# Dissection of the circuitry regulating arousal to pain

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $382,813

## Abstract

Project Summary/Abstract:
Acute and chronic pain is associated with disturbed sleep that leads to enhanced pain sensitivity. However,
less is known of the specific neural pathways that cause arousal in response to painful stimuli. Anatomical
studies have shown that the spino-parabrachial circuit relays nociceptive signals from the spinal cord. The
lateral PB, and especially the external lateral part of the PB (PBel), receives nociceptive spinal afferents from
numerous spinal neurons and then relays to forebrain and brainstem sites. Most of the PBel neurons express
the calcitonin gene-related peptide (CGRP), and we have recently shown that these neurons in the PBel
regulate waking-up response to hypercapnia by projecting to forebrain arousal areas. Based on our recent
study and anatomy known so far, we hypothesize that PBelCGRP neurons is also the critical relay node that
transmits pain to induce cortical arousals from sleep. We will test this hypothesis in Aim1, by inhibiting
PBelCGRP neurons using optogenetic and chemogenetic tools and investigate if PBelCGRP neurons are important
to waking up to pain, in both opto-pain model (activating CGRP nociceptors in foot) and in the conventional
inflammatory-pain model. Our preliminary data suggests that blocking PBelCGRP neurons prevents waking up to
CGRP nociceptor stimulation. In Aim2, we will selectively block each of the terminal fields of PBelCGRP neurons
while activating the CGRP nociceptors to induce acute pain stimuli. We have used this strategy recently to
unravel the pathways regulating waking up to CO2. In Aim2, we will investigate which one of its projection
targets, such as the substantia innominata (SI), the lateral hypothalamus (LH), the central nucleus of the
amygdala (CeA), and the bed nucleus of the stria terminalis (BST) are critical and most effective in blocking
pain induced wakefulness. Finally, in Aim3, using Channel Rhodopsin Assisted Circuit Mapping experimental
approach, we will first establish, if PBelCGRP neurons directly excite BF, CeA, BNST and LH neurons in the
brain slices, and next, we will test the functional synaptic connectivity between dorsal horn (DH) neurons in
spinal cord and PBelCGRP neurons (DH → PBelCGRP). Thus, modulating both peripheral nociceptors and central
pathways in a same mouse will help us to selectively dissect the role of PBelCGRP neurons and their outputs
pathways in regulating pain induced arousals. Investigating this converging neuro-circuitry for regulating pain
and arousal will help us understand their interaction and pave way for designing novel therapeutic
strategies targeted to the non-opioidergic pathways that can effectively block pain induced sleep
disturbances, without limitation of developing tolerance and abuse potential.

## Key facts

- **NIH application ID:** 10131879
- **Project number:** 5R01NS112175-03
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Satvinder Kaur
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $382,813
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10131879

## Citation

> US National Institutes of Health, RePORTER application 10131879, Dissection of the circuitry regulating arousal to pain (5R01NS112175-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10131879. Licensed CC0.

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