Heroin is a highly addictive drug and its abuse continues to be a major public health problem. Heroin abuse is associated with high mortality due to overdose, high risk of contracting diseases such as HIV/AIDS and viral hepatitis, and crime that often exceed that of most other abused drugs. Extensive research efforts have been dedicated to understanding the regulation of 5-opioid receptor (MOR), molecular target of heroin metabolites such as morphine, but limited studies have been conducted directly in the human brain regarding MOR and its intracellular signaling in relation to heroin abuse. Heroin abuse has a high genetic load and mutation of the MOR gene (OPMR1) has been linked with heroin abuse risk. During the first funding period for our studies, we documented that H 90% of subjects with the A118G mutation in our postmortem brain bank collection, from a homogenous Caucasian population, were heroin abusers. Neurobiological studies revealed that the polymorphism was relevant to opioid neuropeptide expression in the nucleus accumbens linked to reward and goal-directed behavior. Moreover, subjects with the 118G allele had higher functional coupling of the MOR in the nucleus accumbens. The proenkephalin (PENK) opioid neuropeptide is also strongly associated with reward and individuals with genetic polymorphism of this gene also had sensitized opioid receptor G-protein coupling in the nucleus accumbens. It is the aim of the next phase of our project to investigate more thoroughly the regulation of MOR;the intracellular G-protein signaling cascades that mediates the physiological actions of this receptor in heroin abusers and in relation to the OPMR1 polymorphism. Factors that modulate MOR function such as receptor density, phoshorylation state, dimerization with 4-opioid receptors, and coupling to 2-arrestin will be studied. Cluster and network analysis will be conducted on RNA data already collected from microarray analysis and customized real-time PCR datasets to identify the intracellular regulatory pathways linked to opioid receptor G-protein signaling. Key proteins within these networks will also be studied to validate the functional disturbances in relation to heroin use and the OPMR1 mutation. Expanding knowledge regarding MOR and its intracellular signaling machinery directly in the human brain will provide a major insight as to the neurobiological correlates linked with heroin abuse vulnerability and targets for medication development.

Public Health Relevance

Heroin is a highly addictive drug and its abuse continues to be a major public health problem. Expanding knowledge regarding the regulation and function of mu opioid receptor, the target for heroin, directly in the human brain and in relation to genetic mutations will provide a major insight as to the neurobiological correlates linked with heroin abuse vulnerability. As such targeted for medications can be development.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Boyce, Cheryl A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
Zip Code
Xu, Jin; Lu, Zhigang; Xu, Mingming et al. (2014) A heroin addiction severity-associated intronic single nucleotide polymorphism modulates alternative pre-mRNA splicing of the ? opioid receptor gene OPRM1 via hnRNPH interactions. J Neurosci 34:11048-66
Linnertz, Colton; Lutz, Michael W; Ervin, John F et al. (2014) The genetic contributions of SNCA and LRRK2 genes to Lewy Body pathology in Alzheimer's disease. Hum Mol Genet 23:4814-21
Xu, Jin; Xu, Ming; Brown, Taylor et al. (2013) Stabilization of the *-opioid receptor by truncated single transmembrane splice variants through a chaperone-like action. J Biol Chem 288:21211-27
Manini, A F; Jacobs, M M; Vlahov, D et al. (2013) Opioid receptor polymorphism A118G associated with clinical severity in a drug overdose population. J Med Toxicol 9:148-54
Jacobs, Michelle M; Murray, Jacinta; Byrd, Desiree A et al. (2013) HIV-related cognitive impairment shows bi-directional association with dopamine receptor DRD1 and DRD2 polymorphisms in substance-dependent and substance-independent populations. J Neurovirol 19:495-504
Sillivan, Stephanie E; Whittard, John D; Jacobs, Michelle M et al. (2013) ELK1 transcription factor linked to dysregulated striatal mu opioid receptor signaling network and OPRM1 polymorphism in human heroin abusers. Biol Psychiatry 74:511-9
Manini, Alex; Jacobs, Michelle; Vlahov, David et al. (2013) On the role of genetic testing for personalized drug overdose management. J Med Toxicol 9:294-5
Mazei-Robison, Michelle S; Koo, Ja Wook; Friedman, Allyson K et al. (2011) Role for mTOR signaling and neuronal activity in morphine-induced adaptations in ventral tegmental area dopamine neurons. Neuron 72:977-90
Okvist, Anna; Fagergren, Pernilla; Whittard, John et al. (2011) Dysregulated postsynaptic density and endocytic zone in the amygdala of human heroin and cocaine abusers. Biol Psychiatry 69:245-52
Lachmann, Alexander; Xu, Huilei; Krishnan, Jayanth et al. (2010) ChEA: transcription factor regulation inferred from integrating genome-wide ChIP-X experiments. Bioinformatics 26:2438-44

Showing the most recent 10 out of 17 publications