Q.E.D

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This study specifically indicates that naltrexone prevents apoptosis.

QED (Quod Erad Demonstrandum)

Yash

Authors

Singhal PC. Bhaskaran M. Patel J. Patel K. Kasinath BS. Duraisamy S.

i N. Reddy K. Kapasi AA.

Institution

Immunology and Inflammation Center, North Shore-Long Island Jewish

Research Institute and Division of Kidney Diseases and Hypertension,

Long Island Jewish Medical Center, New Hyde Park, NY 11040, USA.

singhal@...

Title

Role of p38 mitogen-activated protein kinase phosphorylation and Fas-

Fas ligand interaction in morphine-induced macrophage apoptosis.

Source

Journal of Immunology. 168(8):4025-33, 2002 Apr 15.

Local Messages

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Abstract

In this study, we evaluated the molecular mechanisms involved in

morphine-induced macrophage apoptosis. Both morphine and TGF-beta

promoted P38 mitogen-activated protein kinase (MAPK)

phosphorylation, and this phosphorylation was inhibited by SB 202190

as well as by SB 203580. Anti-TGF-beta Ab as well as naltrexone (an

opiate receptor antagonist) inhibited morphine-induced macrophage

P38 MAPK phosphorylation. Anti-TGF-beta Ab also attenuated morphine-

induced p53 as well as inducible NO synthase expression; in

contrast, N(G)-nitro-L-arginine methyl ester, an inhibitor of NO

synthase, inhibited morphine-induced P38 MAPK phosphorylation and

Bax expression. Morphine also enhanced the expression of both Fas

and Fas ligand (FasL), whereas anti-FasL Ab prevented morphine-

induced macrophage apoptosis. Moreover, naltrexone inhibited

morphine-induced FasL expression. In addition, macrophages either

deficient in FasL or lacking p53 showed resistance to the effect of

morphine. Inhibitors of both caspase-8 and caspase-9 partially

prevented the apoptotic effect of morphine on macrophages. In

addition, caspase-3 inhibitor prevented morphine-induced macrophage

apoptosis. These findings suggest that morphine-induced macrophage

apoptosis proceeds through opiate receptors via P38 MAPK

phosphorylation. Both TGF-beta and inducible NO synthase play an

important role in morphine-induced downstream signaling, which seems

to activate proteins involved in both extrinsic (Fas and FasL) and

intrinsic (p53 and Bax) cell death pathways.

> " The effects of DAMGO, morphine, and etorphine on

apoptosis/necrosis

> were not fully blocked by concomitant administration of naloxone. "

>

> The study by Zagon (below) is important because it suggests that

> naltrexone in relatively low doses, partially blocks apoptosis

> (Apoptosis=programmed cell death), by certain drugs in cancer

cells.

>

> We now know that the Australians have said MS involves apoptosis

of

> neuronal cells. This study provides a plausible justification as

to

> how LDN might work (i.e. by preventing apoptosis). I occasionally

> correspond with Zagon, will check with him to see what he has to

say.

>

> Yash

>

>

> Zagon IS. McLaughlin PJ.

>

> Institution

> Department of Neuroscience and Anatomy, The Milton S. Hershey

> Medical Center, The Pennsylvania State University, College of

> Medicine, 500 University Drive, H-109, Hershey, PA 17033, USA.

> iszl@p...

>

> Title

> Opioids and the apoptotic pathway in human cancer cells.

>

> Source

> Neuropeptides. 37(2):79-88, 2003 Apr.

>

> Local Messages

> Hardin Library has issues up through 1999

>

> Abstract

> This study was designed to examine the role of opioids in cell

> survival, with an emphasis on the mechanism of opioid growth

factor

> (OGF, [Met(5)]-enkephalin)-dependent growth inhibition. Using

three

> human cancer cell lines: MIA PaCa-2 pancreatic adenocarcinoma, HT-

29

> colon adenocarcinoma, and CAL-27 squamous cell carcinoma of the

head

> and neck, and OGF and the opioid antagonist naltrexone (NTX) at a

> dosage (10(-6)M) selected because it is known to repress or

> increase, respectively, cell replication, the effects on apoptosis

> (TUNEL, Annexin V) and necrosis (trypan blue) were investigated on

> days 2, 5, and 7 of exposure. In addition, the influence of a

> variety of other natural and synthetic opioids on apoptosis and

> necrosis was examined at a dosage of 10(-6)M. OGF, NTX, naloxone,

[D-

> Pen(2,5)]-enkephalin, [Leu(5)]-enkephalin, dynorphin A1-8, beta-

> endorphin, endomorphin-1 and -2, and methadone at concentrations

of

> 10(-6)M did not alter cell viability of any cancer cell line.

> Exposure of cultures to [D-Ala(2),MePhe(4),Glycol(5)]-enkephalin

> (DAMGO), morphine, or etorphine at 10(-6)M significantly increased

> the number of adherent cells positively stained for TUNEL and

> Annexin V, as well as the number of necrotic cells in the

> supernatant, from control levels at all time points studied. The

> effects of DAMGO, morphine, and etorphine on apoptosis/necrosis

were

> not fully blocked by concomitant administration of naloxone.

Despite

> the increase in cell death in some opioid-treated groups, the

number

> of apoptotic and necrotic adherent cells, and the number of

necrotic

> cells in the supernatant, was no more than 1-2% of the total cell

> population. These results indicate that the inhibitory (OGF) or

> stimulatory (NTX) action on cell growth in tissue culture is not

due

> to alterations in apoptotic or necrotic pathways. Moreover,

although

> some opioids increased cell death, and dose-effect relationships

> need to be established, this activity was not of great magnitude

and

> supports the previously reported lack of growth inhibition of many

> of these compounds.