Non-analgesic effects of opioids: Peripheral opioid effects on inflammation and wound healing

Current Pharmaceutical Design

Volumn 18, Issue 37, 2012, Pages 6053-6069

  Stein, Christoph ^a   Küchler, Sarah ^b  

^a FREIE UNIVERSITÄT BERLIN   (Germany)

^b UNIVERSITY OF MUNICH   (Germany)

Author keywords

Analgesia; Healing; Inflammation; Leukocytes; Opioids; Pain; Sensory neurons; Skin; Wounds

Indexed keywords

ACETIC ACID; ASIMADOLINE; BETA ENDORPHIN; BRADYKININ; CALCITONIN GENE RELATED PEPTIDE; CALCIUM CALMODULIN DEPENDENT PROTEIN KINASE; CALCIUM ION; CAPSAICIN; COMPLEMENTARY DNA; CYCLIC AMP DEPENDENT PROTEIN KINASE; CYTOKINE; DELTA OPIATE RECEPTOR; EPSILON OPIATE RECEPTOR; FREUND ADJUVANT; G PROTEIN COUPLED INWARDLY RECTIFYING POTASSIUM CHANNEL; KAPPA OPIATE RECEPTOR; LIGAND; LOPERAMIDE; MESSENGER RNA; MORPHINAN DERIVATIVE; MU OPIATE RECEPTOR; NOCICEPTIN RECEPTOR; OPIATE; OPIATE RECEPTOR; POTASSIUM ION; PROTEASE ACTIVATED RECEPTOR AGONIST; PROTEINASE INHIBITOR; SIGMA OPIATE RECEPTOR; SUBSTANCE P; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANALGESIA; ANALGESIC ACTIVITY; ANTIINFLAMMATORY ACTIVITY; ATOPIC DERMATITIS; AUTONOMIC NERVE; BIOASSAY; BLOOD BRAIN BARRIER; CALCIUM TRANSPORT; CELL DIFFERENTIATION; CELL MATURATION; CELL MIGRATION; CELL PROLIFERATION; CELLULAR IMMUNITY; CENTRAL NERVOUS SYSTEM; CYTOKINE PRODUCTION; CYTOTOXICITY; DRUG EFFICACY; DRUG MECHANISM; DRUG MEGADOSE; DRUG PENETRATION; DRUG SAFETY; GENE EXPRESSION; HUMAN; IMMUNOCOMPETENT CELL; IN VITRO STUDY; IN VIVO STUDY; INFLAMMATION; KERATINOCYTE; LIGAND BINDING; NERVE CELL EXCITABILITY; NERVE CELL PLASTICITY; NOCICEPTION; NONHUMAN; PATHOPHYSIOLOGY; PERIPHERAL NERVOUS SYSTEM; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN TRANSPORT; PSORIASIS; REVIEW; SENSORY NERVE CELL; SIGNAL TRANSDUCTION; SKIN FIBROBLAST; SKIN STRUCTURE; SPINAL GANGLION; TISSUES; WOUND; WOUND HEALING;

ANALGESICS, OPIOID; ANIMALS; ANTI-INFLAMMATORY AGENTS; HUMANS; INFLAMMATION; LIGANDS; PAIN; RECEPTORS, OPIOID; SIGNAL TRANSDUCTION; WOUND HEALING;

EID: 84867233009     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/138161212803582513     Document Type: Review

References (264)

1. Medzhitov R. Origin and physiological roles of inflammation. Nature 2008; 454: 428-35.
2. Couzin-Frankel J. Inflammation bares a dark side. Science 2010; 330: 1621.
3. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008; 454: 436-44.
4. Frank KM, Hogarth DK, Miller JL, et al. Investigation of the cause of death in a gene-therapy trial. N Engl J Med 2009; 361: 161-9.
5. Stein C, Machelska H. Modulation of peripheral sensory neurons by the immune system: implications for pain therapy. Pharmacol Rev 2011; 63: 860-881.
6. Binder W, Machelska H, Mousa S, et al. Analgesic and antiinflammatory effects of two novel kappa-opioid peptides. Anesthesiology 2001; 94: 1034-44.
7. Labuz D, Mousa SA, Schäfer M, Stein C, Machelska H. Relative contribution of peripheral versus central opioid receptors to antinociception. Brain Res 2007; 1160: 30-8.
8. Fürst S, Riba P, Friedmann T, et al. Peripheral versus central antinociceptive actions of 6-amino acid-substituted derivatives of 14-O-methyloxymorphone in acute and inflammatory pain in the rat. J Pharmacol Exp Ther 2005; 312: 609-18.
9. Lewanowitsch T, Irvine RJ. Naloxone methiodide reverses opioidinduced respiratory depression and analgesia without withdrawal. Eur J Pharmacol 2002; 445: 61-7.
10. Craft RM, Henley SR, Haaseth RC, Hruby VJ, Porreca F. Opioid antinociception in a rat model of visceral pain: systemic versus local drug administration. J Pharmacol Exp Ther 1995; 275: 1535-42.
11. Shannon HE, Lutz EA. Comparison of the peripheral and central effects of the opioid agonists loperamide and morphine in the formalin test in rats. Neuropharmacology 2002; 42: 253-61.
12. Reichert JA, Daughters RS, Rivard R, Simone DA. Peripheral and preemptive opioid antinociception in a mouse visceral pain model. Pain 2001; 89: 221-7.
13. Gaveriaux-Ruff C, Nozaki C, Nadal X, Hever XC, Weibel R, Matifas A, et al. Genetic ablation of delta opioid receptors in nociceptive sensory neurons increases chronic pain and abolishes opioid analgesia. Pain 2011; 152: 1238-48.
14. Hanna MH, Elliott KM, Fung M. Randomized, double-blind study of the analgesic efficacy of morphine-6-glucuronide versus morphine sulfate for postoperative pain in major surgery. Anesthesiology 2005; 102: 815-21.
