Mechanisms of Pain Associated with Trigeminal Nerve Injury

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Trigeminal nerve injury pain remains a significant problem both because of its intensity and persistence, and the absence of consistently effective therapeutic options. The clinical observations that the anti-seizure drug carbamazepine (CBZ) has generally failed in the treatment of somatic nerve injury pain, but helps with trigeminal nerve injury pain, at least temporarily, suggests it may be possible to identify more effective treatments for trigeminal nerve injury pain by identifying the basis for the difference(s) between somatic and trigeminal nerves in response to injury. Pursuing this possibility, we confirmed that CBZ was more effective at relieving ongoing pain and mechanical hypersensitivity in rats associated with an injury to trigeminal than a somatic nerve. Because the same injury (chronic constriction injury (CCI)) was applied to the sciatic nerve (SN) and the infraorbital nerve (ION), these data suggest that the therapeutic efficacy of CBZ reflects a unique response to injury rather than a unique feature of the way the nerve is injured in patients. Consistent with this suggestion we observed an increase in the potency and efficacy of CBZ-induced block of action potential propagation in isolated nerves following ION-CCI but not SN-CCI. This suggests that the therapeutic selectivity of CBZ is due, at least in part, to an action on primary afferents. Our observations that ION-CCI was associated with an increase in NaV1.1 protein and the efficacy of an NaV1.1 preferring channel blocker suggest that this subunit may not only contribute to trigeminal nerve injury pain, but the therapeutic selectivity of CBZ (generally thought of as a voltage-gated Na+ channel (VGSC) blocker). CBZ is also a GABAA receptor agonist and we observed an ION-CCI-induced increase in the potency and efficacy of CBZ on the isolated trigeminal nerve that was reversed by a GABAA receptor blocker. Furthermore, ION-CCI but not SN-CCI was associated with an increase in expression of GABAAρ3, and hypersensitivity associated with ION-CCI, but not SN-CCI was attenuated by a GABAA receptor agonist with activity at GABAA receptors with ρ-subunits. These discoveries uniquely positioned us to determine why the site of nerve injury influences the efficacy of CBZ. We have proposed to do so in experiments described under three Specific Aims designed to test the hypothesis that the ongoing pain and hypersensitivity associated with trigeminal but not somatic nerve injury are due to an increase in NaV1.1, while the selective therapeutic effect of CBZ is due to an increase in both NaV1.1 and GABAAρ3 receptors along the trigeminal nerve. In Aims 1 and 2 we will determine the contribution of VGSCs and GABAA receptor subtypes to trigeminal nerve injury-induced hypersensitivity and the selective therapeutic utility of CBZ. Finally, to validate these preclinical observations, in Aim 3 we will characterize the functional VGSCs and GABAA receptor subunits in human trigeminal and somatic nerves, including trigeminal nerves from patients suffering from trigeminal pain. Together, the results of these experiments will increase our understanding of the role of two key channel types in neuropathic pain and may suggest more effective ways to treat pain associated with trigeminal nerve injury.