# Investigating the Role of Heme in Acute and Chronic Sickle Cell Disease Pain

> **NIH NIH F30** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $51,064

## Abstract

Project Summary
Individuals with sickle cell disease (SCD) suffer from complex stimulus-evoked and ongoing chronic pain that is
mediated in part by the hyperexcitability of their peripheral sensory neurons. However, how the underlying
disease pathology leads to ongoing inflammatory and neuropathic pain remains poorly understood. Over the last
decade, clinical and pre-clinical research has demonstrated that elevated heme, a key pathological feature of
SCD, may contribute to SCD pain. My preliminary data suggest that wildtype (WT) mice receiving intraplantar
injections of hemin chloride, the common salt of heme, display acute mechanical hypersensitivity and paw
attending behavior. My preliminary data further suggest that reducing the heme burden in SCD mice using
intraperitoneally administered haptoglobin, a heme scavenger, reduces mechanical hypersensitivity.
Considering these observations, I propose to investigate whether elevated heme is required for the maintenance
of pain behavior in Townes SCD. In Aim 1, I hypothesize that elevated heme causes ongoing, non-evoked
pain behavior in WT mice by dysregulation of peripheral nociception. I will administer hemin to C57BL/6
mice and conduct facial grimace and conditioned place aversion to determine the contribution of heme to non-
evoked pain behavior (Aim 1A). Following the treatment window, I will harvest the dorsal root ganglia (DRGs)
sensory neurons from these mice and use patch clamp electrophysiology to determine whether heme-induced
pain behavior is driven by peripheral neuron hyperexcitability (Aim 1B). In a parallel study, I will determine
whether acute application of hemin to cultured WT DRG neuron induces aberrant neuronal activity and if this
dependent on heme's canonical receptor, Toll-like Receptor 4 (TLR4) (Aim 1C). In Aim 2, I hypothesize that
chronically elevated heme is required for the maintenance of SCD pain. I will utilize evoked and non-evoked
pain behavior assays to determine whether the heme scavenger haptoglobin reduces pain behavior in Townes
SCD mice (Aim 2A). Additionally, I will use ex vivo tibial nerve fiber recordings (Aim 2B) and whole-cell patch
clamp electrophysiology (Aim 2C) to determine whether the haptoglobin reduces SCD sensory neuron
hyperexcitability and mechanical hypersensitivity in these mice. Together these aims will determine if heme
drives evoked and non-evoked pain behavior through peripheral sensitization and if heme may be targeted to
alleviated SCD chronic pain.

## Key facts

- **NIH application ID:** 10898642
- **Project number:** 5F30HL170588-02
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Samuel Joshua Zorn
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $51,064
- **Award type:** 5
- **Project period:** 2023-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898642

## Citation

> US National Institutes of Health, RePORTER application 10898642, Investigating the Role of Heme in Acute and Chronic Sickle Cell Disease Pain (5F30HL170588-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10898642. Licensed CC0.

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