15. Tegeder I, Meier S, Burian M, Schmidt H, Geisslinger G, Lotsch J. Peripheral opioid analgesia in experimental human pain models. Brain 2003; 126: 1092-102.
16. van Dorp EL, Morariu A, Dahan A. Morphine-6-glucuronide: potency and safety compared with morphine. Expert Opin Pharmacother 2008; 9: 1955-61.
17. Kieffer BL, Evans CJ. Opioid receptors: from binding sites to visible molecules in vivo. Neuropharmacology 2009; 56 Suppl 1: 205-12.
18. Zöllner C, Stein C. Opioids. In: Stein C, editor. Handbook of Experimental Pharmacology (Vol 177) Analgesia. Heidelberg: Springer; 2007. p. 31-63.
19. Stein C. Peripheral mechanisms of opioid analgesia. Anesthesia & Analgesia 1993; 76: 182-91.
20. Stein C, Hassan AH, Przewlocki R, Gramsch C, Peter K, Herz A. Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation. Proc Natl Acad Sci U S A 1990; 87: 5935-9.
21. Stein C. The control of pain in peripheral tissue by opioids. N Engl J Med 1995; 332: 1685-90.
22. Bartho L, Stein C, Herz A. Involvement of capsaicin-sensitive neurones in hyperalgesia and enhanced opioid antinociception in inflammation. Naunyn Schmiedeberg's Arch Pharmacol 1990; 342: 666-70.
23. Hassan AHS, Ableitner A, Stein C, Herz A. Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue. Neuroscience 1993; 55: 185-95.
24. Zöllner C, Shaqura MA, Bopaiah CP, Mousa SA, Stein C, Schäfer M. Painful inflammation-induced increase in mu-opioid receptor binding and G-protein coupling in primary afferent neurons. Mol Pharmacol 2003; 64: 202-10.
25. Zöllner C, Mousa SA, Fischer O, et al. Chronic morphine use does not induce peripheral tolerance in a rat model of inflammatory pain. J Clin Invest 2008; 118: 1065-73.
26. Endres-Becker J, Heppenstall PA, Mousa SA, et al. Mu-opioid receptor activation modulates transient receptor potential vanilloid 1 (TRPV1) currents in sensory neurons in a model of inflammatory pain. Mol Pharmacol 2007; 71: 12-8.
27. Takeda M, Tanimoto T, Ikeda M, Kadoi J, Nasu M, Matsumoto S. Opioidergic modulation of excitability of rat trigeminal root ganglion neuron projections to the superficial layer of cervical dorsal horn. Neuroscience 2004; 125: 995-1008.
28. Walwyn W, Evans CJ, Hales TG. Beta-arrestin2 and c-Src regulate the constitutive activity and recycling of mu opioid receptors in dorsal root ganglion neurons. J Neurosci 2007; 27: 5092-104.
29. Holzer P. Opioid receptors in the gastrointestinal tract. Regul Pept 2009; 155: 11-7.
30. Bartho L, Ernst R, Pierau FK, Sann H, Faulstroh K, Petho G. An opioid peptide inhibits capsaicin-sensitive vasodilatation in the pig's skin. Neuropeptides 1992; 23: 227-37.
31. Stein C, Clark JD, Oh U, et al. Peripheral mechanisms of pain and analgesia. Brain Res Rev 2009; 60: 90-113.
32. Stein C, Schäfer M, Machelska H. Attacking pain at its source: new perspectives on opioids. Nat Med 2003; 9: 1003-8.
33. Patwardhan AM, Berg KA, Akopain AN, et al. Bradykinin-induced functional competence and trafficking of the delta-opioid receptor in trigeminal nociceptors. J Neurosci 2005; 25: 8825-32.
34. Berg KA, Patwardhan AM, Sanchez TA, Silva YM, Hargreaves KM, Clarke WP. Rapid modulation of mu-opioid receptor signaling in primary sensory neurons. J Pharmacol Exp Ther 2007; 321: 839-47.
35. Bao L, Jin SX, Zhang C, et al. Activation of delta opioid receptors induces receptor insertion and neuropeptide secretion. Neuron 2003; 37: 121-33.
36. Gendron L, Lucido AL, Mennicken F, O'Donnell D, Vincent JP, Stroh T, et al. Morphine and pain-related stimuli enhance cell surface availability of somatic delta-opioid receptors in rat dorsal root ganglia. J Neurosci 2006; 26: 953-62.
37. Rowan MP, Ruparel NB, Patwardhan AM, Berg KA, Clarke WP, Hargreaves KM. Peripheral delta opioid receptors require priming for functional competence in vivo. Eur J Pharmacol 2009; 602: 283-7.
38. Zhang N, Rogers TJ, Caterina M, Oppenheim JJ. Proinflammatory chemokines, such as C-C chemokine ligand 3, desensitize muopioid receptors on dorsal root ganglia neurons. J Immunol 2004; 173: 594-9.
39. Pühler W, Zollner C, Brack A, et al. Rapid upregulation of mu opioid receptor mRNA in dorsal root ganglia in response to peripheral inflammation depends on neuronal conduction. Neuroscience 2004; 129: 473-9.
40. Pühler W, Rittner HL, Mousa SA, et al. Interleukin-1 beta contributes to the upregulation of kappa opioid receptor mRNA in dorsal root ganglia in response to peripheral inflammation. Neuroscience 2006; 141: 989-98.
41. Kraus J. Regulation of mu-opioid receptors by cytokines. Front Biosci (Schol Ed) 2009; 1: 164-70.
42. Poonawala T, Levay-Young BK, Hebbel RP, Gupta K. Opioids heal ischemic wounds in the rat. Wound Repair Regen 2005; 13: 165-74.
43. Jimenez N, Puig MM, Pol O. Antiexudative effects of opioids and expression of kappa-and delta-opioid receptors during intestinal inflammation in mice: involvement of nitric oxide. J Pharmacol Exp Ther 2006; 316: 261-70.
