# Mechanism of Nociception Induced by Innocuous Cold in Trigeminal System

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2023 · $511,465

## Abstract

ABSTRACT: Trigeminal neuropathic pain is the most debilitating pain disorder but current treatments
including opiates are not effective for it in most patients. The pain can often be triggered by a breath of cooling
air blowing on the face. Mechanisms of trigeminal neuropathic pain exacerbation at cooling temperatures are
not well understood, which prevents us from designing mechanistically based therapy to effectively treat this
devastating pain. Our recent studies in rat models have suggested that thermally sensitive two-pore domain K+
channels (thermal K2Ps) may play a key role in trigeminal neuropathic pain exacerbation at cooling
temperatures. Our central hypotheses here are: 1) Thermal K2Ps provide a brake to prevent nociceptor
hyperexcitability under physiological conditions, 2) Trigeminal nerve injury causes thermal K2P down-
regulation to impair the brake leading to trigeminal nociceptor hyperexcitability and neuropathic pain, and 3)
Cooling temperatures further suppress thermal K2Ps to lead to trigeminal neuropathic pain exacerbation. We
will test these hypotheses with the following specific aims. ♦Aim 1. Elucidate the role of thermal K2Ps in
controlling trigeminal nociceptor excitability and determine the effects of cooling temperatures on K2P
functions. We will use immunohistochemistry to characterize thermal K2P expression in trigeminal nociceptors
of normal rats. We will use our newly developed in situ patch-clamp recordings to characterize thermal K2P-
mediated leak K+ currents in trigeminal nociceptors and their role in controlling trigeminal nociceptor excitability
of normal rats. We will study effects of cooling temperatures on thermal K2P functions in trigeminal nociceptors
of normal rats. ♦Aim 2. Elucidate that trigeminal nerve injury down-regulates thermal K2P expression leading to
trigeminal nociceptor hyperexcitability. We will use two established rat models of trigeminal neuropathic pain,
the infraorbital nerve chronic constrictive injury (ION-CCI) and oxaliplatin-induced trigeminal neuropathy
models. We will study changes of thermal K2P expression and thermal K2P-mediated leak K+ currents in
trigeminal nociceptors of these models. We will use pharmacological and genetic approaches to elucidate that
down-regulation of thermal K2Ps leads to trigeminal nociceptor hyperexcitability. We will determine how
cooling temperatures further exacerbate hyperexcitability of trigeminal nociceptors of these rat models. ♦Aim 3.
Elucidate that thermal K2P down-regulation underlies trigeminal neuropathic pain, and establish thermal K2Ps
as therapeutic targets for trigeminal neuropathic pain in rat models. We will use orofacial operant tests to study
whether thermal K2P down-regulation leads to trigeminal neuropathic pain manifested with cold allodynia and
hyperalgesia. We will use ION-CCI and oxaliplatin models to determine whether trigeminal neuropathic pain
can be alleviated by pharmacological and genetic enhancements of thermal K2P funct...

## Key facts

- **NIH application ID:** 10691453
- **Project number:** 5R01DE018661-16
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** JIANGUO GU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $511,465
- **Award type:** 5
- **Project period:** 2008-08-11 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10691453

## Citation

> US National Institutes of Health, RePORTER application 10691453, Mechanism of Nociception Induced by Innocuous Cold in Trigeminal System (5R01DE018661-16). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10691453. Licensed CC0.

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