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.