Intermittent blockade of OGFr and treatment of autoimmune disorders

The opioid growth factor (OGF)–OGF receptor (OGFr) axis is present in normal and abnormal cells and tissues, and functions to maintain homeostatic cell replication. OGF is an inhibitory growth factor that upregulates p16 and/or p21 cyclin-dependent inhibitory kinases to slow cell replication. Blockade of this regulatory pathway can be intermittent or complete with the end result being depressed or accelerated, respectively, cell proliferation and growth. Intermittent blockade of the OGF–OGFr pathway with lose doses of naltrexone (LDN), a general opioid receptor antagonist, has been studied clinically in a number of autoimmune diseases, including fibromyalgia, Crohn’s, and multiple sclerosis (MS). Serum enkephalin levels were decreased in patients with MS relative to subjects with other neurological disorders. The intermittent blockade of OGFr by LDN results in a biofeedback mechanism that upregulates serum enkephalin levels. Clinical studies have reported that LDN is beneficial in enhancing quality of life, reducing fatigue, and increasing motor activity in humans with fibromyalgia, Crohn’s, or MS. LDN treatment is well tolerated even after several years of therapy. Preclinical investigations using experimental autoimmune encephalomyelitis (EAE), an animal model of MS mediated by T and B lymphocyte activation, demonstrate that immunization alone resulted in reduced enkephalin (i.e. OGF) levels. Therapy with LDN restored serum enkephalin levels in EAE mice resulting in improved EAE behavioral scores and diminished CNS pathology. This mini-review summarizes both preclinical and clinical data and focuses on the role of serum enkephalins resulting from intermittent blockade of OGFr by LDN in autoimmune disorders. Impact statement: This mini-review presents information on the intermittent blockade of the opioid growth factor (OGF)–OGF receptor (OGFr) axis by low-dose naltrexone (LDN), and the role of enkephalin (i.e. OGF) in autoimmune disorders, specifically multiple sclerosis, Crohn’s, and fibromyalgia. Clinical reports on subjects taking LDN have documented reduced fatigue, few side-effects, and improved overall health. Preclinical studies on mice with experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis, revealed that immunization for EAE reduces serum OGF. Intermittent OGFr blockade with LDN restores serum enkephalin levels that correlate with reduced behavioral and pathological signs of EAE; LDN also increases enkephalin levels in naïve mice. The interplay between LDN, and the onset and treatment of autoimmune diseases, chronic pain, and other addictive behaviors requires further investigation, but highlights a central role for enkephalins and intermittent blockade of the OGF–OGFr pathway in pathogenesis and treatment of these disorders.