Nazira El-Hage

Research topics

Matched from this investigator's NIH project titles and abstracts.

• Addiction and Substance Use
• Pain and Nociception
• Developmental Cognitive Neuroscience
• Neuroplasticity and Neural Repair

Active NIH awards

• Title: Pharmacokinetic, pharmacodynamic , and toxicological interactions among Opioids and Cabotegravir

  5R01DA057145-04

  NIDA · FY 2025 · $694K

  SUMMARY STATEMENT We have identified a previously overlooked problem regarding a possible drug-drug interaction (DDI) among patients with opioid use disorders (OUDs) with high risk to HIV that are using Pre-Existing Prophylaxis (PrEP). Morphine and cabotegravir are metabolized by the enzyme, uridine diphosphate glucuronosyltransferase (UGT) and when combined, can influence the rate of drug metabolism, creating a potential risk for toxicity in people with comorbid HIV and OUD. Opioids are the cornerstone of pain management, and as long as they are continuing to be widely prescribed for chronic pain and/ or illicitly abused, the opioid epidemic in the United States (US) will continue to soar. OUDs are often comorbid with HIV infection, and studies have shown that individuals who misuse opioid analgesics, as well as other illicit drugs, are most likely to have difficulty adhering to antiretroviral (ART) medication regimens. Adverse DDI between ART and opioid abuse and/or medications to treat OUDs are frequently reported. In a recent publication, we showed that co-exposure with morphine and ART in HIV-infected brain reservoirs led to failure in the attenuation of viral load and increased secretion of viral- induced inflammatory molecules. Co-exposure with morphine and ART caused an increase in several histone- modifying enzymes which correlated with an increase in the mRNA expression of different variants of the μ- opioid receptor; suggesting that changes in epigenetic and opioid receptors may be involved in the regulation of DDI. Gap in Knowledge: Not much is known about the potential DDI among cabotegravir and morphine and/or medications to treat opioid use disorders (naltrexone). On that note, we hypothesize that when taken in combination, cabotegravir and morphine and/or naltrexone exhibit synergism that can influence the pharmacokinetic (PK) and pharmacodynamic (PD) responses, resulting in drug toxicity. We further posit that epigenetic variations due to the combined exposure of cabotegravir and opioids control the PK/PD responses by regulating drug-metabolizing enzymes, transporters, and/or the μ-opioid receptors. The goal of this new application is to evaluate potential interactions among opioids and cabotegravir. Specific Aim 1 will evaluate the PK responses among the three groups of drugs (cabotegravir - morphine - naltrexone) in healthy mice model. Specific Aim 2 will evaluate the PD responses, and toxicological interactions among the three groups of drugs in non-infected or HIV-infected humanized mouse model. Specific Aim 3 will evaluate the PK/PD, and toxicological interactions among the three groups of drugs in non-human primates. Impact: Findings will provide novel insights in the potential mechanisms involved in the adverse DDIs among cabotegravir and opioids which are used in clinical settings. Furthermore, an understanding of the pharmacoepigenetics will identify new targets that might help in the interference with pharmacokinetics or pharmacodynamics of opioids and cabotegravir.

• Function of astrocytes autophagy in brain homeostasis and opioid-induced maladaptive behavior and addiction, in the context of HIV

