Adenosine is present at the extracellular space within spinal cord dorsal horn and engaged in the processing of nociceptive sensory signals. Systemic or spinal administration of exogenous adenosine produces a potent analgesia against pathological pain. Here we found that inhibitory glycinergic neurotransmission was an important target for adenosine regulation. In spinal cord slices from intact rats, adenosine increased the inhibitory postsynaptic currents mediated by glycine receptors (GlyRs). In spinal slices from Complete Freund's Adjuvant-injected rats, adenosine potentiated glycinergic transmission to a more degree than in control rats. This synaptic potentiation was dependent on the activation of adenosine A1 receptor (A1R), and attributed to the modification of postsynaptic GlyRs function. The Gi protein-coupled A1R typically signals through Gái/cAMP-dependent protein kinase (PKA) and Gâã pathways. We found that blockade of either Gái/PKA or Gâã signaling attenuated the ability of adenosine to increase glycinergic synaptic responses in inflamed rats. To identify which GlyRs subunit was subjected to A1R regulation, we recorded glycine-evoked whole-cell currents in HEK293T cells co-transfected with A1R and distinct GlyRs subunit. We found that á1, the most abundant functional GlyRs subunit in adult spinal cord, was insensitive to A1R activation. However, when GlyRs á3 subunit or á1ins subunit, a longer á1 isoform, was co-expressed with A1R, adenosine caused a significant increase of glycinergic currents. Inhibition of PKA and Gâã abolished the stimulatory effects of A1R on á3 and á1ins, respectively. These data suggested that A1R might potentiate glycinergic transmission through Gái/PKA/á3 and Gâã/á1ins pathways in inflamed rat.
Adenosine Animals