44. Shaqura MA, Zöllner C, Mousa SA, Stein C, Schäfer M. Characterization of mu opioid receptor binding and G protein coupling in rat hypothalamus, spinal cord, and primary afferent neurons during inflammatory pain. J Pharmacol Exp Ther 2004; 308: 712-8.
45. Andreev N, Urban L, Dray A. Opioids suppress spontaneous activity of polymodal nociceptors in rat paw skin induced by ultraviolet irradiation. Neuroscience 1994; 58: 793-8.
46. Wenk HN, Brederson JD, Honda CN. Morphine directly inhibits nociceptors in inflamed skin. J Neurophysiol 2006; 95: 2083-97.
47. Antonijevic I, Mousa SA, Schäfer M, Stein C. Perineurial defect and peripheral opioid analgesia in inflammation. The Journal of Neuroscience 1995; 15: 165-72.
48. Sharp BM. Multiple opioid receptors on immune cells modulate intracellular signaling. Brain Behav Immun 2006; 20: 9-14.
49. Sacerdote P, Limiroli E, Gaspani L. Experimental evidence for immunomodulatory effects of opioids. Advances in experimental medicine and biology 2003; 521: 106-16.
50. Bigliardi-Qi M, Bigliardi PL, Buchner S, Rufli T. Characterization of mu-opiate receptor in human epidermis and keratinocytes. Ann N Y Acad Sci 1999; 885: 368-71.
51. Bigliardi PL, Bigliardi-Qi M, Buechner S, Rufli T. Expression of mu-opiate receptor in human epidermis and keratinocytes. J Invest Dermatol 1998; 111: 297-301.
52. Bigliardi-Qi M, Sumanovski LT, Buchner S, Rufli T, Bigliardi PL. Mu-opiate receptor and Beta-endorphin expression in nerve endings and keratinocytes in human skin. Dermatology 2004; 209: 183-9.
53. Stander S, Gunzer M, Metze D, Luger T, Steinhoff M. Localization of mu-opioid receptor 1A on sensory nerve fibers in human skin. Regul Pept 2002; 110: 75-83.
54. Salemi S, Aeschlimann A, Reisch N, et al. Detection of kappa and delta opioid receptors in skin--Outside the nervous system. Biochemical and Biophysical Research Communications 2005; 338: 1012-7.
55. Cheng B, Liu HW, Fu XB, Sheng ZY, Li JF. Coexistence and upregulation of three types of opioid receptors, mu, delta and kappa, in human hypertrophic scars. Br J Dermatol 2008; 158: 713-20.
56. Bigliardi PL, Tobin DJ, Gaveriaux-Ruff C, Bigliardi-Qi M. Opioids and the skin--where do we stand? Exp Dermatol 2009; 18: 424-30.
57. Bigliardi-Qi M, Gaveriaux-Ruff C, Pfaltz K, et al. Deletion of muand kappa-opioid receptors in mice changes epidermal hypertrophy, density of peripheral nerve endings, and itch behavior. J Invest Dermatol 2007; 127: 1479-88.
58. Bigliardi-Qi M, Gaveriaux-Ruff C, Zhou H, et al. Deletion of deltaopioid receptor in mice alters skin differentiation and delays wound healing. Differentiation 2006; 74: 174-85.
59. Bigliardi-Qi M, Bigliardi PL, Eberle AN, Buchner S, Rufli T. betaendorphin stimulates cytokeratin 16 expression and downregulates mu-opiate receptor expression in human epidermis. J Invest Dermatol 2000; 114: 527-32.
60. Bigliardi-Qi M, Lipp B, Sumanovski LT, Buechner SA, Bigliardi PL. Changes of epidermal mu-opiate receptor expression and nerve endings in chronic atopic dermatitis. Dermatology 2005; 210: 91-9.
61. Bigliardi PL, Sumanovski LT, Buchner S, Rufli T, Bigliardi-Qi M. 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 2003; 120: 145-52.
62. Kauser S, Schallreuter KU, Thody AJ, Gummer C, Tobin DJ. Regulation of human epidermal melanocyte biology by betaendorphin. Journal of Investigative Dermatology 2003; 120: 1073-80.
63. Kauser S, Thody AJ, Schallreuter KU, Gummer CL, Tobin DJ. beta-endorphin as a regulator of human hair follicle melanocyte biology. Journal of Investigative Dermatology 2004; 123: 184-95.
64. Slominski A. beta-endorphin/mu-opiate receptor system in the skin. Journal of Investigative Dermatology 2003; 120: Xii-Xiii.
65. Spencer JD, Gibbons NCJ, Rokos H, Peters EMJ, Wood JM, Schallreuter KU. Oxidative stress via hydrogen peroxide affects proopiomelanocortin peptides directly in the epidermis of patients with vitiligo. Journal of Investigative Dermatology 2007; 127: 411-20.
66. Stein C, Clark JD, Oh U, et al. Peripheral mechanisms of pain and analgesia. Brain Research Reviews 2009; 60: 90-113.
67. Machelska H, Pfluger M, Weber W, et al. Peripheral effects of the kappa-opioid agonist EMD 61753 on pain and inflammation in rats and humans. J Pharmacol Exp Ther 1999; 290: 354-61.
68. Guan Y, Johanek LM, Hartke TV, et al. Peripherally acting muopioid receptor agonist attenuates neuropathic pain in rats after L5 spinal nerve injury. Pain 2008; 138: 318-29.
69. DeHaven-Hudkins DL, Dolle RE. Peripherally restricted opioid agonists as novel analgesic agents. Curr Pharm Des 2004; 10: 743-57.
70. Fichna J, Janecka A, Costentin J, Do Rego JC. The endomorphin system and its evolving neurophysiological role. Pharmacol Rev 2007; 59: 88-123.
71. Smith EM. Opioid peptides in immune cells. Adv Exp Med Biol 2003; 521: 51-68.
72. Rittner HL, Machelska H, Stein C. Immune system, pain and analgesia. In: Basbaum AI, Kaneko A, Shepherd GA, Westheimer G, editors. The senses: a comprehensive reference. San Diego: Academic Press; 2008. p. 407-28.