  5R01DA057884-03

  NIDA · FY 2025 · $349K

  SUMMARY/ABSTRACT The overarching goal of this proposal is to identify and characterize mechanistic pathways in astrocytes responsible for changes in drug-evoked structural and synaptic plasticity that underlie the maladaptive behavior in opioid drug abuse. Astrocytes are a logical focus for these studies, as they are intimately involved in diverse neuronal function, including modulation of synaptic function and plasticity, regulating concentrations of the excitatory neurotransmitter glutamate, and yet secrete and response to neuroinflammatory cytokines, chemokines, and growth factors. These processes are themselves regulated by autophagy: the process by which cells both engage in orderly degradation and recycling of cellular components as well as balancing energy metabolism. Although astrocyte-mediated excitation and inflammation have been implicated in neuroadaptations and drug-seeking behavior, the role of astrocytes autophagy in the mechanism underlying the intersection between the glutamate system and neuroimmune signaling, is not well understood. Findings from our lab showed that a key autophagy protein, Beclin1, is strongly associated with the secretion of cytokines, chemokines, and growth factors released from glia and neurons. We also showed that activation of autophagy increases glutamate uptake along with glutamate transporters expressed in astrocytes, collectively establishing a strong premise for the current proposed investigations. Extending our initial studies, here we hypothesize that autophagy- mediated neuroimmune signaling and glutamate metabolism in astrocytes ± HIV alters neuronal circuitry to promote opioid use disorder (OUD) and abuse. Since opioid and HIV-infection are common comorbidities, and opioids are commonly prescribed to HIV-infected individuals experiencing pain, studies will include assessment of HIV-infection through use of EcoHIV in a series of mouse models, facilitating the needed behavioral, neuroanatomical, and mechanistic studies to address the current knowledge gap. In Specific Aim (SA) 1 we will use Becn1+/- and Becn1+/+ mice to define the role of astrocyte autophagy with or without HIV and/or chronic opioid exposure on the progression and magnitude of opioid addiction, withdrawal, long-term abstinence, and relapse in validated behavioral models. In SA 2 we will use brain tissue harvested from mice tested in Aim 1 to decipher the interlink between excitation and inflammation-evoked changes in neurochemical and neuroanatomical plasticity and maladaptive behavior in opioid drug abuse (with or without HIV), through the lens of astrocytes autophagy. In SA 3 we will use brain cells to further investigate the mechanisms by which Beclin1 interacts with the μ-opioid receptor and/or associated proteins and analyze how Beclin1 activity modulates endolysosomal trafficking and degradation of MOR intracellular trafficking in brain cells in response to opioid (with and without HIV). Findings are expected to produce mechanistic insights into how autophagy regulates the underlying crosstalk between astrocytes and neuronal circuitry mediating OUD and abuse behaviors, yielding both novel therapeutic targets for development and strategies for preventing OUD in at risk HIV populations.

• Title: Pharmacokinetic, pharmacodynamic , and toxicological interactions among Opioids and Cabotegravir

  5R01DA057145-03

  NIDA · FY 2024 · $356K

  SUMMARY STATEMENT We have identified a previously overlooked problem regarding a possible drug-drug interaction (DDI) among patients with opioid use disorders (OUDs) with high risk to HIV that are using Pre-Existing Prophylaxis (PrEP). Morphine and cabotegravir are metabolized by the enzyme, uridine diphosphate glucuronosyltransferase (UGT) and when combined, can influence the rate of drug metabolism, creating a potential risk for toxicity in people with comorbid HIV and OUD. Opioids are the cornerstone of pain management, and as long as they are continuing to be widely prescribed for chronic pain and/ or illicitly abused, the opioid epidemic in the United States (US) will continue to soar. OUDs are often comorbid with HIV infection, and studies have shown that individuals who misuse opioid analgesics, as well as other illicit drugs, are most likely to have difficulty adhering to antiretroviral (ART) medication regimens. Adverse DDI between ART and opioid abuse and/or medications to treat OUDs are frequently reported. In a recent publication, we showed that co-exposure with morphine and ART in HIV-infected brain reservoirs led to failure in the attenuation of viral load and increased secretion of viral- induced inflammatory molecules. Co-exposure with morphine and ART caused an increase in several histone- modifying enzymes which correlated with an increase in the mRNA expression of different variants of the μ- opioid receptor; suggesting that changes in epigenetic and opioid receptors may be involved in the regulation of DDI. Gap in Knowledge: Not much is known about the potential DDI among cabotegravir and morphine and/or medications to treat opioid use disorders (naltrexone). On that note, we hypothesize that when taken in combination, cabotegravir and morphine and/or naltrexone exhibit synergism that can influence the pharmacokinetic (PK) and pharmacodynamic (PD) responses, resulting in drug toxicity. We further posit that epigenetic variations due to the combined exposure of cabotegravir and opioids control the PK/PD responses by regulating drug-metabolizing enzymes, transporters, and/or the μ-opioid receptors. The goal of this new application is to evaluate potential interactions among opioids and cabotegravir. Specific Aim 1 will evaluate the PK responses among the three groups of drugs (cabotegravir - morphine - naltrexone) in healthy mice model. Specific Aim 2 will evaluate the PD responses, and toxicological interactions among the three groups of drugs in non-infected or HIV-infected humanized mouse model. Specific Aim 3 will evaluate the PK/PD, and toxicological interactions among the three groups of drugs in non-human primates. Impact: Findings will provide novel insights in the potential mechanisms involved in the adverse DDIs among cabotegravir and opioids which are used in clinical settings. Furthermore, an understanding of the pharmacoepigenetics will identify new targets that might help in the interference with pharmacokinetics or pharmacodynamics of opioids and cabotegravir.

