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Prenatal alcohol exposure generates vulnerability to the proinflammatory effects of morphine and adverse neuroimmune consequences

Award Number: R01AA029694
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Exposure to alcohol during gestation can lead to a constellation of mild to severe cognitive and behavioral deficits referred to as Fetal Alcohol Spectrum Disorders (FASD), having a US prevalence as high as ~4.8%. Although clinical studies on long-term consequences of prenatal alcohol exposure (PAE) are sparse, high prevalence of substance use (e.g., alcohol, opioids) is observed in adult FASD populations which may stem from aberrant neuroimmune interactions following exposure to alcohol or opioids. This proposal examines whether PAE induces susceptibility to neuroimmune dysfunction following opioid pain therapy in animal models. In PAE animal models, heightened production of proinflammatory cytokines including interleukin-1ß (IL-1ß) in the adult central nervous system (CNS) is observed. Our recent work in animal models suggest that PAE is a risk factor for developing CNS pathology such as pathological pain (allodynia) through the actions of spinal astrocyte and macrophage activation by their release of IL-1ß and tumor necrosis factor-a (TNF-a). A critical innate immune receptor underlying increased IL-1ß and TNF-a is Toll Like Receptor (TLR4), that upon its activation, produces downstream NLRP3 inflammasome signaling and consequent IL-1ß. Curiously, morphine, a standard pain therapeutic acting on the µ-opioid receptor, also activates proinflammatory TLR4 signaling resulting in opponent processes; µ-opioid cellular actions to blunt pain and immune TLR4 cellular actions that cause pain. Consequently, higher doses of morphine may be required to achieve pain alleviation in some populations. Based on this background, we speculate that PAE may generate biological vulnerability to CNS pathology by sensitizing TLR4 responses to endogenous factors and morphine that readily interact with TLR4. Thus, one goal of this proposal is to identify if morphine treatment in mice unmasks the insidious effects of PAE on neuroimmune function resulting in chronic CNS pathological consequences. Preliminary data show morphine exposure paradoxically prolongs the course of allodynia in minor nerve-injured adult PAE mice. The potential convergence of PAE and opioid-induced TLR4 actions is entirely unexplored. Therefore, our hypothesis is: PAE primes the TLR4-NLRP3-IL-1ß pathway that is unmasked by endogenous pain-enhancing factors and morphine interacting with TLR4 resulting in chronic pathological neuroimmune function. The Aims of the proposal will determine if : (I) PAE augments morphine-mediated TLR4 &/or NLRP3 activation in minor nerve-injured mice causing prolonged allodynia, (II) PAE sensitizes the effects of morphine on TLR4/NLRP3 responses in spinal astrocytes and peripheral macrophages, and (III) the contribution of non-coding circ-Vopp1 dysregulation in PAE-primed TLR4 signaling in response to morphine. Results will provide new evidence for PAE as a risk factor for adverse opioid responses and will identify novel targets to mitigate the risk of neuroimmune dysfunction from adverse TLR4 actions in individuals with FASD.


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: 2024 ( Subtotal = $338,927 )
2024	2024	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Alcohol Research Programs	000	3	2/21/2024	NON-COMPETING CONTINUATION	$338,927
														Subtotal = $338,927

Issue Date FY: 2023 ( Subtotal = $379,600 )
2023	2023	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Alcohol Research Programs	000	2	2/21/2023	NON-COMPETING CONTINUATION	$379,600
														Subtotal = $379,600

Issue Date FY: 2022 ( Subtotal = $382,574 )
2022	2022	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Alcohol Research Programs	000	1	2/22/2022	NEW	$382,574
														Subtotal = $382,574

Grand Total All Awards = $1,101,101

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Prenatal alcohol exposure generates vulnerability to the proinflammatory effects of morphine and adverse neuroimmune consequences

Award Number: R01AA029694

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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