73. Busch-Dienstfertig M, Stein C. Opioid receptors and opioid peptide-producing leukocytes in inflammatory pain--basic and therapeutic aspects. Brain Behav Immun 2010; 24: 683-94.
74. Lolait SJ, Clements JA, Markwick AJ, et al. Pro-opiomelanocortin messenger ribonucleic acid and posttranslational processing of beta-endorphin in spleen macrophages. J Clin Invest 1986; 77: 1776-9.
75. Westly HJ, Kleiss AJ, Kelley KW, Wong PKY, Yuen PH. Newcastle disease virus-infected splenocytes express the proopiomelanocortin gene. J Exp Med 1986; 163: 1589-93.
76. Cabot PJ, Carter L, Gaiddon C, et al. Immune cell-derived.-endorphin: production, release and control of inflammatory pain in rats. J Clin Invest 1997; 100: 142-8.
77. Sitte N, Busch M, Mousa SA, et al. Lymphocytes upregulate signal sequence-encoding proopiomelanocortin mRNA and betaendorphin during painful inflammation in vivo. J Neuroimmunol 2007; 183: 133-45.
78. Smith EM, Morril AC, Meyer WJ, Blalock JE. Corticotropin releasing factor induction of leukocyte-derived immunoreactive ACTH and endorphins. Nature 1986; 321: 881-2.
79. Lyons PD, Blalock JE. Pro-opiomelanocortin gene expression and protein processing in rat mononuclear leukocytes. J Neuroimmunol 1997; 78: 47-56.
80. Stephanou A, Knight RA, De Laurenzi V, Melino G, Lightman SL. Expression of pre-opiomelanocortin (POMC) mRNA in undifferentiated and in vitro differentiated human neuroblastoma cell lines. Prog Clin Biol Res 1991; 366: 173-80.
81. Boue J, Blanpied C, Brousset P, Vergnolle N, Dietrich G. Endogenous opioid-mediated analgesia is dependent on adaptive T cell response in mice. Journal of immunology 2011; 186: 5078-84.
82. Zelenika D, Adams E, Humm S, et al. Regulatory T cells overexpress a subset of Th2 gene transcripts. J Immunol 2002; 168: 1069-79.
83. McHugh RS, Whitters MJ, Piccirillo CA, et al. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 2002; 16: 311-23.
84. Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 2007; 7: 678-89.
85. Machelska H, Cabot PJ, Mousa SA, Zhang Q, Stein C. Pain control in inflammation governed by selectins. Nat Med 1998; 4: 1425-8.
86. Machelska H, Mousa SA, Brack A, et al. Opioid control of inflammatory pain regulated by intercellular adhesion molecule-1. J Neurosci 2002; 22: 5588-96.
87. Machelska H, Brack A, Mousa SA, et al. Selectins and integrins but not platelet-endothelial cell adhesion molecule-1 regulate opioid inhibition of inflammatory pain. Br J Pharmacol 2004; 142: 772-80.
88. Brack A, Rittner HL, Machelska H, et al. Control of inflammatory pain by chemokine-mediated recruitment of opioid-containing polymorphonuclear cells. Pain 2004; 112: 229-38.
89. Labuz D, Schmidt Y, Schreiter A, Rittner HL, Mousa SA, Machelska H. Immune cell-derived opioids protect against neuropathic pain in mice. The Journal of clinical investigation 2009; 119: 278-86.
90. Mousa SA, Shakibaei M, Sitte N, Schäfer M, Stein C. Subcellular pathways of beta-endorphin synthesis, processing, and release from immunocytes in inflammatory pain. Endocrinology 2004; 145: 1331-41.
91. Stein C, Hassan AHS, Lehrberger K, Giefing J, Yassouridis A. Local Analgesic Effect of Endogenous Opioid-Peptides. Lancet 1993; 342: 321-4.
92. Rittner HL, Hackel D, Voigt P, et al. Mycobacteria attenuate nociceptive responses by formyl peptide receptor triggered opioid peptide release from neutrophils. PLoS Pathog 2009; 5: e1000362.
93. Schäfer M, Carter L, Stein C. Interleukin-1 and corticotropinreleasing-factor inhibit pain by releasing opioids from immune cells in inflamed tissue. Proceedings of the National Academy of Sciences of the USA 1994; 91: 4219-23.
94. Binder W, Mousa SA, Sitte N, Kaiser M, Stein C, Schäfer M. Sympathetic activation triggers endogenous opioid release and analgesia within peripheral inflamed tissue. Eur J Neurosci 2004; 20: 92-100.
95. Rittner HL, Labuz D, Schaefer M, et al. Pain control by CXCR2 ligands through Ca2+-regulated release of opioid peptides from polymorphonuclear cells. FASEB J 2006; 20: 2627-9.
96. Rittner HL, Labuz D, Richter JF, et al. CXCR1/2 ligands induce p38 MAPK-dependent translocation and release of opioid peptides from primary granules in vitro and in vivo. Brain Behav Immun 2007; 21: 1021-32.
97. Rittner HL, Hackel D, Yamdeu RS, et al. Antinociception by neutrophil-derived opioid peptides in noninflamed tissue--role of hypertonicity and the perineurium. Brain Behav Immun 2009; 23: 548-57.
98. Tegeder I, Geisslinger G. Opioids as modulators of cell death and survival--unraveling mechanisms and revealing new indications. Pharmacol Rev 2004; 56: 351-69.
99. Rittner HL, Machelska H, Stein C. Leukocytes in the regulation of pain and analgesia. J Leukoc Biol 2005; 78: 1215-22.
100. Chen YL, Law PY, Loh HH. The other side of the opioid story: Modulation of cell growth and survival signaling. Curr Med Chem 2008; 15: 772-8.
101. Sharp BM. Opioid receptor expression and intracellular signaling by cells involved in host defense and immunity. Advances in experimental medicine and biology 2003; 521: 98-105.
102. Chaisson RE, Keruly JC, Moore RD. Race, sex, drug use, and progression of human immunodeficiency virus disease. The New England journal of medicine 1995; 333: 751-6.
