A “tetrapartite” synapse in the CNS: A GABAergic synapse modulated by reciprocal signaling and homeostatic interactions with neighboring astrocytes and microglia [7]. GABAergic synapses employ ionotropic (GABA-A receptors) and metabotropic (GABA-B) receptors to evoke postsynaptic potentials [1]. The ionotropic GABA-A receptor is a ligand-gated chloride channel. The metabotropic GABA-B receptor activates a hyperpolarizing potassium conductance through a G-protein-mediated pathway [1]. As part of their neuroprotective response, activated microglia release brain-derived neurotropic factor (BDNF) in response to neuronal or vascular injury. BDNF triggers a transcriptional downregulation of KCC2 (potassium-chloride cotransporter 2), leading to reduced chloride extrusion from the cell [3]. Pathological accumulation of intracellular chloride can be reduced by blocking the inward sodium-potassium-chloride cotransporter (NKCC1) with bumetanide [6]. Diminished functioning of the GABA-A receptor, because of a collapsed chloride gradient, could be compensated for applying baclofen, a GABA-B agonist [22]. As pain therapeutics, bumetanide and baclofen, offer different physiological approaches to deal with the chloride-opathy in the postsynaptic neuronal cell.