4.7 Article

Engagement of the GABA to KCC2 Signaling Pathway Contributes to the Analgesic Effects of A(3)AR Agonists in Neuropathic Pain

期刊

JOURNAL OF NEUROSCIENCE
卷 35, 期 15, 页码 6057-6067

出版社

SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4495-14.2015

关键词

adenosine; adenosine receptors; GABA; KCC2; neuropathic pain

资金

  1. National Cancer Institute [RO1CA169519]
  2. St. Louis Cancer Center
  3. Canadian Institutes of Health Research [MOP12942]
  4. National Institute of Diabetes and Digestive and Kidney Diseases
  5. NATIONAL CANCER INSTITUTE [R01CA169519] Funding Source: NIH RePORTER
  6. NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [ZIADK031117] Funding Source: NIH RePORTER

向作者/读者索取更多资源

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 A(1) and A(2A) receptor subtypes. We have since demonstrated that A(3)AR agonists have potent analgesic actions in preclinical rodent models of neuropathic pain and that A(3)AR analgesia is independent of adenosine A(1) or A(2A) unwanted effects. Herein, we explored the contribution of the GABA inhibitory system to A(3)AR-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, GABA(A)R-mediated signaling can be further disrupted by the loss of the KCC2 chloride anion gradient. Here, we demonstrate that A(3)AR agonists (IB-MECA and MRS5698) reverse neuropathic pain via a spinal mechanism of action that modulates GABA activity. Spinal administration of the GABA(A) antagonist, bicuculline, disrupted A(3)AR-mediated analgesia. Furthermore, A(3)AR-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 A(3)AR-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 A(3)AR agonists in chronic pain.

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