# Hyaluronan signaling to nociceptors in inflammatory pain

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $587,384

## Abstract

PROJECT SUMMARY/ABSTRACT
The extracellular matrix (ECM) plays a major role in the pathophysiology of painful connective tissue diseases
characterized by inflammation and tissue injury, such as arthritis and dermatitis. High molecular weight
hyaluronan (HMWH), the major non-protein component of the ECM, is metabolized to low molecular weight
hyaluronans (LMWH) in these clinical conditions. In preliminary studies we have shown that LMWH sensitizes
synovial and cutaneous nociceptors, and produces articular and cutaneous mechanical hyperalgesia. In contrast,
HMWH is currently used in the treatment of pain in patients with arthritis and other connective tissue diseases,
and while current dogma teaches that the analgesic properties of HMWH are due to its viscoelastic properties,
we propose the novel hypothesis that both HMWH-induced analgesia/anti-hyperalgesia, and LMWH-induced
mechanical hyperalgesia are both generated by their action at the cognate hyaluronan (HA) receptor, CD44, in
the plasma membrane of pain sensory neurons (nociceptors). To test this hypothesis, we will: 1)
comprehensively study the pro- and anti-nociceptive properties of these two size classes of HA to establish the
properties of LMWH that induce pain (hyperalgesia) and HMWH that induce analgesia (anti-hyperalgesia); 2)
use in vitro patch-clamp electrophysiology to establish that HA acts directly on nociceptors to sensitize (LMWH)
or reverse sensitization (HMWH) of nociceptor excitability, and determine the nociceptor populations upon which
HAs act to produce their effects and the ion channels in each population whose function is modulated by HA; 3)
confirm the role of the cognate hyaluronan receptor, CD44 and its downstream second messenger signaling
pathways, in LMWH hyperalgesia and HMWH analgesia, and that the CD44 is in nociceptors; and, 4) use
preclinical models of inflammatory, neuropathic and stress-induced pain to demonstrate that nociceptor CD44 is
involved in the pain in with these syndromes, and that HMWH can be used as an anti-hyperalgesia/analgesia
therapeutic modality. The proposed experiments will provide insight into the role of an important element of the
ECM in diverse pain syndromes, and a rationale for developing new, more effective forms of HMWH to treat
pain.

## Key facts

- **NIH application ID:** 9908043
- **Project number:** 5R01AR075334-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** JON DAVID LEVINE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $587,384
- **Award type:** 5
- **Project period:** 2019-04-05 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9908043

## Citation

> US National Institutes of Health, RePORTER application 9908043, Hyaluronan signaling to nociceptors in inflammatory pain (5R01AR075334-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9908043. Licensed CC0.

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