Engagement of the GABA to KCC2 signaling pathway contributes to the analgesic effects of A3AR agonists in neuropathic pain

Amanda Ford, Annie Castonguay, Martin Cottet, Joshua W. Little, Zhoumou Chen, Ashley M. Symons-Liguori, Timothy Doyle, Terrance M. Egan, Todd W. Vanderah, Yves De Konnick, Dilip K. Tosh, Kenneth A. Jacobson, Daniela Salvemini

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6057-6067
Number of pages11
JournalJournal of Neuroscience
Volume35
Issue number15
DOIs
StatePublished - Apr 15 2015

Keywords

  • Adenosine
  • Adenosine receptors
  • GABA
  • KCC2
  • Neuropathic pain

ASJC Scopus subject areas

  • Neuroscience(all)

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    Ford, A., Castonguay, A., Cottet, M., Little, J. W., Chen, Z., Symons-Liguori, A. M., Doyle, T., Egan, T. M., Vanderah, T. W., De Konnick, Y., Tosh, D. K., Jacobson, K. A., & Salvemini, D. (2015). Engagement of the GABA to KCC2 signaling pathway contributes to the analgesic effects of A3AR agonists in neuropathic pain. Journal of Neuroscience, 35(15), 6057-6067. https://doi.org/10.1523/JNEUROSCI.4495-14.2015