Skip to main content
SpringerLink
Log in

The Roles of Opioid Receptors in Cutaneous Wound Healing

  • Chapter
  • First Online:
Delta Opioid Receptor Pharmacology and Therapeutic Applications

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 247))

Abstract

The process of recovery from skin wounding can be protracted and painful, and scarring may lead to weakness of the tissue, unpleasant sensations such as pain or itch, and unfavorable cosmetic outcomes. Moreover, some wounds simply fail to heal and become a chronic burden for the sufferer. Understanding the mechanisms underlying wound healing and the concomitant sensory disorders and how they might be manipulated for therapeutic benefit has attracted much interest in recent years, and here we discuss the latest developments in the field, focusing on the emergent roles of the peripheral opioid receptor (OPr) system.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Abbreviations

DOPr:

Delta OPr

ECM:

Extracellular matrix

KO:

Knockout

KOPr:

Kappa OPr

MMP:

Matrix metalloproteinase

MOPr:

Mu OPr

NOPr:

Nociceptin OPr

OPr:

Opioid receptor

PNS:

Peripheral nervous system

TGF:

Transforming growth factor

References

  • Akoev GN, Il’inskii OB, Kolosova LI, Titov MI, Trofimova OG (1989) The effect of the opioid peptide dalargin on the regeneration of the rat sciatic nerve. Fiziol Zh SSSR Im I M Sechenova 75:33–37

    CAS  PubMed  Google Scholar 

  • Awad H, Abas M, Elgharably H, Tripathi R, Theofilos T, Bhandary S, Sai-Sudhakar C, Sen CK, Roy S (2012) Endogenous opioids in wound-site neutrophils of sternotomy patients. PLoS One 7:e47569

    Article  CAS  Google Scholar 

  • Bigliardi PL, Bigliardi-Qi M, Buechner S, Rufli T (1998) Expression of mu-opiate receptor in human epidermis and keratinocytes. J Invest Dermatol 111:297–301

    Article  CAS  Google Scholar 

  • Bigliardi PL, Sumanovski LT, Buchner S, Rufli T, Bigliardi-Qi M (2003) Different expression of mu-opiate receptor in chronic and acute wounds and the effect of beta-endorphin on transforming growth factor beta type II receptor and cytokeratin 16 expression. J Invest Dermatol 120:145–152

    Article  CAS  Google Scholar 

  • Bigliardi PL, Tobin DJ, Gaveriaux-Ruff C, Bigliardi-Qi M (2009) Opioids and the skin – where do we stand? Exp Dermatol 18:424–430

    Article  CAS  Google Scholar 

  • Bigliardi PL, Neumann C, Teo YL, Pant A, Bigliardi-Qi M (2015) Activation of the delta-opioid receptor promotes cutaneous wound healing by affecting keratinocyte intercellular adhesion and migration. Br J Pharmacol 172(2):501–514

    Article  CAS  Google Scholar 

  • Bigliardi-Qi M, Bigliardi PL (2015) The role of opioid receptors in migration and wound recovery in-vitro in cultured human keratinocytes and fibroblasts. Methods Mol Biol 1230:273–277

    Article  CAS  Google Scholar 

  • Bigliardi-Qi M, Bigliardi PL, Eberle AN, Buchner S, Rufli T (2000) Beta-endorphin stimulates cytokeratin 16 expression and downregulates mu-opiate receptor expression in human epidermis. J Invest Dermatol 114:527–532

    Article  CAS  Google Scholar 

  • Bigliardi-Qi M, Gaveriaux-Ruff C, Zhou H, Hell C, Bady P, Rufli T, Kieffer B, Bigliardi P (2006) Deletion of delta-opioid receptor in mice alters skin differentiation and delays wound healing. Differentiation 74:174–185

    Article  CAS  Google Scholar 

  • Chang PJ, Chen MY, Huang YS, Lee CH, Huang CC, Lam CF, Tsai YC (2010) Morphine enhances tissue content of collagen and increases wound tensile strength. J Anesth 24:240–246

    Article  Google Scholar 

  • Charbaji N, Schafer-Korting M, Kuchler S (2012) Morphine stimulates cell migration of oral epithelial cells by delta-opioid receptor activation. PLoS One 7:e42616

    Article  CAS  Google Scholar 

  • Cheng B, Liu HW, Fu XB, Sheng ZY, Li JF (2008) Coexistence and upregulation of three types of opioid receptors, mu, delta and kappa, in human hypertrophic scars. Br J Dermatol 158:713–720

    Article  CAS  Google Scholar 

  • Deitch EA, Xu D, Bridges RM (1988) Opioids modulate human neutrophil and lymphocyte function: thermal injury alters plasma beta-endorphin levels. Surgery 104:41–48

