Papers of the Week

Normalization of the excitatory and inhibitory balance by increasing the levels of endogenous inhibitory neurotransmitters by blocking their reuptake is a promising therapeutic strategy for relieving chronic pain. Pharmacological blockade of spinal GABA transporter subtypes 1 and 3 (GAT1 and GAT3) has been reported to generate analgesic effects in animal models of neuropathic pain. Here we explored the synaptic mechanisms underlying their analgesic effects in the spinal dorsal horn. Whole-cell recordings were made from dorsal horn neurons in spinal slices with attached dorsal roots from adult mice, and the effects of GAT inhibitors on miniature and evoked postsynaptic currents were examined. Behaviorally, GAT inhibitors were intrathecally applied to assess their effects on mechanical hypersensitivity in mice developing neuropathic pain after partial sciatic nerve ligation. The GAT1 inhibitor NNC-711 reduced the frequency of mEPSCs and the amplitude of C-fiber-mediated EPSCs, and the GAT3 inhibitor SNAP-5114 reduced the amplitude of A- and C-fiber-mediated EPSCs. These effects were antagonized by the GABAB receptor antagonist CGP55845. Consistently, the analgesic effect of intrathecally injected NNC-711 and SNAP-5114 in mice developing mechanical hypersensitivity after partial sciatic nerve ligation was abolished by CGP55845. Thus, GAT1 and GAT3 inhibitors exert distinct GABAB receptor-mediated inhibitory effects on excitatory synaptic transmission in the spinal dorsal horn, which most likely contributes to their analgesic effects.