# Primary afferent plasticity in chronic pain

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $494,912

## Abstract

PROJECT SUMMARY
Trigeminal neuropathic pain (TNP) is a major medical problem. Injury or surgery in the trigeminal area induces
debilitating persistent neuropathic pain. Since TNP is often resistant to current pharmacotherapy, there is a
pressing need to develop more efficacious treatments for TNP with fewer side effects. Neuropathic pain is
maintained by a myriad of mechanisms involving multiple molecules and neural circuits across peripheral and
central nervous systems. A recent study found that sensitized nociceptors likely maintain pain in approximately
one third of neuropathic pain patients. Thus, identifying and determining mechanisms of dominant peripheral
contributors to pain is critical for developing selective treatment for this subset of chronic pain patients. Lack of
understanding of detailed mechanisms underlying the role of nociceptors in neuropathic pain poses a significant
hurdle to improving nociceptor-targeted pain management in chronic pain sufferers. TRPV1 is a nociceptor-
enriched receptor for capsaicin. Topical capsaicin invariably induces burning pain. Paradoxically, such
nociception is often followed by prolonged analgesia attenuating pre-existing persistent pain. Topical capsaicin
has been approved by the FDA for treatment of post-herpetic neuralgia, and provides months-long relief.
However, the mechanisms underlying capsaicin-induced analgesia are not well understood. Despite clear
therapeutic effects of capsaicin, the involvement of TRPV1 and TRPV1+ nociceptors in neuropathic pain is
controversial. We recently reported evidence in a mouse model that TRPV1 and TRPV1+ nociceptors contributed
to mechanical hyperalgesia and allodynia following neuropathy in the trigeminal area. The mechanical
hyperalgesia and allodynia usually observed in mice subjected to chronic constriction injury of the infraorbital
nerve (ION-CCI) was prevented by systemic pretreatment with resiniferatoxin, an ultrapotent TRPV1 agonist
which desensitizes TRPV1+ afferents. We also found that local pharmacological inhibition of TRPV1 at the
central terminals of primary afferents was sufficient to attenuate mechanical hyperalgesia and allodynia. Our
objectives here are to determine the roles of TRPV1 and TRPV1+ nociceptors in TNP and to elucidate
mechanisms of capsaicin-induced analgesia for TNP. Our central hypothesis is that plastic changes in trigeminal
TRPV1+ nociceptors caused by nerve injury and vanilloid compounds, respectively, are critical for the
maintenance and treatment of chronic TNP. To test this, we will determine the effects of ablation or inhibition of
TRPV1+ afferents on mechanical hyperalgesia or spontaneous pain in mice with ION-CCI (Aim 1), define the
major molecular pathway determining both capsaicin-induced ablation of peripheral terminals of TRPV1+
afferents and capsaicin-induced analgesia (Aim 2) and dissect the contribution of distinct genetically defined
subpopulations of TRPV1+ afferents to TNP through conditional TRPV1 knockdow...

## Key facts

- **NIH application ID:** 10438566
- **Project number:** 5R01DE027731-05
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Man-Kyo Chung
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $494,912
- **Award type:** 5
- **Project period:** 2018-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10438566

## Citation

> US National Institutes of Health, RePORTER application 10438566, Primary afferent plasticity in chronic pain (5R01DE027731-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10438566. Licensed CC0.

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