    CAS  PubMed  Google Scholar 

  • Gerritsen MJ, Elbers ME, de Jong EM, van de Kerkhof PC (1997) Recruitment of cycling epidermal cells and expression of filaggrin, involucrin and tenascin in the margin of the active psoriatic plaque, in the uninvolved skin of psoriatic patients and in the normal healthy skin. J Dermatol Sci 14:179–188

    Article  CAS  Google Scholar 

  • Heurich M, Mousa SA, Lenzner M, Morciniec P, Kopf A, Welte M, Stein C (2007) Influence of pain treatment by epidural fentanyl and bupivacaine on homing of opioid-containing leukocytes to surgical wounds. Brain Behav Immun 21:544–552

    Article  CAS  Google Scholar 

  • Il’inskii OB, Kozlova MV, Kondrikova ES, Kalenchuk VU (1985) Action of opioid peptides on nerve tissue growth and regeneration processes in the rat. Zh Evol Biokhim Fiziol 21:511–515

    PubMed  Google Scholar 

  • Kangesu T, Manek S, Terenghi G, Gu XH, Navsaria HA, Polak JM, Green CJ, Leigh IM (1998) Nerve and blood vessel growth in response to grafted dermis and cultured keratinocytes. Plast Reconstr Surg 101:1029–1038

    Article  CAS  Google Scholar 

  • Kohl A, Werner A, Buntrock P, Diezel W, Adrian K, Titov MI (1989) The effect of the peptide dalargin on wound healing. Dermatol Monatsschr 175:561–572

    CAS  PubMed  Google Scholar 

  • Kuchler S, Wolf NB, Heilmann S, Weindl G, Helfmann J, Yahya MM, Stein C, Schafer-Korting M (2010) 3D-wound healing model: influence of morphine and solid lipid nanoparticles. J Biotechnol 148:24–30

    Article  Google Scholar 

  • Kutty VK, Bigliardi PL, Dykas MM, Pomp O, Venkatesan T, Bigliardi-Qi M (2016) Human peripheral nerve fibers form complex physical interactions with human keratinocytes in a novel 2D culture model. Exp Dermatol. doi:10.1111/exd.13181, ISSN: 1600-0625/0906-6705

    Article  Google Scholar 

  • Lam CF, Chang PJ, Huang YS, Sung YH, Huang CC, Lin MW, Liu YC, Tsai YC (2008) Prolonged use of high-dose morphine impairs angiogenesis and mobilization of endothelial progenitor cells in mice. Anesth Analg 107:686–692

    Article  CAS  Google Scholar 

  • Legeza VP, Koshcheev AG, Konovalova LN (1995) Effect of dalargin on healing of a bullet wound of the soft tissues in rabbits. Patol Fiziol Eksp Ter:45–48

    Google Scholar 

  • Levy EM, Mcintosh T, Black PH (1986) Elevation of circulating beta-endorphin levels with concomitant depression of immune parameters after traumatic injury. J Trauma 26:246–249

    Article  CAS  Google Scholar 

  • Martin JL, Charboneau R, Barke RA, Roy S (2010a) Chronic morphine treatment inhibits LPS-induced angiogenesis: implications in wound healing. Cell Immunol 265:139–145

    Article  CAS  Google Scholar 

  • Martin JL, Koodie L, Krishnan AG, Charboneau R, Barke RA, Roy S (2010b) Chronic morphine administration delays wound healing by inhibiting immune cell recruitment to the wound site. Am J Pathol 176:786–799

    Article  CAS  Google Scholar 

  • McLaughlin PJ, Immonen JA, Zagon IS (2013) Topical naltrexone accelerates full-thickness wound closure in type 1 diabetic rats by stimulating angiogenesis. Exp Biol Med (Maywood) 238:733–743

    Article  Google Scholar 

  • Narita M, Kuzumaki N, Miyatake M, Sato F, Wachi H, Seyama Y, Suzuki T (2006) Role of delta-opioid receptor function in neurogenesis and neuroprotection. J Neurochem 97:1494–1505

    Article  CAS  Google Scholar 

  • Neumann C, Bigliardi-Qi M, Widmann C, Bigliardi PL (2015) The δ-opioid receptor affects epidermal homeostasis via ERK-dependent inhibition of transcription factor POU2F3. J Invest Dermatol 135(2):471–480

    Article  CAS  Google Scholar 

  • Nezami BG, Talab SS, Emami H, Assa S, Rasouli MR, Asadi S, Tavangar SM, Dehpour AR (2009) Chronic upregulation of the endogenous opioid system impairs the skin flap survival in rats. Ann Plast Surg 63:558–563