• Function of astrocytes autophagy in brain homeostasis and opioid-induced maladaptive behavior and addiction, in the context of HIV

  5R01DA057884-02

  NIDA · FY 2024 · $349K

  SUMMARY/ABSTRACT The overarching goal of this proposal is to identify and characterize mechanistic pathways in astrocytes responsible for changes in drug-evoked structural and synaptic plasticity that underlie the maladaptive behavior in opioid drug abuse. Astrocytes are a logical focus for these studies, as they are intimately involved in diverse neuronal function, including modulation of synaptic function and plasticity, regulating concentrations of the excitatory neurotransmitter glutamate, and yet secrete and response to neuroinflammatory cytokines, chemokines, and growth factors. These processes are themselves regulated by autophagy: the process by which cells both engage in orderly degradation and recycling of cellular components as well as balancing energy metabolism. Although astrocyte-mediated excitation and inflammation have been implicated in neuroadaptations and drug-seeking behavior, the role of astrocytes autophagy in the mechanism underlying the intersection between the glutamate system and neuroimmune signaling, is not well understood. Findings from our lab showed that a key autophagy protein, Beclin1, is strongly associated with the secretion of cytokines, chemokines, and growth factors released from glia and neurons. We also showed that activation of autophagy increases glutamate uptake along with glutamate transporters expressed in astrocytes, collectively establishing a strong premise for the current proposed investigations. Extending our initial studies, here we hypothesize that autophagy- mediated neuroimmune signaling and glutamate metabolism in astrocytes ± HIV alters neuronal circuitry to promote opioid use disorder (OUD) and abuse. Since opioid and HIV-infection are common comorbidities, and opioids are commonly prescribed to HIV-infected individuals experiencing pain, studies will include assessment of HIV-infection through use of EcoHIV in a series of mouse models, facilitating the needed behavioral, neuroanatomical, and mechanistic studies to address the current knowledge gap. In Specific Aim (SA) 1 we will use Becn1+/- and Becn1+/+ mice to define the role of astrocyte autophagy with or without HIV and/or chronic opioid exposure on the progression and magnitude of opioid addiction, withdrawal, long-term abstinence, and relapse in validated behavioral models. In SA 2 we will use brain tissue harvested from mice tested in Aim 1 to decipher the interlink between excitation and inflammation-evoked changes in neurochemical and neuroanatomical plasticity and maladaptive behavior in opioid drug abuse (with or without HIV), through the lens of astrocytes autophagy. In SA 3 we will use brain cells to further investigate the mechanisms by which Beclin1 interacts with the μ-opioid receptor and/or associated proteins and analyze how Beclin1 activity modulates endolysosomal trafficking and degradation of MOR intracellular trafficking in brain cells in response to opioid (with and without HIV). Findings are expected to produce mechanistic insights into how autophagy regulates the underlying crosstalk between astrocytes and neuronal circuitry mediating OUD and abuse behaviors, yielding both novel therapeutic targets for development and strategies for preventing OUD in at risk HIV populations.

• Title: Pharmacokinetic, pharmacodynamic , and toxicological interactions among Opioids and Cabotegravir

