disrupted A3AR-mediated analgesia. Furthermore, A3AR-mediated analgesia was associated with reductions in CCI-related GAD65 and GAT-1 serine dephosphorylation as well as an enhancement of KCC2 serine phosphorylation and activity. Our results suggest that A3AR-mediated reversal of neuropathic pain increases modulation of GABA inhibitory neurotransmission both directly and indirectly through protection of KCC2 function, underscoring the unique utility of A3AR agonists in chronic pain.