Selective blockade of the OGF–OGFr pathway by naltrexone accelerates fibroblast proliferation and wound healing

Jessica A. Immonen, Ian Zagon, Patricia McLaughlin

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Naltrexone (NTX) is an opioid receptor antagonist that acts at classical and non-classical opioid receptors including the opioid growth factor receptor (OGFr). Animal models of type 1 and type 2 diabetes, as well as normal rodents, have shown that topical NTX enhances the healing rates of corneal epithelium and full-thickness cutaneous wounds. The mechanism of this general opioid antagonist on growth, and in particular the specific receptor pathway involved, is not understood. Tissue culture studies using NIH 3T3 fibroblasts and primary rat auricular fibroblasts were established to evaluate growth following opioid receptor antagonist treatment. Treatment of cells with CTOP, naltrindole, or nalmefene, selective antagonists for mu, delta, and kappa opioid receptors, respectively, did not accelerate cell replication. Addition of the classical opioid receptor peptides DAMGO, DPDPE, or EKC did not alter cell growth, suggesting that the classical opioid receptors were not involved in cutaneous wound healing. However, NTX (10-6M) increased the growth of NIH 3T3 fibroblasts in culture over a 96-h period, and the specific ligand OGF decreased cell growth, supporting that the OGF-OGFr axis is tonically active and constitutively expressed in fibroblasts, the primary cell type in granulation tissue of the skin. Transfection of NIH 3T3 cells with OGFr siRNA reduced receptor protein; subsequent treatment with NTX did not accelerate cell proliferation. These data indicate that blockade of the OGFr pathway enhances proliferation of fibroblasts in vitro, and in a primary culture of auricular fibroblasts, suggesting that the effect of NTX on growth is mediated through the OGF-OGFr axis. Finally, antagonists for classical opioid receptors as well as NTX were topically applied to cutaneous wounds in type 1 diabetic rats; only NTX accelerated wound closure. These studies indicate that the mechanistic pathway underlying the effects of NTX to enhance cutaneous wound closure in diabetic and nondiabetic subjects is specific blockade of the OGF–OGFr regulatory axis.

Original languageEnglish (US)
Pages (from-to)1300-1309
Number of pages10
JournalExperimental Biology and Medicine
Volume239
Issue number10
DOIs
StatePublished - Jan 1 2014

Fingerprint

Naltrexone
Fibroblasts
Wound Healing
Narcotic Antagonists
Opioid Receptors
Growth
Skin
naltrindole
Wounds and Injuries
Cell growth
Cell culture
Rats
D-Penicillamine (2,5)-Enkephalin
Ala(2)-MePhe(4)-Gly(5)-enkephalin
NIH 3T3 Cells
Tissue culture
kappa Opioid Receptor
Corneal Epithelium
delta Opioid Receptor
Granulation

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

@article{edcadc93ef8f4439b8fb84d9ab25fc1c,
title = "Selective blockade of the OGF–OGFr pathway by naltrexone accelerates fibroblast proliferation and wound healing",
abstract = "Naltrexone (NTX) is an opioid receptor antagonist that acts at classical and non-classical opioid receptors including the opioid growth factor receptor (OGFr). Animal models of type 1 and type 2 diabetes, as well as normal rodents, have shown that topical NTX enhances the healing rates of corneal epithelium and full-thickness cutaneous wounds. The mechanism of this general opioid antagonist on growth, and in particular the specific receptor pathway involved, is not understood. Tissue culture studies using NIH 3T3 fibroblasts and primary rat auricular fibroblasts were established to evaluate growth following opioid receptor antagonist treatment. Treatment of cells with CTOP, naltrindole, or nalmefene, selective antagonists for mu, delta, and kappa opioid receptors, respectively, did not accelerate cell replication. Addition of the classical opioid receptor peptides DAMGO, DPDPE, or EKC did not alter cell growth, suggesting that the classical opioid receptors were not involved in cutaneous wound healing. However, NTX (10-6M) increased the growth of NIH 3T3 fibroblasts in culture over a 96-h period, and the specific ligand OGF decreased cell growth, supporting that the OGF-OGFr axis is tonically active and constitutively expressed in fibroblasts, the primary cell type in granulation tissue of the skin. Transfection of NIH 3T3 cells with OGFr siRNA reduced receptor protein; subsequent treatment with NTX did not accelerate cell proliferation. These data indicate that blockade of the OGFr pathway enhances proliferation of fibroblasts in vitro, and in a primary culture of auricular fibroblasts, suggesting that the effect of NTX on growth is mediated through the OGF-OGFr axis. Finally, antagonists for classical opioid receptors as well as NTX were topically applied to cutaneous wounds in type 1 diabetic rats; only NTX accelerated wound closure. These studies indicate that the mechanistic pathway underlying the effects of NTX to enhance cutaneous wound closure in diabetic and nondiabetic subjects is specific blockade of the OGF–OGFr regulatory axis.",
author = "Immonen, {Jessica A.} and Ian Zagon and Patricia McLaughlin",
year = "2014",
month = "1",
day = "1",
doi = "10.1177/1535370214543061",
language = "English (US)",
volume = "239",
pages = "1300--1309",
journal = "Experimental Biology and Medicine",
issn = "1535-3702",
publisher = "SAGE Publications Ltd",
number = "10",

}

Selective blockade of the OGF–OGFr pathway by naltrexone accelerates fibroblast proliferation and wound healing. / Immonen, Jessica A.; Zagon, Ian; McLaughlin, Patricia.

