Opioid growth factor inhibits intimal hyperplasia in balloon-injured rat carotid artery.
OBJECTIVE
The endogenous opioid [Met(5)]-enkephalin (opioid growth factor [OGF]) is a tonically active, receptor-mediated inhibitory growth peptide in developing and adult vasculature. This study was designed to determine the role of OGF in neointimal hyperplasia.


METHODS
The carotid artery in adult male Sprague-Dawley rats was denuded with balloon catheterization. OGF (10 mg/kg), the opioid antagonist naltrexone (NTX; 30 mg/kg), or saline solution (0.2 mL) was injected intraperitoneally daily for 28 days into the rats, and restenosis of the carotid artery was examined with morphometric analysis using Optimas software. Proliferation of the neointima and media was measured by radioactive thymidine incorporation over 3 hours. The presence of OGF and its receptor, OGFr, were examined with immunofluorescence microscopy.


RESULTS
OGF depressed DNA synthesis in the intima and media from 16% to 78% of control levels in the first 2 weeks after deendothelialization, whereas NTX exposure elevated DNA synthesis by 21% to 89%. OGF action was receptor-mediated. In the month after injury the thickness of the intima in OGF-treated rats was decreased by 18% to 31% from control values, whereas intimal thickness was increased in the NTX group by 10% to 31%. Luminal area was almost 25% greater than control values in the OGF group, but was reduced 17% by NTX. OGF and the OGF receptor were detected in the carotid artery with immunohistochemistry.


CONCLUSIONS
These results demonstrate for the first time that a native opioid system modulates repair of vascular injury. OGF is a constitutively active peptide that has a receptor-mediated action in the negative regulation of neointimal growth, a major cause of restenosis.
Zagon
Ian S
IS
Department of Neuroscience and Anatomy, H-109, The Pennsylvania State University College of Medicine, M.S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA. isz1@psu.edu
Essis
Frank M
FM
Verderame
Michael F
MF
Healy
Dean A
DA
Atnip
Robert G
RG
McLaughlin
Patricia J
PJ
D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000473:pathology*; D002404:Catheterization; D002455:Cell Division; D004247:DNA / Q000096:biosynthesis; D004744:Enkephalin, Methionine / Q000032:analysis / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D006965:Hyperplasia; D007150:Immunohistochemistry; D008297:Male; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000032:analysis; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
D009292:Narcotic Antagonists; D011957:Receptors, Opioid; C033593:methionine-enkephalin receptor; D004744:Enkephalin, Methionine; D009271:Naltrexone; D004247:DNA