Low-dose naltrexone (LDN): Tricking the body to heal itself
From the page: “Researchers at The Pennsylvania State University College of Medicine, Hershey, Pennsylvania have discovered the mechanism by which a low dose of the opioid antagonist naltrexone (LDN), an agent used clinically (off-label) to treat cancer and autoimmune diseases, exerts a profound inhibitory effect on cell proliferation.
It has been postulated that opioid receptor blockade by LDN provokes a compensatory elevation in endogenous opioids and opioid receptors that can function after LDN is no longer available. Using a novel tissue culture model of LDN action, the mechanism of LDN has been found to target the opioid growth factor (OGF, Met5-enkephalin) and OGF receptor (OGFr) axis. This discovery, reported in the September 2011 issue of Experimental Biology and Medicine, provides new insights into the molecular pathway utilized by an increasingly important clinically prescribed agent that serves as a basic biological regulator of cell proliferative events related to pathobiological states such as cancer and autoimmune diseases
Although the antitumor effects of opioid antagonists were first noted by Drs. Zagon and McLaughlin in 1981 (Life Sci. 28:1095-1102, 1981), the first full reports about opioid antagonists modulating growth processes occurred in 1983 (Science 221:671-673; ibid, 221:1179-1180). This led to the hypothesis that endogenous opioid systems play a role in cancer, development, and cellular renewal (Life Sci. 35:409-416, 1984; ibid, 35:2057-2064, 1984). These papers revealed that a short-term opioid receptor blockade with naltrexone (NTX), a general opioid receptor antagonist devoid of intrinsic activity, results in an elevation in endogenous opioids and opioid receptors in response to the opioid receptor blockade. Interference of opioid peptide-opioid receptor interactions for a short time each day (4-6 hr) with LDN provided a subsequent window of time (18-20 hr) for the increased levels of endogenous opioids and opioid receptors to interface and elicit a robust functional response: inhibition of cell proliferation. The question that now can be addressed is which endogenous opioid(s) and opioid receptor(s) are responsible for LDNâ,s effects on cell proliferative processes.
The present study was structured to focus on the relationship of endogenous opioid pathways and the repercussions of intermittent opioid receptor blockade with regard to cell proliferation. A unique tissue culture model of LDN using a short-term exposure to NTX was developed, thereby avoiding the confounding variables introduced by systemic influences and allowing a dissection of the biological events involved. Screening of a wide variety of opioids (some selective for specific opioid receptors) revealed that only exogenous OGF had a profound effect on depressing cell proliferation. Removal of endogenous OGF by antibody neutralization in cultures given a short-term opioid receptor blockade by NTX eliminated the repressive effects of this peptide on cell proliferation, indicating that the repercussions of short-term NTX exposure in vitro was dependent on OGF. Short-term NTX blockade continued to exert a negative effect on cell proliferation even when the classical opioid receptors, i, a, and e, were knocked down by siRNA technology. However, short-term NTX treatment did not repress cell proliferation when cells were subjected to siRNA to the non-classical opioid receptor, OGFr. These results indicate that the effects of short-term NTX in vitro are dependent on the OGF-OGFr axis. Previous studies have shown that the OGF-OGFr axis regulates cell proliferation by altering the G1/S phase of the cell cycle through the cyclin-dependent inhibitory kinases p16 and p21. Knockdown experiments with siRNA show that a short interval of exposure to NTX in tissue culture required p16 and/or p21 in order to have a functional outcome on cellular processes.”