In: Experimental Biology and Medicine, Vol. 239, No. 10, 01.01.2014, p. 1300-1309.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Selective blockade of the OGF–OGFr pathway by naltrexone accelerates fibroblast proliferation and wound healing

AU - Immonen, Jessica A.

AU - Zagon, Ian

AU - McLaughlin, Patricia

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Naltrexone (NTX) is an opioid receptor antagonist that acts at classical and non-classical opioid receptors including the opioid growth factor receptor (OGFr). Animal models of type 1 and type 2 diabetes, as well as normal rodents, have shown that topical NTX enhances the healing rates of corneal epithelium and full-thickness cutaneous wounds. The mechanism of this general opioid antagonist on growth, and in particular the specific receptor pathway involved, is not understood. Tissue culture studies using NIH 3T3 fibroblasts and primary rat auricular fibroblasts were established to evaluate growth following opioid receptor antagonist treatment. Treatment of cells with CTOP, naltrindole, or nalmefene, selective antagonists for mu, delta, and kappa opioid receptors, respectively, did not accelerate cell replication. Addition of the classical opioid receptor peptides DAMGO, DPDPE, or EKC did not alter cell growth, suggesting that the classical opioid receptors were not involved in cutaneous wound healing. However, NTX (10-6M) increased the growth of NIH 3T3 fibroblasts in culture over a 96-h period, and the specific ligand OGF decreased cell growth, supporting that the OGF-OGFr axis is tonically active and constitutively expressed in fibroblasts, the primary cell type in granulation tissue of the skin. Transfection of NIH 3T3 cells with OGFr siRNA reduced receptor protein; subsequent treatment with NTX did not accelerate cell proliferation. These data indicate that blockade of the OGFr pathway enhances proliferation of fibroblasts in vitro, and in a primary culture of auricular fibroblasts, suggesting that the effect of NTX on growth is mediated through the OGF-OGFr axis. Finally, antagonists for classical opioid receptors as well as NTX were topically applied to cutaneous wounds in type 1 diabetic rats; only NTX accelerated wound closure. These studies indicate that the mechanistic pathway underlying the effects of NTX to enhance cutaneous wound closure in diabetic and nondiabetic subjects is specific blockade of the OGF–OGFr regulatory axis.

AB - Naltrexone (NTX) is an opioid receptor antagonist that acts at classical and non-classical opioid receptors including the opioid growth factor receptor (OGFr). Animal models of type 1 and type 2 diabetes, as well as normal rodents, have shown that topical NTX enhances the healing rates of corneal epithelium and full-thickness cutaneous wounds. The mechanism of this general opioid antagonist on growth, and in particular the specific receptor pathway involved, is not understood. Tissue culture studies using NIH 3T3 fibroblasts and primary rat auricular fibroblasts were established to evaluate growth following opioid receptor antagonist treatment. Treatment of cells with CTOP, naltrindole, or nalmefene, selective antagonists for mu, delta, and kappa opioid receptors, respectively, did not accelerate cell replication. Addition of the classical opioid receptor peptides DAMGO, DPDPE, or EKC did not alter cell growth, suggesting that the classical opioid receptors were not involved in cutaneous wound healing. However, NTX (10-6M) increased the growth of NIH 3T3 fibroblasts in culture over a 96-h period, and the specific ligand OGF decreased cell growth, supporting that the OGF-OGFr axis is tonically active and constitutively expressed in fibroblasts, the primary cell type in granulation tissue of the skin. Transfection of NIH 3T3 cells with OGFr siRNA reduced receptor protein; subsequent treatment with NTX did not accelerate cell proliferation. These data indicate that blockade of the OGFr pathway enhances proliferation of fibroblasts in vitro, and in a primary culture of auricular fibroblasts, suggesting that the effect of NTX on growth is mediated through the OGF-OGFr axis. Finally, antagonists for classical opioid receptors as well as NTX were topically applied to cutaneous wounds in type 1 diabetic rats; only NTX accelerated wound closure. These studies indicate that the mechanistic pathway underlying the effects of NTX to enhance cutaneous wound closure in diabetic and nondiabetic subjects is specific blockade of the OGF–OGFr regulatory axis.

UR - http://www.scopus.com/inward/record.url?scp=84921792751&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84921792751&partnerID=8YFLogxK

U2 - 10.1177/1535370214543061

DO - 10.1177/1535370214543061

M3 - Article

C2 - 25030485

AN - SCOPUS:84921792751

VL - 239

SP - 1300

EP - 1309

JO - Experimental Biology and Medicine

JF - Experimental Biology and Medicine

SN - 1535-3702

IS - 10

ER -