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Functional anatomy, physiology and behavioral responses mediated by mu opioid receptor signaling on medial thalamic neurons.

Award Number: R01DA062636
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2031

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Functional anatomy, physiology and behavioral responses mediated by mu opioid receptor signaling on medial thalamic neurons. - Project Summary/ Abstract Opioids like morphine are the most effective pain relieving drugs available but their rewarding properties lead to misuse. The rewarding and analgesic properties of opioids are mediated by activation of mu opioid receptors (MOR). Hyperalgesia is an exaggerated pain perception in response to a stimulus that is normally mildly uncomfortable. Hyperalgesia occurs when opioid-dependent people discontinue opioid use, known as opioid withdrawal-induced hyperalgesia (OWIH). Opioids also relieve this hyperalgesia providing motivation for continued opioid use and dose escalation. Midline thalamic (MThal) nuclei are key hubs responsible for activating brain regions involved in opioid modulation of pain and motivation. However, we lack critical details about what aspects of opioid-mediated behavior and physiology are due to MOR activation on thalamic neurons. We have found that glutamate transmission from MThal neurons to cortical and striatal brain regions is inhibited by MOR agonists like morphine. We hypothesize that MThal neurons are a heterogeneous mix of MOR-expressing and MOR-lacking neurons. We further hypothesize that prolonged inhibition of MThal neurons by opioids can induce adaptations leading to hyperalgesia upon opioid withdrawal (OWIH) while acute opioid-inhibition of MThal neurons will attenuate hyperalgesia. The long term goal of this project is to understand what neurons in the MThal express MOR, how these MOR-expressing MThal neurons respond to conditions that cause hyperalgesia, including OWIH, and whether inhibition of these neurons is sufficient to suppress hyperalgesia. We will use behavioral pharmacology, imaging, whole-cell electrophysiology, and optogenetic manipulations in mice to gain a foundational understanding of how opioid action in thalamo- cortico-striatal brain circuits ultimately affect hyperalgesia and antihyperalgesia. Aim 1 will determine the relative abundance of both MOR-expressing and MOR-lacking medial thalamic neurons and determine whether these neuronal populations share convergent or divergent innervation patterns. From this we will learn whether morphine inhibition of neurotransmission in the medial thalamus shows anatomic specificity or is a consistent effect across medial thalamic neurons. Aim 2 will determine whether MOR-expressing medial thalamic neurons are preferentially activated by conditions that cause hyperalgesia. Aim 3 will investigate whether inhibition of MOR-expressing MThal neurons is necessary and sufficient to block hyperalgesia. This will link opioid effects in specific cell populations to behavioral effects on pain processing so that we can better dissociate brain circuits mediating reward and pain relief by opioids. This knowledge will lead to a better understanding of MThal functional anatomy and the role of thalamic neurons in both inducing OWIH and relieving hyperalgesia.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $595,171 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Drug Use and Addiction Research Programs	000	1	5/7/2026	NEW	$595,171
														Subtotal = $595,171

Grand Total All Awards = $595,171

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Functional anatomy, physiology and behavioral responses mediated by mu opioid receptor signaling on medial thalamic neurons.

Award Number: R01DA062636

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2031

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