103. Pezzotti P, Dal Maso L, Serraino D, Franceschi S, Rezza G. Has the spectrum of AIDS-defining illnesses been changing since the introduction of new treatments and combination of treatments? J Acquir Immune Defic Syndr Hum Retrovirol 1999; 20: 515-6.
104. Celentano DD, Jittiwutikorn J, Hodge MJ, Beyrer C, Nelson KE. Epidemiology of HIV-1 infection in opiate users in Northern Thailand. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 17: 73-8.
105. McLachlan C, Crofts N, Wodak A, Crowe S. The effects of methadone on immune function among injecting drug users: a review. Addiction 1993; 88: 257-63.
106. Weinert CR, Kethireddy S, Roy S. Opioids and infections in the intensive care unit should clinicians and patients be concerned? J Neuroimmune Pharmacol 2008; 3: 218-29.
107. Brack A, Rittner HL, Stein C. Immunosuppressive Effects of Opioids-Clinical Relevance. J Neuroimmune Pharmacol 2011; 6: 490-502.
108. Hall TJ, Jagher B, Schaeublin M, Wiesenberg I. The analgesic drug buprenorphine inhibits osteoclastic bone resorption in vitro, but is proinflammatory in rat adjuvant arthritis. Inflamm Res 1996; 45: 299-302.
109. Richardson JD, Vasko MR. Cellular mechanisms of neurogenic inflammation. The Journal of pharmacology and experimental therapeutics 2002; 302: 839-45.
110. Straub RH, Wolff C, Fassold A, et al. Antiinflammatory role of endomorphins in osteoarthritis, rheumatoid arthritis, and adjuvantinduced polyarthritis. Arthritis and rheumatism 2008; 58: 456-66.
111. Fehrenbacher JC, Sun XX, Locke EE, Henry MA, Hargreaves KM. Capsaicin-evoked iCGRP release from human dental pulp: a model system for the study of peripheral neuropeptide secretion in normal healthy tissue. Pain 2009; 144: 253-61.
112. Bartho L, Szolcsanyi J. Opiate agonists inhibit neurogenic plasma extravasation in the rat. European journal of pharmacology 1981; 73: 101-4.
113. Lembeck F, Donnerer J, Bartho L. Inhibition of neurogenic vasodilation and plasma extravasation by substance P antagonists, somatostatin and [D-Met2, Pro5]enkephalinamide. European journal of pharmacology 1982; 85: 171-6.
114. Smith TW, Buchan P. Peripheral opioid receptors located on the rat saphenous nerve. Neuropeptides 1984; 5: 217-20.
115. Wei ET, Kiang JG, Buchan P, Smith TW. Corticotropin-releasing factor inhibits neurogenic plasma extravasation in the rat paw. The Journal of pharmacology and experimental therapeutics 1986; 238: 783-7.
116. Ma RC, Szurszewski JH. Modulation by opioid peptides of mechanosensory pathways supplying the guinea-pig inferior mesenteric ganglion. The Journal of physiology 1996; 491 (Pt 2): 435-45.
117. Yaksh TL. Substance P release from knee joint afferent terminals: modulation by opioids. Brain Res 1988; 458: 319-24.
118. Binder W, Scott C, Walker JS. Involvement of substance P in the anti-inflammatory effects of the peripherally selective kappa-opioid asimadoline and the NK1 antagonist GR205171. The European journal of neuroscience 1999; 11: 2065-72.
119. Borzsei R, Pozsgai G, Bagoly T, et al. Inhibitory action of endomorphin-1 on sensory neuropeptide release and neurogenic inflammation in rats and mice. Neuroscience 2008; 152: 82-8.
120. Belvisi MG, Rogers DF, Barnes PJ. Neurogenic plasma extravasation: inhibition by morphine in guinea pig airways in vivo. Journal of applied physiology 1989; 66: 268-72.
121. Yonehara N, Imai Y, Chen J-Q, Takiuchi S, Inoki R. Influence of opioids on substance P release evoked by antidromic stimulation of primary afferent fibers in the hind instep of rats. Regul Pept 1992; 38: 13-22.
122. Shakhanbeh J, Lynn B. Morphine inhibits antidromic vasodilatation without affecting the excitability of C-polymodal nociceptors in the skin of the rat. Brain Research 1993; 607: 314-8.
123. Barber A. Mu-and kappa-opioid receptor agonists produce peripheral inhibition of neurogenic plasma extravasation in rat skin. European journal of pharmacology 1993; 236: 113-20.
124. Averbeck B, Reeh PW, Michaelis M. Modulation of CGRP and PGE2 release from isolated rat skin by alpha-adrenoceptors and kappa-opioid-receptors. Neuroreport 2001; 12: 2097-100.
125. Yonehara N, Takiuchi S. Involvement of calcium-activated potassium channels in the inhibitory prejunctional effect of morphine on peripheral sensory nerves. Regul Pept 1997; 68: 147-53.
126. Lembeck F, Donnerer J. Opioid control of the function of primary afferent substance P fibres. European journal of pharmacology 1985; 114: 241-6.
127. Kress M, Guthmann C, Averbeck B, Reeh PW. Calcitonin generelated peptide and prostaglandin E2 but not substance P release induced by antidromic nerve stimulation from rat skin in vitro. Neuroscience 1999; 89: 303-10.
128. Mudge AW, Leeman SE, Fischbach GD. Enkephalin inhibits release of substance P from sensory neurons in culture and decreases action potential duration. Proceedings of the National Academy of Sciences of the United States of America 1979; 76: 526-30.
129. Schaafsma L, Sun H, Zochodne D. Exogenous opioids influence the microcirculation of injured peripheral nerves. Am J Physiol 1997; 272: H76-82.
130. Khalil Z, Sanderson K, Modig M, Nyberg F. Modulation of peripheral inflammation by locally administered endomorphin-1. Inflamm Res 1999; 48: 550-6.
