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Morphine-responsive neurons of the medial habenula : a role in aversive states of morphine withdrawal ?

Award Number: R01DA048796
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Morphine-responsive neurons of the medial habenula : a role in aversive states of morphine withdrawal ? - Abstract Opioids target the mu opioid receptor (MOR). Opioid use is essentially motivated by pain relief and/or reward-seeking, however opioid abuse is strongly driven by other factors that include aversive emotional aspects of opioid withdrawal, which are at the center of this proposal. Here, we hypothesize that MOR- expressing neurons of the medial habenula (hereafter called MHb-MOR neurons) play a key role in the development of negative emotional responses characterizing opioid withdrawal. The proposal is based on four premises: (i) the MHb has become a recognized aversion center in addiction research, (ii) MOR-expressing neurons are highly abundant in the MHb, (iii) MOR-expressing neurons of the MHb modulate aversive states (our recent publication) and (iv) MOR-MHb neurons project to the raphe nucleus (RN), a major center for mood control (our unpublished data). Overall, we speculate that stimulating MHb-MOR neurons enhances the negative emotional experience of opioid withdrawal, whereas silencing these neurons alleviates the negative affect of withdrawal. Manipulating MOR-neurons has now become possible, as we have created a new transgenic MOR-Cre mouse line (unpublished). These mice will be used to manipulate MHb-MOR neurons in two behavioral models of short- (Aim 1) and long- (Aim 2) term withdrawal well established in our laboratory, and behavioral hallmarks of negative affect and their associated brain connectivity patterns will be studied. Aim 1 will use optogenetics to interrogate the contribution of MHb-MOR neurons in conditioned place aversion to low dose naloxone, and fMRI to characterize whole brain functional connectivity (WBFC) of the naloxone-evoked aversive state. Aim 2 will use chemogenetics to interrogate the contribution of MHb-MOR neurons in depressive-like behavior and social interaction deficits that develop upon prolonged withdrawal, and fMRI to identify the causal role of MHb-MOR in WBFC patterns alterations. Innovative aspects of this proposal are: (i) the focus on the function of MOR-expressing neurons for the first time; (ii) the notion that MOR neurons modulates activity of an aversion brain center (the MHb), providing a yet unexplored mechanistic angle on aversive states of opioid withdrawal; (iii) the study of a poorly known neural pathway (MHb/IPN/DRN microcircuitry), which has strong relevance to both addiction and depression research, (iv) the analysis of brain wide adaptations to chronic morphine using animal fMRI and (v) the translational potential for human research in growing efforts to fight the opioid crisis. We anticipate discovering novel neural mechanisms contributing to the negative affect of opioid withdrawal, and relevant to opioid use disorders. In the long-term, fMRI signatures may be translatable to human research. This proposal has strong basic and clinical implications, and can uniquely be developed by our team at the Douglas Research Center, McGill University Montréal. 1


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: 2025 ( Subtotal = $270,000 )
2025	2025	INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE	BATIMENT EXPLORA	STRASBOURG				FRA	Drug Use and Addiction Research Programs	000	6	6/27/2025	NON-COMPETING CONTINUATION	$270,000
														Subtotal = $270,000

Issue Date FY: 2024 ( Subtotal = $270,000 )
2024	2024	INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE	5 RUE JACOB MAYER BP 10005	STRASBOURG CEDEX 2				FRA	Drug Use and Addiction Research Programs	000	5	5/20/2024	NON-COMPETING CONTINUATION	$270,000
														Subtotal = $270,000

Issue Date FY: 2023 ( Subtotal = $270,000 )
2023	2023	INSERM ADR STRASBOURG	5 RUE J MAYER	STRASBOURG				FRA	Drug Use and Addiction Research Programs	000	4	5/19/2023	NON-COMPETING CONTINUATION	$270,000
														Subtotal = $270,000

Issue Date FY: 2022 ( Subtotal = $270,000 )
2022	2022	INSERM ADR STRASBOURG	5 RUE J MAYER	STRASBOURG	NULL			FRA	Drug Use and Addiction Research Programs	000	3	5/27/2022	NON-COMPETING CONTINUATION	$270,000
														Subtotal = $270,000

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	INSERM ADR STRASBOURG	5 RUE J MAYER	STRASBOURG				FRA	Drug Use and Addiction Research Programs	002	2	6/10/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$270,000
2021	2020	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL	845 RUE SHERBROOKE O	MONTREAL	PQ			CAN	Drug Use and Addiction Research Programs	001	1	6/10/2021	NEW	-$270,000
2021	2020	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL	845 RUE SHERBROOKE O	MONTREAL	PQ			CAN	Drug Use and Addiction Research Programs	000	1	10/16/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $270,000 )
2020	2020	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL	845 RUE SHERBROOKE O	MONTREAL	PQ	H3A 0G4		CAN	Drug Use and Addiction Research Programs	000	1	9/26/2020	NEW	$270,000
														Subtotal = $270,000

Grand Total All Awards = $1,350,000

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Morphine-responsive neurons of the medial habenula : a role in aversive states of morphine withdrawal ?

Award Number: R01DA048796

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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