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This study is based on the clinical observations that a subpopulation of patients suffering from classical trigeminal neuralgia are responsive to the anti-seizure, voltage-gated Na+ channel (VGSC)-blocking drugs carbamazepine (CBZ) and oxcarbamazepine while these drugs have failed to demonstrate efficacy in clinical trials with other neuropathic pain conditions, even those associated with nerve compression injuries. Furthermore, with preclinical evidence of afferent subpopulation specific responses to injury, we hypothesized that the therapeutic selectivity of carbamazepine for TN reflects the unique combination of injury-induced changes in VGSCs in the trigeminal nerve. We found that potency and efficacy of CBZ-induced inhibition of the compound action potential (CAP) was increased following chronic constriction injury (CCI) of the infraorbital nerve (ION), but not of the sciatic nerve (SN).. The potency of CBZ-induced block of the CAP evoked in human spinal nerves was comparable to the SN from rats, but was more potent in the block of the CAP evoked in human trigeminal nerves. Among different VGSCs blockers evaluated, the efficacy of ICA121431 (Nav 1.1 and 1.3 blocker) was significantly greater in the inhibition of the Ab and C components of the ION CAP compared to the SN CAP from the sham group, and CCI of the ION but not SN was associated with an increase in efficacy and potency of ICA121431 on the inhibition of the Ab and C components of the CAP. A CCI-induced increase in Nav 1.1-like immunoreactivity was detected with western blot of protein extracted from the ION, while a CCI-induced increase in Nav 1.3-like immunoreactivity was detected in the SN. Finally, local administration of ICA121431 on the ION alleviated mechanical hypersensitivity in rats with ION-CCI. Our results are consistent with our initial hypothesis and suggest that the therapeutic selectivity of CBZ is related to a differential regulation of the VGSC. This work was supported by generous donations from TN patients and family members as well as NIH grant R01NS064988.
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