131. Barin AK, McDougall JJ. Endomorphin-1 causes synovial hypoaemia in rat knee joints via a capsaicin-sensitive neural pathway. Neuroscience letters 2003; 344: 21-4.
132. Martinez JH, Mondragon CE, Cespedes A. An evaluation of the antiinflammatory effects of intraarticular synthetic beta-endorphin in the canine model. Anesthesia and analgesia 1996; 82: 177-81.
133. Pol O, Puig MM. Expression of opioid receptors during peripheral inflammation. Curr Top Med Chem 2004; 4: 51-61.
134. Mogil JS. Animal models of pain: progress and challenges. Nature reviews Neuroscience 2009; 10: 283-94.
135. Wengner AM, Hopken UE, Petrow PK, et al. CXCR5-and CCR7-dependent lymphoid neogenesis in a murine model of chronic antigen-induced arthritis. Arthritis and rheumatism 2007; 56: 3271-83.
136. Hultqvist M, Olofsson P, Gelderman KA, Holmberg J, Holmdahl R. A new arthritis therapy with oxidative burst inducers. PLoS medicine 2006; 3: e348.
137. Yonehara N, Imai Y, Inoki R. Effects of opioids on the heat stimulus-evoked substance P release and thermal edema in the rat hind paw. European journal of pharmacology 1988; 151: 381-7.
138. Khalil Z, Helme RD. Modulation of a peripheral inflammatory response to substance P by locally administered opioid receptor agonists. Neuropeptides 1990; 17: 45-53.
139. Green PG, Levine JD. Delta-and kappa-opioid agonists inhibit plasma extravasation induced by bradykinin in the knee joint of the rat. Neuroscience 1992; 49: 129-33.
140. Zochodne DW, Ho LT. Evidence that capsaicin hyperaemia of rat sciatic vasa nervorum is local, opiate-sensitive and involves mast cells. J physiol 1993; 468: 325-33.
141. Earl JR, Grootveld MC, Blake DR, Morris CJ. Effect of mu, delta and kappa opioid receptor agonists on a reactive oxygen species mediated model of skin inflammation. Skin Pharmacol 1996; 9: 250-8.
142. Hong Y, Abbott FV. Peripheral opioid modulation of pain and inflammation in the formalin test. European journal of pharmacology 1995; 277: 21-8.
143. Taylor BK, Peterson MA, Roderick RE, et al. Opioid inhibition of formalin-induced changes in plasma extravasation and local blood flow in rats. Pain 2000; 84: 263-70.
144. Denko CW, Gabriel P. Effects of peptide hormones in urate crystal inflammation. The Journal of rheumatology 1985; 12: 971-5.
145. Gyires K, Budavari I, Furst S, Molnar I. Morphine inhibits the carrageenan-induced oedema and the chemoluminescence of leucocytes stimulated by zymosan. J Pharm Pharmacol 1985; 37: 100-4.
146. Sacerdote P, Bianchi M, Panerai AE. Involvement of betaendorphin in the modulation of paw inflammatory edema in the rat. Regul Pept 1996; 63: 79-83.
147. Catheline G, Le Guen S, Besson JM. Effects of U-69,593, a kappaopioid receptor agonist, on carrageenin-induced peripheral oedema and Fos expression in the rat spinal cord. European journal of pharmacology 1999; 370: 287-96.
148. Planas E, Sanchez S, Rodriguez L, Pol O, Puig MM. Antinociceptive/anti-edema effects of liposomal morphine during acute inflammation of the rat paw. Pharmacology 2000; 60: 121-7.
149. Joris J, Costello A, Dubner R, Hargreaves KM. Opiates suppress carrageenan-induced edema and hyperthermia at doses that inhibit hyperalgesia. Pain 1990; 43: 95-103.
150. Planas ME, Rodriguez L, Sanchez S, Pol O, Puig MM. Pharmacological evidence for the involvement of the endogenous opioid system in the response to local inflammation in the rat paw. Pain 1995; 60: 67-71.
151. Honore P, Buritova J, Besson JM. Intraplantar morphine depresses spinal c-Fos expression induced by carrageenin inflammation but not by noxious heat. British journal of pharmacology 1996; 118: 671-80.
152. Jin S, Lei L, Wang Y, Da D, Zhao Z. Endomorphin-1 reduces carrageenan-induced fos expression in the rat spinal dorsal horn. Neuropeptides 1999; 33: 281-4.
153. Fletcher D, Gentili M, Mazoit JX, Samii K. Additivity of bupivacaine and morphine for peripheral analgesia in rats. Fundam Clin Pharmacol 2000; 14: 327-34.
154. Perrot S, Guilbaud G, Kayser V. Effects of intraplantar morphine on paw edema and pain-related behaviour in a rat model of repeated acute inflammation. Pain 1999; 83: 249-57.
155. Whiteside GT, Boulet JM, Walker K. The role of central and peripheral mu opioid receptors in inflammatory pain and edema: a study using morphine and DiPOA ([8-(3,3-diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-yl]-acetic acid). The Journal of pharmacology and experimental therapeutics 2005; 314: 1234-40.
156. Romero A, Planas E, Poveda R, Sanchez S, Pol O, Puig MM. Antiexudative effects of opioid receptor agonists in a rat model of carrageenan-induced acute inflammation of the paw. European journal of pharmacology 2005; 511: 207-17.
157. McDougall JJ, Baker CL, Hermann PM. Attenuation of knee joint inflammation by peripherally administered endomorphin-1. J Mol Neurosci 2004; 22: 125-37.
158. Stein C, Millan MJ, Herz A. Unilateral inflammation of the hindpaw in rats as a model of prolonged noxious stimulation: alterations in behavior and nociceptive thresholds. Pharmacol Biochem Behav 1988; 31: 445-51.
159. Kalso E, Smith L, McQuay HJ, Moore RA. No pain, no gain: clinical excellence and scientific rigour-lessons learned from IA morphine. Pain 2002; 98: 269-75.
