Treatment of
neuropathic pain is a major clinical challenge that has been met with minimal success. After
peripheral nerve injury, a decrease in the expression of the
K-Cl cotransporter KCC2, a major neuronal Cl(-) extruder, leads to pathologic alterations in
GABA(A) and
glycine receptor function in the spinal cord. The down-regulation of KCC2 is expected to cause a reduction in Cl(-) extrusion capacity in dorsal horn neurons, which, together with the depolarizing efflux of HCO(3)(-)
anions via
GABA(A) channels, would result in a decrease in the efficacy of
GABA(A)-mediated inhibition.
Carbonic anhydrases (CA) facilitate intracellular HCO(3)(-) generation and hence, we hypothesized that inhibition of CAs would enhance the efficacy of GABAergic inhibition in the context of
neuropathic pain. Despite the decrease in KCC2 expression, spinal administration of
benzodiazepines has been shown to be anti-allodynic in neuropathic conditions. Thus, we also hypothesized that spinal inhibition of CAs might enhance the anti-allodynic effects of spinally administered
benzodiazepines. Here, we show that inhibition of spinal CA activity with
acetazolamide (ACT) reduces neuropathic
allodynia. Moreover, we demonstrate that spinal co-administration of ACT and
midazolam (MZL) act synergistically to reduce neuropathic
allodynia after
peripheral nerve injury. These findings indicate that the combined use of CA inhibitors and
benzodiazepines may be effective in the clinical management of
neuropathic pain in humans.