# Mechanisms of Pain Associated with Trigeminal Nerve Injury

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $551,793

## Abstract

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 ner...

## Key facts

- **NIH application ID:** 10459477
- **Project number:** 5R01NS122784-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** MICHAEL S GOLD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $551,793
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459477

## Citation

> US National Institutes of Health, RePORTER application 10459477, Mechanisms of Pain Associated with Trigeminal Nerve Injury (5R01NS122784-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10459477. Licensed CC0.

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