160. Sawynok J. Topical and peripherally acting analgesics. Pharmacol Rev 2003; 55: 1-20.
161. Walker JS, Howlett CR, Nayanar V. Anti-inflammatory effects of kappa-opioids in adjuvant arthritis. Life sciences 1995; 57: 371-8.
162. Wilson JL, Nayanar V, Walker JS. The site of anti-arthritic action of the kappa-opioid, U-50, 488H, in adjuvant arthritis: importance of local administration. British journal of pharmacology 1996; 118: 1754-60.
163. Almarestani L, Fitzcharles MA, Bennett GJ, Ribeiro-da-Silva A. Imaging studies in Freund's complete adjuvant model of regional polyarthritis, a model suitable for the study of pain mechanisms, in the rat. Arthritis and rheumatism 2011; 63: 1573-81.
164. Poveda R, Fernandez-Duenas V, Fernandez A, Sanchez S, Puig MM, Planas E. Synergistic interaction between fentanyl and the histamine H3 receptor agonist R-(alpha)-methylhistamine, on the inhibition of nociception and plasma extravasation in mice. European journal of pharmacology 2006; 541: 53-6.
165. McDougall JJ, Barin AK, McDougall CM. Loss of vasomotor responsiveness to the mu-opioid receptor ligand endomorphin-1 in adjuvant monoarthritic rat knee joints. American journal of physiology Regulatory, integrative and comparative physiology 2004; 286: R634-41.
166. Earl JR, Claxson AW, Blake DR, Morris CJ. Proinflammatory effects of morphine in the rat adjuvant arthritis model. Int J Tissue React 1994; 16: 163-70.
167. Antic J, Vasiljevic T, Stanojevic S, et al. Suppression of adjuvant arthritis by kappa-opioid receptor agonist: effect of route of administration and strain differences. Immunopharmacology 1996; 34: 105-12.
168. Walker JS, Chandler AK, Wilson JL, Binder W, Day RO. Effect of mu-opioids morphine and buprenorphine on the development of adjuvant arthritis in rats. Inflamm Res 1996; 45: 557-63.
169. Jessop DS, Fassold A, Wolff C, et al. Endomorphins in rheumatoid arthritis, osteoarthritis, and experimental arthritis. Annals of the New York Academy of Sciences 2010; 1193: 117-22.
170. Wilson JL, Walker JS, Antoon JS, Perry MA. Intercellular adhesion molecule-1 expression in adjuvant arthritis in rats: inhibition by kappa-opioid agonist but not by NSAID. The Journal of rheumatology 1998; 25: 499-505.
171. Wilson JL, Carmody JJ, Walker JS. The importance of the hypothalamo-hypophyseal-adrenal axis to the anti-inflammatory actions of the kappa-opioid agonist PNU-50,488H in rats with adjuvant arthritis. The Journal of pharmacology and experimental therapeutics 2000; 294: 1131-6.
172. Binder W, Carmody J, Walker J. Effect of gender on antiinflammatory and analgesic actions of two kappa-opioids. J Pharmacol Exp Ther 2000; 292: 303-9.
173. Binder W, Walker JS. Effect of the peripherally selective kappaopioid agonist, asimadoline, on adjuvant arthritis. British journal of pharmacology 1998; 124: 647-54.
174. Bush KA, Kirkham BW, Walker JS. The kappa-opioid agonist, asimadoline, alters cytokine gene expression in adjuvant arthritis. Rheumatology (Oxford) 2001; 40: 1013-21.
175. Walker JS, Scott C, Bush KA, Kirkham BW. Effects of the peripherally selective kappa-opioid asimadoline, on substance P and CGRP mRNA expression in chronic arthritis of the rat. Neuropeptides 2000; 34: 193-202.
176. Braz J, Beaufour C, Coutaux A, et al. Therapeutic efficacy in experimental polyarthritis of viral-driven enkephalin overproduction in sensory neurons. The Journal of neuroscience: the official journal of the Society for Neuroscience 2001; 21: 7881-8.
177. Kyrkanides S, Fiorentino PM, Miller JN, et al. Amelioration of pain and histopathologic joint abnormalities in the Col1-IL-1beta(XAT) mouse model of arthritis by intraarticular induction of mu-opioid receptor into the temporomandibular joint. Arthritis and rheumatism 2007; 56: 2038-48.
178. Coussons-Read ME, Daniels M, Gilmour MI. Morphine reduces pulmonary inflammation in response to influenza infection. Life sciences 1999; 65: 1141-52.
179. Chadzinska M, Kolaczkowska E, Seljelid R, Plytycz B. Morphine modulation of peritoneal inflammation in Atlantic salmon and CB6 mice. J Leukoc Biol 1999; 65: 590-6.
180. Chadzinska M, Starowicz K, Scislowska-Czarnecka A, et al. Morphine-induced changes in the activity of proopiomelanocortin and prodynorphin systems in zymosan-induced peritonitis in mice. Immunol Lett 2005; 101: 185-92.
181. Philippe D, Dubuquoy L, Groux H, et al. Anti-inflammatory properties of the mu opioid receptor support its use in the treatment of colon inflammation. J Clin Invest 2003; 111: 1329-38.
182. Chakass D, Philippe D, Erdual E, et al. mu-Opioid receptor activation prevents acute hepatic inflammation and cell death. Gut 2007; 56: 974-81.
183. Stein C, Comisel K, Haimerl E, Yassouridis A, Lehrberger K, Herz A, et al. Analgesic effect of intraarticular morphine after arthroscopic knee surgery. N Engl J Med 1991; 325: 1123-6.
184. Khoury GF, Chen ACN, Garland DE, Stein C. Intraarticular morphine, bupivacaine and morphine/bupivacaine for pain control after knee videoarthroscopy. Anesthesiology 1992; 77: 263-6.
185. Stein C, Pflüger M, Yassouridis A, et al. No tolerance to peripheral morphine analgesia in presence of opioid expression in inflamed synovia. J Clin Invest 1996; 98: 793-9.
