Featured Article: Serum [Met⁵]-enkephalin levels are reduced in multiple sclerosis and restored by low-dose naltrexone

Abstract

This report presents human and animal data identifying a novel biomarker for the onset and progression of multiple sclerosis (MS). Humans diagnosed with MS have reduced serum levels of OGF (i.e. [Met 5 ]-enkephalin) relative to non-MS neurologic patients, and low-dose naltrexone (LDN) therapy restored their enkephalin levels. Serum OGF levels were reduced in mice immunized with MOG 35-55 prior to any clinical behavioral sign of experimental autoimmune encephalomyelitis, and LDN therapy restored their serum OGF levels. b-endorphin concentrations were not altered by LDN in humans or mice. Thus, blood levels of OGF may serve as a new, selective biomarker for the progression of MS, as well as response to therapy. AbstractLow-dose naltrexone is a widely used off-label therapeutic prescribed for a variety of immune-related disorders. The mechanism underlying low-dose naltrexone's efficacy for fatigue, Crohn's disease, fibromyalgia, and multiple sclerosis is, in part, intermittent blockade of opioid receptors followed by upregulation of endogenous opioids. Short, intermittent blockade by naltrexone specifically blocks the opioid growth factor receptor resulting in biofeedback events that increase production of the endogenous opioid growth factor (OGF) (chemically termed [Met 5 ]-enkephalin) facilitating interactions between opioid growth factor and opioid growth factor receptor that ultimately, result in inhibited cell proliferation. Preclinical studies have reported that enkephalin levels are deficient in animal models of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our hypothesis is that serum enkephalin levels are diminished in humans with multiple sclerosis and experimental autoimmune encephalomyelitis mice, and that change in serum opioid growth factor levels may serve as a reasonable candidate biomarker for the onset of experimental autoimmune encephalomyelitis and response to therapy. To address this, we designed a two-part study to measure endogenous opioids in multiple sclerosis patients, and to investigate the temporal pattern of decline in serum enkephalin concentrations in mice with chronic progressive experimental autoimmune encephalomyelitis and treated with low-dose naltrexone. For comparison, we investigated whether low-dose naltrexone exposure in normal mice also resulted in altered enkephalin levels.In both animal models, we monitored tactile and heat sensitivity, as well as differential white blood cell counts as indicators of inflammation. Serum [Met 5 ]-enkephalin levels were lower in humans with multiple sclerosis relative to non-multiple sclerosis patients, and low-dose naltrexone restored their levels. In experimental autoimmune encephalomyelitis mice, [Met 5 ]-enkephalin levels were depressed prior to the appearance of clinical disease, and were restored with low-dose naltrexone treatment. Low-dose naltrexone therapy had no effect on serum [Met 5 ]-enkephalin or b-endorphin in normal mice. Thus, [Met 5 ]-enkephalin (i.e. opioid growth factor)...

Endogenous Opioids in the Etiology and Treatment of Multiple Sclerosis

“…Treatment with OGF or LDN restored serum enkephalin levels to normal and often correlated with reduced clinical behavior and restored sensitivity to pain and heat in mice. The animal work facilitated measurement of serum enkephalins in a longitudinal manner and was able to demonstrate that normal animals inoculated with MOG antigen expressed decreased enkephalins as the disease progressed (47,48). This work is the first to suggest that OGF (chemically termed [Met 5 ]-enkephalin) may be a specific marker for the onset of MS.…”

“…Extension of this work has resulted in studies that have shown that animals with EAE (47,48) or individuals with MS (48) have decreased enkephalin levels. Treatment with OGF or LDN restored serum enkephalin levels to normal and often correlated with reduced clinical behavior and restored sensitivity to pain and heat in mice.…”

Enkephalin Therapy Improves Relapsing-Remitting Multiple Sclerosis

“…At a dosage less than 5 mg, LDN acts as a biotherapeutic and modulates the activity of endogenous enkephalins and endorphins [49,50]. In the multiple sclerosis patient population, endogenous [Met 5 ]-enkephalin (i.e., OGF) is reduced when compared to non-multiple sclerosis patients [51]. It is hypothesized that the reduction in serum levels of this inhibitory growth factor are unable to control the increase in T cell proliferation that occurs with immune-related flares.…”

“…The key component in the mechanistic pathway is the duration of opioid receptor blockade. This work is detailed in animal studies [51][52][53][54][55][56][57]. LDN produces an intermittent blockade of OGFr preventing OGF from binding and thereby increasing cellular replication, similar to what is seen with high doses of Naltrexone (HDN) through a prolonged blockade of OGFr [49].…”

“…However, these studies did not measure serum enkephalins, endorphins, or cytokines in an effort to gain more information on the mechanism of action for this biotherapeutic. A small study obtained stored serum from relapsing-remitting multiple sclerosis subjects and reported that enkephalin (i.e., OGF) levels were depressed relative to controls [51]. In the few individuals on LDN alone, serum OGF levels were elevated 2-fold in comparison to multiple sclerosis subjects on Copaxone ® alone, suggesting that LDN may be effective at restoring serum enkephalin.…”