Naltrexone is a mu-endorphin antgonist that is used as an opioid antagonist. It will reverse intoxication from opioid analgesics and has a longer duration of action than naloxone. Naloxone is preferred in emergency settings because of its faster onset of action, but naltrexone, unlike naloxone, is effective given by mouth, and its long duration of action (10 hrs) makes it a safer treatment for overdose with long-acting opioids such as methadone (24 hrs, but the half-life of methadone can be significantly decreased by urinary acidifiers such as ascorbic acid or citric acid, and is increased by urinary alkalizers such as sodium bicarbonate as methadone has low solubility at high urinary pH). Naltrexone's most common clinical use is in doses of 50mg daily as a maintenance treatment to blockade the addictive effects of both opiates and alcohol. Recently I spoke to an AOD patient using naltrexone in this way and was surprised that they reported that the drug had an anti-depressant effect. This isn't what would we'd expect under the old endorphin receptor model from a full-time blockade; dysphoria would be the predicted side-effect.
A clue lies in the popular off-label use of naltrexone at low doses (3-4.5 mg nocte) as an immune-modulating agent. The Low Dose Naltrexone homepage claims
Mu opioid receptor activation modulates Toll like receptor 4 in murine macrophages.
SourceDipartimento di Farmacologia Chemioterapia e Tossicologia medica, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milano, Italy.
Toll like receptors (TLRs) play a crucial role in the signaling pathways which lead to NFkB activation. TLR4 is considered the Lipopolysaccaride (LPS) receptor.
The data here presented show that, in murine macrophages, morphine impacts on the immune function acting on the early step of pathogen recognition. Morphine, when added to RAW 264.7 cells and when injected into mice (s.c. 20mg/kg) is in fact able to decrease TLR4 both at mRNA and protein level in RAW cells and peritoneal macrophages. In the same cells, the mu opioid receptor (MOR) antagonist Naltrexone increases TLR4 levels, thus suggesting a role of the endogenous opioid system in TLR4 regulation. The effect of the two drugs is moreover lost in case of co-administration.
Experiments with MOR KO mice and with DAMGO (MOR specific agonist) confirm that the effect of morphine on TLR4 mRNA in peritoneal macrophages is due to the MOR activation. Moreover the effect on TLR4 is blocked by PTX thus indicating the involvement of a G(i) protein after MOR binding. This work unveils a clear link between MOR activation and TLR4, suggesting a new possible mechanism at the basis of the peripheral immunosuppressive effect of opioids.
Make no mistake, this is edge-of-your seat scientific stuff that for my money is predictive of rapid medical progress in unexpected directions. For example: Recent evidence implicates toll-like receptor 4 (TLR4) in opioid analgesia, tolerance, conditioned place preference, and self-administration. In other words, some of the anti-addictive effect of naltrexone blockade is due to its TLR-4 agonism, not its mu-endorphin antagonism (though the two are probably indirectly connected). One obvious implication of this research is that the dose range for both LDN and addiction treatment should probably be much wider. Some people will need larger doses or more frequent dosing for LDN to work, or even smaller doses; VLDN, (0.125-0.250mg) treatment has been used to suport methadone withdrawal; while AOD patients who do not tolerate 50mg naltrexone may well benefit from lower doses. The dose thresholds for endorphin and TLR-4 effects are likely to be different and to vary between indviduals.
Exciting - nay, exhilarating. Sometimes you just gotta love science. It's one of those gifts that just keeps on giving.
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