# Defining the descending pain modulatory circuit

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2023 · $458,257

## Abstract

PROJECT SUMMARY
 The central nervous system has an intrinsic pain modulatory system that regulates nociceptive processing
through descending projections from the brainstem to the spinal cord dorsal horn. The ventrolateral
periaqueductal gray (vlPAG) integrates sensory information with input from higher cortical and subcortical
areas, and sends projections to the rostral ventromedial medulla (RVM) that are relayed to the dorsal horn of
the spinal cord. Both the vlPAG and RVM are heterogenous with respect to participating in multiple behavioral
circuits. The proposed studies build on extensive previous work from the Heinricher laboratory that has defined
the output from the RVM, showing that bidirectional pain control from this region is mediated by two
physiologically defined cell classes, “ON-cells” and “OFF-cells,” that respectively facilitate and inhibit dorsal
horn nociceptive transmission under different conditions. The Ingram laboratory has expertise studying opioid
actions within the PAG and RVM, as well as adaptations in both areas with persistent inflammation. Proposed
viral optogenetic strategies will map and define the vlPAG circuit that regulates RVM ON-cells involved in the
facilitation of pain and elucidate underlying cellular mechanisms that shift the balance of RVM output from
inhibition of pain to facilitation of pain with persistent inflammation. The combined expertise of the two
laboratories will focus on identified PAG-RVM synapses using optogenetic stimulation of RVM terminals
originating from the PAG. In vitro brain-slice recordings (Ingram lab) will examine the heterogeneity of PAG
output to the RVM and PAG-RVM synapses, as well as cellular mechanisms of synaptic plasticity induced in
persistent inflammation. These studies will use a fluorescent label for the μ-opioid receptor to differentiate
presumed ON-cells from other classes in the slice to determine whether PAG terminals directly synapse on
ON-cells, OFF-cells, or both, as well as what neurotransmitters are released. In vivo single-cell recording
studies (Heinricher lab) will determine how inflammation-induced changes in PAG-RVM synapses control
excitability of specific populations of RVM neurons and establish the link between these changes and pain
behaviors. A better understanding of molecular, cellular, and circuit-level mechanisms that underlie pain is
essential if we are to develop better treatments. By carefully mapping the descending projections from PAG to
RVM during the development of persistent inflammation, and by tying these to defined RVM outputs and
behavior, we can begin to determine the interactions in this complex network, and gain new insights into how
pain-modulating systems are recruited and modulated in acute and chronic pain.

## Key facts

- **NIH application ID:** 10656343
- **Project number:** 5R01NS120486-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Mary Magdalen Heinricher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $458,257
- **Award type:** 5
- **Project period:** 2022-10-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10656343

## Citation

> US National Institutes of Health, RePORTER application 10656343, Defining the descending pain modulatory circuit (5R01NS120486-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10656343. Licensed CC0.

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