To examine these observations, Dr. Ian Zagon and his colleagues at Pennsylvania State University conducted an animal study demonstrating the effects of low dose naltrexone (LDN), an opiate antagonist, on disease development and progression. The study was partially funded by grants from the National Multiple Sclerosis Society and the Paul K. and Anna E. Shockey Family Foundation.
Opioids in Multiple Sclerosis
Multiple sclerosis is an inflammatory autoimmune demyelinating disease of the central nervous system. MS affects more than 400,000 people in the U.S. and approximately two million people worldwide. The origin of MS is unknown although several theories have been proposed to explain why the myelin sheath covering nerve fibers is destroyed.
The endogenous opioid system is comprised of native opioid peptides (endorphins, enkephalins, metenkephalins) and opioid receptors. Related to neurotransmitters, the opioid peptides have a number of biological actions, including those associated with immunity and cell proliferation.
Various clinical observations suggest that endogenous opioids may be involved in MS. For instance, Maria Gironi and her colleagues in Italy have reported low endorphin levels in mononuclear white blood cells in patients with active MS. In addition, Jankovic has found a beneficial effect when enkephalin treatment is used in patients with chronic severe progressive MS.
Do Endogenous Opioids Influence MS?
In this study, Dr. Zagon and his colleagues studied mice induced with EAE, a model often used in studies of MS. To understand the role of opioids, these mice were treated with high and low doses of naltrexone. High doses of naltrexone cause a sustained blockade of the opioid receptor, thereby reducing the body’s production of endogenous opioids. When low dose naltrexone (LDN) is given, the opioid receptor is blocked for four to six hours. During the 18-20 hours daily following the blockade, a supersensitive response occurs in which endogenous opioid production and production of opioid receptors are dramatically increased.
The effects of naltrexone in this technique are not only stereospecific but dependent on the duration of opioid receptor blockade rather than the drug dosage. In this way, the endogenous opioid system’s effects on EAE development and progression can be studied.
Study Results
The results showed that high doses of naltrexone, which reduce endogenous opioid production, resulted in disease progression. Intermittent blockade with LDN prevents behavioral signs of disease in some animals and markedly reduces the severity of clinical signs and neuropathology of EAE in others. These results suggest that endogenous opioids act as inhibitory factors that partially determine the onset and progression of EAE. This study offers a new paradigm in understanding the biology of EAE and providing implications for the pathogenesis and treatment of MS.
Investigators also drew parallels to the observations that women with MS who are pregnant have a high rate of remission of MS and fewer relapses. However, these women have a marked increase in relapse rate three months after delivery, when endogenous opioid levels are decreased. This finding could be interpreted that one or more of the elevated opioids elicited during pregnancy are acting with relevant opioid receptors to reduce the overt expression of MS. Once these high levels fall to basal values following delivery, the protective effects decline and the disease course is exaggerated.
Conclusion
The study results are novel in that they suggest for the first time that endogenous opioid peptides interfere with the development, onset and progression of EAE. LDN produced no symptoms of toxicity and it produced a remarkable neuroprotective effect.
Animals drug-induced to develop EAE that were simultaneously treated with LDN didn’t express any neurological signs of EAE in comparison to 100 percent of the other induced mice. However, the LDN treated animals showed some pathological changes. Animals who were treated with LDN 20 days following EAE-induction demonstrated mild disease, with disease index scores and mean maximal severity scores markedly reduced. High doses of naltrexone (continuous receptor blockade) had no effect on the onset, incidence or severity of EAE.
Longer-term studies are required to understand the full temporal-spatial sequence of events related to EAE and LDN. It’s also unknown whether these results can be extrapolated to other EAE models or to humans with MS. However, further clinical studies are merited to investigate LDN in patients with established MS and patients presenting with clinically isolated syndromes. To date, studies of LDN in patients with MS and other autoimmune diseases (Gironi in Italy, Cree at the University of San Francisco, Younger at Stanford, Smith at Pennsylvania State University) have shown promising results.
Resource:
Ian Zagon, Kristen Rahn, Anthony Turel, and Patricia McLaughlin, Endogenous Opioids Regulate Expression of Experimental Autoimmune Encephalomyelitis: A New Paradigm for the Treatment of Multiple Sclerosis, Society for Experimental Biology and Medicine, Nov 2009.
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