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Optogenetic Manipulation of Neural Circuits During Monitoring Sleep/wakefulness States in Mice
Published on: June 19, 2019
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Identifying the Brain Circuits that Regulate Pain-Induced Sleep Disturbances
Nicole Lynch1, Roberto De Luca1, Richard L Spinieli1
1Department of Neurology, Division of Sleep Medicine, and Program in Neuroscience, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, 02215, USA.
Biorxiv : the Preprint Server for Biology
|January 7, 2025
Summary
Targeting specific brain pathways that promote wakefulness can effectively reduce pain-induced sleep disturbances. This approach offers a promising alternative to traditional pain medications, minimizing risks and improving sleep quality.
Area of Science:
- Neuroscience
- Pain Research
- Sleep Science
Background:
- Chronic pain and sleep loss impair the effectiveness of opioid analgesia by reducing opioidergic system sensitivity.
- Understanding the neural mechanisms linking pain and sleep disturbances is crucial for developing effective treatments.
- The spino-parabrachial pathway and parabrachial nucleus expressing Calcitonin Gene-Related Peptide (PBelCGRP) neurons are implicated in gating aversive stimuli.
Purpose of the Study:
- To investigate the link between nociceptor activation, pain, and subsequent sleep disturbances.
- To determine if targeted blockade of the PBelCGRP wake pathway can alleviate pain-induced sleep issues without causing somnolence.
- To identify specific brain regions and receptors involved in mediating pain-induced sleep disturbances.
Main Methods:
- Acute inflammatory pain (AIP) and opto-pain models were used to induce pain.
- Selective genetic ablations and optogenetic silencing techniques were employed to inactivate PBelCGRP neurons and their terminals.
- Pharmacological blockade of CGRP and NMDA receptors at specific brain sites (SI-BF, CeA) was performed.
Main Results:
- Nociceptor activation in both pain models induced sleep loss, reduced sleep spindle density, and increased sleep fragmentation.
- Inactivation of glutamatergic PBelCGRP neurons prevented these pain-induced sleep disturbances.
- Silencing PBelCGRP terminals in the substantia innominata of the basal forebrain (SI-BF) and the central nucleus of the Amygdala (CeA) reversed sleep loss, mediated by CGRP and NMDA receptors.
Conclusions:
- The glutamatergic PBelCGRP pathway plays a critical role in mediating sleep disturbances associated with acute pain.
- Targeting specific wake pathways, particularly within the SI-BF and CeA, offers a potential therapeutic strategy for co-treating pain and sleep disorders.
- This approach may provide a safer alternative to traditional analgesics by avoiding risks associated with opioid medications.
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