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Graphical Abstract

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.

The antiepileptic drug carbamazepine is effective in a subpopulation of trigeminal neuralgia patients, in particular those suffering from pain associated with vascular compression of a trigeminal nerve. However, carbamazepine has failed in clinical trials for other neuropathic pain conditions, even those associated with peripheral nerve compression injuries. Carbamazepine is both a GABAA receptor (GAR) agonist and a blocker of voltage-gated Na+ channels (VGSC), and our recent data suggest that differences between trigeminal and somatic nerves with respect to the VGSC present are not sufficient to account for the therapeutic selectivity of carbamazepine. Therefore, we hypothesized that these observations reflected a differential involvement of GARs in somatic and trigeminal nerves. To test this, we employed a combination of electrophysiological and behavioral experiments in rat models of somatic (sciatic nerve, SN) and trigeminal (infraorbital nerve, ION) nerve compression (CCI). We observed that the potency of carbamazepine-induced compound action potential (CAP) block was increased by CCI of the ION but not the SN, and this increase in potency was reduced by the GAR blocker picrotoxin. The potency of the GAR agonist muscimol-induced block of the ION was greater than the SN, and CCI produced a further increase in efficacy. The GABAA-rho subunit mRNA and protein was increased by CCI of the ION, but not SN. The GABAA-rho receptor selective antagonist TPMPA reduced carbamazepine-induced CAP block of the ION. CCI was also associated with an increase in the potency of the GABAA-rho receptor preferring agonist TACA-induced block of the ION, but not SN. Finally, local administration of TACA to the ION but not SN, dose-dependently reversed CCI-induced mechanical sensitivity. Taken altogether, our results suggest GABAA-rho receptors are present and functional in ION, but not SN. This differential distribution of GABAA receptors could account for the therapeutic selectivity of carbamazepine for the treatment of TN. The work was supported by generous donations from TN patients and family members as well as NIH grant R01NS064988.

Graphical Abstract