Endogenous opioid regulation of locus coeruleus-mediated analgesia

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Ream  Al-Hasani
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $497,550
Funding agency: National Institute of Neurological Disorders and Stroke

Abstract
The overall goal of this research is to better understand how endogenous opioids control the analgesic properties
of the central noradrenergic system. Endogenous opioid systems provide powerful inhibition of locus coeruleus
noradrenergic neurons and acute activation of mu opioid receptors in the locus coeruleus is antinociceptive.
Therefore, we hypothesized that this endogenous mu opioid receptor-mediated inhibition could be critical to how
the locus coeruleus modulates pain. Using conditional knockout and rescue of locus coeruleus-mu opioid
receptor signaling, we show that the presence of these receptors in locus coeruleus neurons following
neuropathic injury can reverse the expression of mechanical allodynia and thermal hyperalgesia. However, it is
it is unknown whether the locus coeruleus-mu opioid receptor system is differentially modulated in pain states.
This research focuses on understanding the mechanisms by which endogenous opioids inhibit the locus
coeruleus noradrenergic system to promote endogenous analgesia and how chronic neuropathic injury disrupts
this system. The central hypothesis of this proposal is that loss of mu opioid receptor-mediated locus coeruleus
inhibition following long-term neuropathic injury promotes and maintains chronic pain. The first aim of this
proposal will use neurochemical and gene expression studies to determine how endogenous opioid ligand and
receptor systems in the locus coeruleus evolve following long-term neuropathic injury. The second aim seeks to
understand whether projections from the locus coeruleus to the medial prefrontal cortex are selectively
disinhibited after injury. This aim seeks to determine whether opioid sensitivity in these neurons is decreased in
chronic pain. To do so we will use a high-throughput calcium imaging assay and in vivo optogenetics test the
function of locus coeruleus neurons that project to the medial prefrontal cortex. The final aim seeks to identify
non-opioid strategies for inhibiting the locus coeruleus to discover new analgesic targets. These studies will
define the role of locus coeruleus mu opioid receptors 1) in pain from neuropathic injury, 2) along projections to
the medial prefrontal cortex, and 3) identify mechanisms to suppress pain-generating locus coeruleus activity.
This information will be critical for translational research targeting the noradrenergic system in the treatment of
pain and neuropsychiatric disorders.

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