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Sex-specific mechanisms underlying the effects of pain on opioid seeking

Award Number: R01DA054900
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Sex-specific mechanisms underlying the effects of pain on opioid seeking - Pain is experienced by up to 20% of the US population at any given time. Opioid pain medications are potent analgesics commonly used to treat pain symptoms, but the misuse of opioids presents a major limitation for pain management. There is increasing support for sex differences for opioid misuse among pain patients. Although, prevalence rates for prescription opioid misuse between men and women are often found to be similar, this finding contrasts with the consistently higher prevalence of abuse in men compared to women. For example, male pain patients treated with opioids are more likely to increase intake of their opioid doses, misuse prescriptions, and die from overdose. However, little is known about sex-specific trends in long-term use of prescribed opioids for pain conditions. Sexual differences appear to play an important role in opioid misuse, but preclinical data on how pain or prior history of opioid intake contributes to sex differences in opioid abuse liability are limited. Preliminary findings from our lab have recapitulated the sex-dependent trends found in clinical data using a preclinical model. Our data show that male rats self-administer higher amounts of fentanyl than females. In addition, we found that persistent inflammatory pain increases fentanyl intake in males relative to females. This suggests that inflammatory pain conditions lead to a higher misuse liability selectively in males. In this project, we propose to investigate how pain alters neuroadaptative processes during long-term opioid use in a sex-specific manner and whether these functional changes are predictive of maladaptive patterns of fentanyl intake. The mesolimbic system is a key network node that integrates pain and reward. DA transmission in the mesolimbic system, via the ventral tegmental area (VTA) to the nucleus accumbens (NAc), has long been recognized for its role in reward processing and motivated behaviors. However, it remains unclear whether sex- dependent effects of pain on opioid use are mediated by sex differences in the patterns of VTA DA activity. Our preliminary data shows that persistent inflammatory pain reduces VTA DA neuron excitability by increasing the inhibitory drive onto VTA DA neurons from the GABAergic inputs of the rostromedial tegmental nucleus (RMTg). This suggests that under conditions of pain, higher opioid doses are necessary to trigger levels of VTA DA release comparable to those produced in non-pain conditions. However, it is unknown whether similar mechanisms underlie sex differences in the patterns of opioid misuse. Based on our preliminary findings, we hypothesize that pain exacerbates RMTg-mediated inhibition of VTA DA cell activity in males, but not females following opioid self-administration. This project aims to address this gap in our understanding by investigating the sex-specific functional consequences of pain and long-term opioid use within the RMTgVTA pathway.


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 = $557,264 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Drug Use and Addiction Research Programs	000	4	6/17/2025	NON-COMPETING CONTINUATION	$557,264
														Subtotal = $557,264

Issue Date FY: 2024 ( Subtotal = $557,264 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Drug Use and Addiction Research Programs	000	3	6/19/2024	NON-COMPETING CONTINUATION	$557,264
														Subtotal = $557,264

Issue Date FY: 2023 ( Subtotal = $522,276 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Drug Use and Addiction Research Programs	000	2	6/21/2023	NON-COMPETING CONTINUATION	$522,276
														Subtotal = $522,276

Issue Date FY: 2022 ( Subtotal = $526,867 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Drug Use and Addiction Research Programs	000	1	9/14/2022	NEW	$526,867
														Subtotal = $526,867

Grand Total All Awards = $2,163,671

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Sex-specific mechanisms underlying the effects of pain on opioid seeking

Award Number: R01DA054900

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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