The opioid growth factor-opioid growth factor receptor axis: homeostatic regulator of cell proliferation and its implications for health and disease

Biochem Pharmacol. 2012 Sep 15;84(6):746-55. doi: 10.1016/j.bcp.2012.05.018. Epub 2012 Jun 1.


The opioid growth factor (OGF), chemically termed [Met(5)]-enkephalin, is an endogenous opioid peptide that interacts with the OGF receptor (OGFr) to delay the G(1)/S interface of the cell cycle by modulating cyclin-dependent inhibitory kinase (CKI) pathways. The OGF-OGFr axis is a tonically active, inhibitory pathway that is an important regulator during homeostasis and re-epithelialization, and plays a role in the onset and progression of autoimmune diseases and cancer. Modulation of the OGF-OGFr axis can be accomplished by a variety of pharmacological and molecular approaches including use of intermittent or continuous exposure to the opioid antagonist naltrexone, genetic manipulation of OGFr expression, and antibody neutralization of OGF. Clinically, OGF is a biological therapy that has potential application for treatment of cancer. Currently, naltrexone at low dosages is being evaluated for treatment of autoimmune diseases such as Crohn's and multiple sclerosis. High dosages of naltrexone are effective in reversing dry eye and accelerating the repair of corneal abrasions in normal and diabetic rats; these studies are under investigation in the clinical setting. Naltrexone also enhances full-thickness wound closure in animal models of Type 1 or Type 2 diabetes, and translation of this knowledge to the clinic is planned. In summary, understanding the OGF-OGFr axis as a homeostatic regulator of proliferation has substantial implications for maintaining human health and treatment of disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Autoimmune Diseases / drug therapy
  • Cell Cycle / physiology
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Diabetes Complications / drug therapy
  • Enkephalin, Methionine / pharmacology
  • Enkephalin, Methionine / physiology*
  • Enkephalin, Methionine / therapeutic use
  • Epithelium / drug effects
  • Epithelium / metabolism
  • Homeostasis
  • Humans
  • Lymphocytes / cytology
  • Lymphocytes / physiology
  • Naltrexone / pharmacology
  • Naltrexone / therapeutic use
  • Narcotic Antagonists / pharmacology
  • Narcotic Antagonists / therapeutic use
  • Neoplasms / drug therapy
  • Neoplasms / pathology
  • Receptors, Opioid / physiology*
  • Wound Healing / drug effects


  • Antineoplastic Agents
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p21
  • Narcotic Antagonists
  • Receptors, Opioid
  • methionine-enkephalin receptor
  • Enkephalin, Methionine
  • Naltrexone