Synaptic Conversion of Chloride-Dependent Synapses in Spinal Nociceptive Circuits: Roles in Neuropathic Pain

Figure 7

Pharmacological management of chloride-opathies. 𝐶^anion_𝐹 dependence on Cl and HCO₃ driving potentials (see (12)). In the above hypothetical case, the 𝐼^𝑜_Cl/𝐼^𝑜_HCO3ratio for normal anion currents through ligand-gated chloride channel (a GABA-A or a glycine receptor) is assumed to be 10 : 1. No change in resting membrane potential occurs (i.e., Δ^𝑉=0) in this example, as anion driving potentials deviate from their norm-averaged values (Δ^𝜇_Cl and Δ^𝜇_HCO3). At 𝐶^anion_𝐹=0, the inward flux of chloride is counterbalanced by an equal and opposite flux of HCO₃. Chloride-dependent inhibitory tone in the affected synapse has been lost. Bumetanide, an inhibitor of NKCC1 (sodium-potassium-chloride cotransporter 1), reduces the transport of chloride into the postsynaptic neuron (Figure 2). With a reduction of intracellular chloride, 𝐶^anion_𝐹 moves back towards a normal value of 1. A novel approach to restoring a positive value of 𝐶^anion_𝐹 is to reduce intracellular bicarbonate (HCO₃) concentration with the carbonic anhydrase inhibitor, acetazolamide [28]. This occurs while the collapsed chloride driving potential, Δ^𝜇_Cl, remains unchanged. Bumetanide and acetazolamide have antiallodynic actions in animal models of neuropathic pain [6].