Deling Yin M.D., Ph.D. Associate Professor

Department of Internal MedicineCollege of Medicine

East Tennessee State UniversityJohnson City, TN 37614

Role of Cell Apoptosis in Drug Abuse and Human Diseases

Apoptosis

Apoptosis is an active process that results in membrane blebbing, DNA fragmentation. It is gene-directed process responsible for a number of membrane receptors and cytoplamic proteins. Apoptosis plays a fundamental role in a variety of physiological process and its deregulation contributes to many diseases, including AIDS and autoimmune diseases.

Growing evidence demonstrated that HIV-1/AIDS and opioid drugs are capable to induce apoptosis of immune cells, but the mechanism is not clear.

ApoptosisProgrammed Cell Death

Flow cytometry is a powerful tool to determine the number of apoptotic cells.

DNA content

Two years ago, Dr. Junying Yuan’s group reported for the first time that “necroptosis” contributes to delayed mouse ischemic brain injury in vivo (Nature Chemical Biology. 2005. 1, 112-119). “Necroptosis” is from necrosis and apoptosis.

Absence of trophic factor: Caspase activation

Opioids (e.g. morphine)are an old class of drugs derived from the poppy of opium plant Papaver somniferum.

Opioids

Opioids have been used for centuries as pain relievers. Opioids have effects on perception of pain, consciousness, and motor control.

Long-term use of opioid leads to tolerance, dependence, and addiction and their mechanisms remain to be elucidated. Previous research suggested that the abnormal gene expression in brain, impairment of neuronal cells and changes in the plasticity of neuron may play important roles in the development of opioid addiction.

30% of HIV-1 infected individuals are drug abuse, and most of these individuals abuse opioids.

Opioids induce specific signal transduction processes through specific opioid receptors.

Although the last 30 years extraordinary progress have been marked in efforts to deal with the interactions of opioid abuse and HIV-1/AIDS, we still lack fundamental knowledge of the cause of addiction, and certainly lack definitive treatments and cures for many patients.

Opioids ReceptorsOpioid receptors belong to G protein-coupled receptors (GPCRs)

Morphine, heroin, and many related synthetic opioids produce their major effects through specific cell surface opioid receptors.

Opioid receptors and their agonists and antagonists

µ қ δ All other

Agonists DAMGOEndormorphine-1Endormorphine-2

U69593Dynorphine A

U-50,488HRU51599

PhenylacetamineMethylpiperidine

DADLEDPDPEDSLETSNC 80

SNC 121

MorphineEtorphineCodeine

EnkephalinEndorphineDynorphine

Nociceptin(orphanin

FQ)(ORL1)

Antagonists

CTAPBeta-

FunaltrexamineNaloxonazine

DIPPANor-

binaltorphimine

DALCEICI-154,129

NatrindoleTIPP

BNTXmaleate

NatrexoneNaloxone

DiprenorphineNocistatin

Note: µ-receptor is the main receptor for morphine, heroin and other opioids

Mu-Opioid Receptor Mediated Signaling

HIV-1/AIDS and Apoptosis

HIV-1 is a retrovirus. Continuous HIV-1 replication leads to the destructionOf immune cells, profound immune dysfunction, and finally, progressionto AIDS.

Disease progression during HIV-1 infection correlates with both elevated levels of apoptosis and increased virus load. However, the molecular mechanisms of the HIV-1-assocaite loss of CD4+ T cells in HIV-1Infected individuals.

Gp120, the HIV-1 envelope glycoprotein, stimulates pro-apoptotic signaling.

Further understanding of the regulation of apoptosis in HIV-1 disease Will lead to the development of novel immune-based therapies for HIV-1Infection and AIDS treatment.

Opioid Drug Abuse and HIV-1 Interactions

Injection drug users comprise over 30% of the HIV-1-infected population, and many of subjects abuse opioids

Opioid drugs (e.g. morphine, heroin) are major risk factors and are the fastest growing means for spread of HIV-1 infection.

A few studies have demonstrated that morphine significantly increase Gp120-induced cell apoptosis through the p38 mitogen-activated protein kinase (MAPK) signaling pathway.

However, the molecular mechanism by which gp120 affects the immune response, particularly in the opioid-addicted individual, remains to be defined.

Mechanisms of HIV-1 Gp120-Induced Apoptosis

β-Arrestin-Mediated Signaling

Lefkowitz RJ et al. Science. 2005;308:512-517

Beta-Arrestin-Mediated Signaling in the Heart

Critical involvement of beta-arr 1 in experimental autoimmune encephalomyelitis (for multiple sclerosis)

Nat Immunol. 2007 Aug;8(8):817-24

Beta-Arr2 Deficiency Promotes Lung Tumor Growth, Lung Metastasis, and Mortality

J. Immunol. 2008;180;5699-5706.

Model of β-arrestin Mediated Migration and Metastasis