# Nociceptive Mechanisms Underlying Sickle Cell Pain

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $598,464

## Abstract

Project Summary:
The circulating lipid metabolite lysophosphatidylcholine (lysoPC) is profoundly upregulated in the blood of
patients and mice with sickle cell disease (SCD); its over-abundance in RBC membranes drives RBC sickling.
However, nothing is known about whether the elevated lysoPC levels contributes to pain in SCD. The objective
of this proposal is to investigate the role lysoPC plays in acute and chronic SCD pain. Acute pain during vaso-
occlusive crisis (VOC) and chronic pain are major comorbidities for patients with SCD that severely impact the
patients' quality of life. Improved, mechanism-targeted pain treatments are desperately needed for SCD pain
because the main treatment currently used is opioid-class drugs, which have serious adverse side effects, risk
addiction, do not fully alleviate the pain, and in some patients, exacerbate the pain even further. The fact that
acute and chronic SCD pain arise from many body sites, both deep and superficial, suggests that a circulating
factor, such as lysoPC, may drive and maintain the pain in SCD. The Scientific Premise of this proposal is
that in SCD, the elevated blood borne lysoPC which originates in RBCs gains access to sensory neurons via
the permeable blood-nerve barrier, and then sensitizes a variety of receptors within these neurons that detect
noxious stimuli. We hypothesize that during an acute VOC, soluble lysoPC sensitizes the G-protein Receptor 4
(GPR4) and/or Acid Sensing Ion Channel 3 (ASIC3) to protons that are released locally in tissue during
ischemia, thereby driving the acute mechanical sensitization in SCD. Second, we hypothesize that lysoPC
contributes to chronic mechanical steady state pain by activating the Transient Receptor Potential 5 (TRPC5)
channel on sensory neurons thereby mediating the chronic mechanical pain in SCD. Three Specific Aims will
interrogate this hypothesis: 1) Will global inhibition of lysoPC generation prevent acute crisis and chronic pain?
2) Does soluble lysoPC contribute to acute crisis pain by sensitizing the proton receptors GPR4 and/or ASIC3?
3) Does lysoPC contribute to chronic steady state pain by sensitizing the stretch-activated channel TRPC5?
We hypothesize that therapeutically targeting one dysregulated lipid for the prevention of acute VOC and
chronic pain, alleviation of VOC pain, and alleviation of chronic SCD pain will present a single, unique
opportunity for novel drug development for SCD pain. To date, lysoPC has not yet been linked directly to pain
mechanisms even though it has been shown to be dysregulated in various diseases, including rheumatoid
arthritis, osteoarthritis, psoriasis, migraine, dysmenorrhea, multiple sclerosis and angina. Thus, this proposal
may also reveal the mechanism through which lysoPC drives the pain in these disorders. More broadly, our
experiments will uncover basic mechanisms by which lipids modulate ion channels and receptors in sensory
neurons to alter their mechanical response properties.

## Key facts

- **NIH application ID:** 9952431
- **Project number:** 5R01NS070711-11
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Cheryl Louise Stucky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $598,464
- **Award type:** 5
- **Project period:** 2009-09-30 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952431

## Citation

> US National Institutes of Health, RePORTER application 9952431, Nociceptive Mechanisms Underlying Sickle Cell Pain (5R01NS070711-11). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9952431. Licensed CC0.

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