    Article  CAS  Google Scholar 

  • Nissen JB, Lund M, Stengaard-Pedersen K, Kragballe K (1997) Enkephalin-like immunoreactivity in human skin is found selectively in a fraction of CD68-positive dermal cells: increase in enkephalin-positive cells in lesional psoriasis. Arch Dermatol Res 289:265–271

    Article  CAS  Google Scholar 

  • Peyman GA, Rahimy MH, Fernandes ML (1994) Effects of morphine on corneal sensitivity and epithelial wound healing: implications for topical ophthalmic analgesia. Br J Ophthalmol 78:138–141

    Article  CAS  Google Scholar 

  • Poonawala T, Levay-Young BK, Hebbel RP, Gupta K (2005) Opioids heal ischemic wounds in the rat. Wound Repair Regen 13:165–174

    Article  Google Scholar 

  • Rook JM, Hasan W, Mccarson KE (2008) Temporal effects of topical morphine application on cutaneous wound healing. Anesthesiology 109:130–136

    Article  CAS  Google Scholar 

  • Rook JM, Hasan W, Mccarson KE (2009) Morphine-induced early delays in wound closure: involvement of sensory neuropeptides and modification of neurokinin receptor expression. Biochem Pharmacol 77:1747–1755

    Article  CAS  Google Scholar 

  • Shekhter AB, Solov’eva AI, Spevak SE, Titov MI (1988) Effects of opioid peptide dalargin on reparative processes in wound healing. Biull Eksp Biol Med 106:487–490

    Article  CAS  Google Scholar 

  • Soledad Cepeda M, Lipkowski AW, Langlade A, Osgood PF, Ehrlich HP, Hargreaves K, Szyfelbein SK, Carr DB (1993) Local increases of subcutaneous beta-endorphin immunoactivity at the site of thermal injury. Immunopharmacology 25:205–213

    Article  Google Scholar 

  • Summer GJ, Puntillo KA, Miaskowski C, Green PG, Levine JD (2007) Burn injury pain: the continuing challenge. J Pain 8:533–548

    Article  Google Scholar 

  • Van Epps DE, Kutvirt SL (1987) Modulation of human neutrophil adherence by beta-endorphin and met-enkephalin. J Neuroimmunol 15:219–228

    Article  CAS  Google Scholar 

  • Velnar T, Bailey T, Smrkolj V (2009) The wound healing process: an overview of the cellular and molecular mechanisms. J Int Med Res 37:1528–1542

    Article  CAS  Google Scholar 

  • Wintzen M, Yaar M, Avila E, Vermeer BJ, Gilchrest BA (1995) Keratinocytes produce b-endorphin and b-lipotropin hormone after stimulation by UV, IL-1a or phorbol esters. J Invest Dermatol 104:641

    Google Scholar 

  • Xue JZ (1991) Changes in plasma immunoreactive beta-endorphin in burn and its clinical significance. Zhonghua Zheng Xing Shao Shang Wai Ke Za Zhi 7:253–256, 317

    CAS  PubMed  Google Scholar 

  • Zanello SB, Jackson DM, Holick MF (1999) An immunocytochemical approach to the study of beta-endorphin production in human keratinocytes using confocal microscopy. Ann N Y Acad Sci 885:85–99

    Article  CAS  Google Scholar 

  • Zeng YS, Nie JH, Zhang W, Chen SJ, Wu W (2007) Morphine acts via mu-opioid receptors to enhance spinal regeneration and synaptic reconstruction of primary afferent fibers injured by sciatic nerve crush. Brain Res 1130:108–113

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Experimental Dermatology Group, Institute of Medical Biology, A*STAR, Singapore, Singapore, 138648

    Mei Bigliardi-Qi

  2. NUH/NUS, National University Hospital/National University of Singapore, Singapore, Singapore, 119228

    Paul Bigliardi

  3. Experimental Dermatology Group, Institute of Medical Biology, A*STAR, Singapore, Singapore, 138648

    Paul Bigliardi

Authors
  1. Mei Bigliardi-Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul Bigliardi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mei Bigliardi-Qi .

Editor information

Editors and Affiliations

  1. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA

    Emily M. Jutkiewicz

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Bigliardi-Qi, M., Bigliardi, P. (2017). The Roles of Opioid Receptors in Cutaneous Wound Healing. In: Jutkiewicz, E. (eds) Delta Opioid Receptor Pharmacology and Therapeutic Applications. Handbook of Experimental Pharmacology, vol 247. Springer, Cham. https://doi.org/10.1007/164_2017_14

Download citation

Publish with us

Policies and ethics

Search

Navigation