  5R01DA057145-02

  NIDA · FY 2023 · $365K

  SUMMARY STATEMENT We have identified a previously overlooked problem regarding a possible drug-drug interaction (DDI) among patients with opioid use disorders (OUDs) with high risk to HIV that are using Pre-Existing Prophylaxis (PrEP). Morphine and cabotegravir are metabolized by the enzyme, uridine diphosphate glucuronosyltransferase (UGT) and when combined, can influence the rate of drug metabolism, creating a potential risk for toxicity in people with comorbid HIV and OUD. Opioids are the cornerstone of pain management, and as long as they are continuing to be widely prescribed for chronic pain and/ or illicitly abused, the opioid epidemic in the United States (US) will continue to soar. OUDs are often comorbid with HIV infection, and studies have shown that individuals who misuse opioid analgesics, as well as other illicit drugs, are most likely to have difficulty adhering to antiretroviral (ART) medication regimens. Adverse DDI between ART and opioid abuse and/or medications to treat OUDs are frequently reported. In a recent publication, we showed that co-exposure with morphine and ART in HIV-infected brain reservoirs led to failure in the attenuation of viral load and increased secretion of viral- induced inflammatory molecules. Co-exposure with morphine and ART caused an increase in several histone- modifying enzymes which correlated with an increase in the mRNA expression of different variants of the μ- opioid receptor; suggesting that changes in epigenetic and opioid receptors may be involved in the regulation of DDI. Gap in Knowledge: Not much is known about the potential DDI among cabotegravir and morphine and/or medications to treat opioid use disorders (naltrexone). On that note, we hypothesize that when taken in combination, cabotegravir and morphine and/or naltrexone exhibit synergism that can influence the pharmacokinetic (PK) and pharmacodynamic (PD) responses, resulting in drug toxicity. We further posit that epigenetic variations due to the combined exposure of cabotegravir and opioids control the PK/PD responses by regulating drug-metabolizing enzymes, transporters, and/or the μ-opioid receptors. The goal of this new application is to evaluate potential interactions among opioids and cabotegravir. Specific Aim 1 will evaluate the PK responses among the three groups of drugs (cabotegravir - morphine - naltrexone) in healthy mice model. Specific Aim 2 will evaluate the PD responses, and toxicological interactions among the three groups of drugs in non-infected or HIV-infected humanized mouse model. Specific Aim 3 will evaluate the PK/PD, and toxicological interactions among the three groups of drugs in non-human primates. Impact: Findings will provide novel insights in the potential mechanisms involved in the adverse DDIs among cabotegravir and opioids which are used in clinical settings. Furthermore, an understanding of the pharmacoepigenetics will identify new targets that might help in the interference with pharmacokinetics or pharmacodynamics of opioids and cabotegravir.

• Function of astrocytes autophagy in brain homeostasis and opioid-induced maladaptive behavior and addiction, in the context of HIV

  1R01DA057884-01

  NIDA · FY 2023 · $361K

  SUMMARY/ABSTRACT The overarching goal of this proposal is to identify and characterize mechanistic pathways in astrocytes responsible for changes in drug-evoked structural and synaptic plasticity that underlie the maladaptive behavior in opioid drug abuse. Astrocytes are a logical focus for these studies, as they are intimately involved in diverse neuronal function, including modulation of synaptic function and plasticity, regulating concentrations of the excitatory neurotransmitter glutamate, and yet secrete and response to neuroinflammatory cytokines, chemokines, and growth factors. These processes are themselves regulated by autophagy: the process by which cells both engage in orderly degradation and recycling of cellular components as well as balancing energy metabolism. Although astrocyte-mediated excitation and inflammation have been implicated in neuroadaptations and drug-seeking behavior, the role of astrocytes autophagy in the mechanism underlying the intersection between the glutamate system and neuroimmune signaling, is not well understood. Findings from our lab showed that a key autophagy protein, Beclin1, is strongly associated with the secretion of cytokines, chemokines, and growth factors released from glia and neurons. We also showed that activation of autophagy increases glutamate uptake along with glutamate transporters expressed in astrocytes, collectively establishing a strong premise for the current proposed investigations. Extending our initial studies, here we hypothesize that autophagy- mediated neuroimmune signaling and glutamate metabolism in astrocytes ± HIV alters neuronal circuitry to promote opioid use disorder (OUD) and abuse. Since opioid and HIV-infection are common comorbidities, and opioids are commonly prescribed to HIV-infected individuals experiencing pain, studies will include assessment of HIV-infection through use of EcoHIV in a series of mouse models, facilitating the needed behavioral, neuroanatomical, and mechanistic studies to address the current knowledge gap. In Specific Aim (SA) 1 we will use Becn1+/- and Becn1+/+ mice to define the role of astrocyte autophagy with or without HIV and/or chronic opioid exposure on the progression and magnitude of opioid addiction, withdrawal, long-term abstinence, and relapse in validated behavioral models. In SA 2 we will use brain tissue harvested from mice tested in Aim 1 to decipher the interlink between excitation and inflammation-evoked changes in neurochemical and neuroanatomical plasticity and maladaptive behavior in opioid drug abuse (with or without HIV), through the lens of astrocytes autophagy. In SA 3 we will use brain cells to further investigate the mechanisms by which Beclin1 interacts with the μ-opioid receptor and/or associated proteins and analyze how Beclin1 activity modulates endolysosomal trafficking and degradation of MOR intracellular trafficking in brain cells in response to opioid (with and without HIV). Findings are expected to produce mechanistic insights into how autophagy regulates the underlying crosstalk between astrocytes and neuronal circuitry mediating OUD and abuse behaviors, yielding both novel therapeutic targets for development and strategies for preventing OUD in at risk HIV populations.