# Defining Mechanisms of Pain Relief Associated with Dorsal Root Ganglion and Spinal Cord Stimulation

> **NIH NIH RM1** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $5,583,518

## Abstract

Chronic pain is a debilitating condition for which there is a pressing need for safe, effective treatments as is
highlighted by the ongoing opioid crisis. One potential solution to this problem are neuromodulatory devices
such as spinal cord stimulators and dorsal root ganglion stimulators that are currently approved by the FDA for
the treatment of pain. While these devices have consistently generated promising results, they are only used in
a fraction of chronic pain patients as an intervention of last resort. One of the reasons that these devices are
not used more broadly is because their mechanism of action is largely unknown. Here we propose a series of
parallel and complementary experiments to investigate the mechanisms of pain relief for spinal cord (SCS) and
dorsal root ganglion (DRGS) stimulation, where conventional stimulation parameters will be used for DRGS,
and conventional, burst and kilohertz (kHz) stimulation will be used for SCS. We will focus on the two
prevailing models used to explain the therapeutic efficacy of these devices: 1) Gate-control, wherein
stimulation of large diameter afferent fibers activates inhibitory interneurons that block nociceptive signals from
reaching the brain; and 2) T-junction filtering, wherein stimulation of sensory neurons leads to conduction
failure at the T-junction in nociceptive fibers in the DRG, blocking nociceptive inputs from reaching the spinal
cord. Experiments designed to test these models are described under four Specific Aim in mice and rats with
and without chronic pain induced with chronic compression of the DRG, and in a human DRG nerve
preparation. In Aim 1 we will determine which neurons (primary afferent and/or dorsal horn) are activated by
SCS and DRGS with 2P-calcium imaging in mice, and single unit recording in rats and human tissue. We will
use the data generated at an unprecedented level of detail to refine computational models of the cells and
circuits engaged by these devices. In Aim 2 we will confirm the efficacy of DRGS and SCS neuromodulation on
simple reflexive responses and complex nociceptive behaviors in rats and mice. The timing and relative
efficacy of the site and parameters of neuromodulation will inform computational models and mechanistic
studies. In Aim 3 we will directly test the gate-control model using a novel strategy of 2P Ca2+ imaging in mice
enabling identification of subpopulations of inhibitory, excitatory, and projection neurons in the same
preparation. This will be combined with single unit and MEA recordings from rats and mice, all done in an
iterative fashion with computational modeling. In Aim 4 we will test the T-junction filtering model with direct
measurements of transmission efficiency in rat and human tissue. Pharmacological studies and computational
modeling will investigate specific mechanisms responsible for this filtering. The results from these conceptually
and technically innovative studies will provide a major advance in our understan...

## Key facts

- **NIH application ID:** 10519404
- **Project number:** 1RM1NS128775-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** H Richard Koerber
- **Activity code:** RM1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $5,583,518
- **Award type:** 1
- **Project period:** 2022-09-17 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10519404

## Citation

> US National Institutes of Health, RePORTER application 10519404, Defining Mechanisms of Pain Relief Associated with Dorsal Root Ganglion and Spinal Cord Stimulation (1RM1NS128775-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10519404. Licensed CC0.

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