186. Likar R, Schafer M, Paulak F, et al. Intraarticular morphine analgesia in chronic pain patients with osteoarthritis. Anesth Analg 1997; 84: 1313-7.
187. Stein A, Yassouridis A, Szopko C, Helmke K, Stein C. Intraarticular morphine versus dexamethasone in chronic arthritis. Pain 1999; 83: 525-32.
188. Tulamo RM, Raekallio M, Taylor P, Johnson CB, Salonen M. Intra-articular morphine and saline injections induce release of large molecular weight proteoglycans into equine synovial fluid. Zentralblatt fur Veterinarmedizin Reihe A 1996; 43: 147-53.
189. Jaureguito JW, Wilcox JF, Thisted RA, Phillips C, Cunningham B, Reider B. The effects of morphine on human articular cartilage of the knee: an in vitro study. Arthroscopy 2002; 18: 631-6.
190. Santos LC, de Moraes AN, Saito ME. Effects of intraarticular ropivacaine and morphine on lipopolysaccharide-induced synovitis in horses. Veterinary anaesthesia and analgesia 2009; 36: 280-6.
191. Lindegaard C, Gleerup KB, Thomsen MH, Martinussen T, Jacobsen S, Andersen PH. Anti-inflammatory effects of intraarticular administration of morphine in horses with experimentally induced synovitis. American journal of veterinary research 2010; 71: 69-75.
192. Raap T, Justen HP, Miller LE, Cutolo M, Scholmerich J, Straub RH. Neurotransmitter modulation of interleukin 6 (IL-6) and IL-8 secretion of synovial fibroblasts in patients with rheumatoid arthritis compared to osteoarthritis. The Journal of rheumatology 2000; 27: 2558-65.
193. Takeba Y, Suzuki N, Kaneko A, Asai T, Sakane T. Endorphin and enkephalin ameliorate excessive synovial cell functions in patients with rheumatoid arthritis. J Rheumatol 2001; 28: 2176-83.
194. Stalman A, Tsai JA, Segerdahl M, Dungner E, Arner P, Fellander-Tsai L. Ketorolac but not morphine exerts inflammatory and metabolic effects in synovial membrane after knee arthroscopy: a double-blind randomized prospective study using the microdialysis technique. Regional anesthesia and pain medicine 2009; 34: 557-64.
195. Anesthesiologists ASo. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology 2004; 100: 1573-81.
196. Valverde A, Gunkel CI. Pain management in horses and farm animals J Vet Emerg Crit Care 2005; 15: 295-307.
197. Baum CL, Arpey CJ. Normal cutaneous wound healing: Clinical correlation with cellular and molecular events. Dermatol Surg 2005; 31: 674-86.
198. Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature 2008; 453: 314-21.
199. Coulombe PA. Wound epithelialization: Accelerationg the pace of discovery. Journal of Investigative Dermatology 2003; 121: 219-30.
200. Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev 2003; 83: 835-70.
201. Pilcher BK, Dumin JA, Sudbeck BD, Krane SM, Welgus HG, Parks WC. The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix. J Cell Biol 1997; 137: 1445-57.
202. Soo C, Shaw WW, Zhang XL, Longaker MT, Howard EW, Ting K. Differential expression of matrix metalloproteinases and their tissue-derived inhibitors in cutaneous wound repair. Plast Reconstr Surg 2000; 105: 638-47.
203. Greenhalgh DG. Models of wound healing. J Burn Care Rehabil 2005; 26: 293-305.
204. Bartolmas T, Heyn T, Mickeleit M, Fischer A, Reutter W, Danker K. Glucosamine-glycerophospholipids that activate cell-matrix adhesion and migration. J Med Chem 2005; 48: 6750-5.
205. Sauer B, Vogler R, Zimmermann K, et al. Lysophosphatidic acid interacts with transforming growth factor-beta signaling to mediate keratinocyte growth arrest and chemotaxis. Journal of Investigative Dermatology 2004; 123: 840-9.
206. Vogler R, Sauer B, Kim DS, Schafer-Korting M, Kleuser B. Sphingosine-1-phosphate and its potentially paradoxical effects on critical parameters of cutaneous wound healing. Journal of Investigative Dermatology 2003; 120: 693-700.
207. Koivisto L, Jiang GQ, Hakkinen L, Chan BC, Larjava H. HaCaT keratinocyte migration is dependent on epidermal growth factor receptor signaling and glycogen synthase kinase-3 alpha. Exp Cell Res 2006; 312: 2791-805.
208. Geback T, Schulz MM, Koumoutsakos P, Detmar M. TScratch: a novel and simple software tool for automated analysis of monolayer wound healing assays. Biotechniques 2009; 46: 265-74.
209. Laplante AF, Germain L, Auger FA, Moulin V. Mechanisms of wound reepithelialization: hints from a tissue-engineered reconstructed skin to long-standing questions. Faseb J 2001; 15: 2377-89.
210. El Ghalbzouri A, Hensbergen P, Gibbs S, Kempenaar J, van der Schors R, Ponec M. Fibroblasts facilitate re-epithelialization in wounded human skin equivalents. Lab Invest 2004; 84: 102-12.
211. Falanga V, Isaacs C, Paquette D, et al. Wounding of bioengineered skin: Cellular and molecular aspects after injury. Journal of Investigative Dermatology 2002; 119: 653-60.
212. Schafer-Korting M, Mahmoud A, Borgia SL, et al. Reconstructed epidermis and full-thickness skin for absorption testing: Influence of the vehicles used on steroid permeation. Atla-Altern Lab Anim 2008; 36: 441-52.
213. Spielmann H, Liebsch M, Kandarova H, et al. Results of the ECVAM skin irritation validation study (SIVS). N-S Arch Pharmacol 2007; 375: 98-.
214. Vaughan MB, Ramirez RD, Brown SA, Yang JC, Wright WE, Shay JW. A reproducible laser-wounded skin equivalent model to study the effects of aging in vitro. Rejuvenation Res 2004; 7: 99-110.
215. Küchler S, Wolf NB, Heilmann S, et al. 3D-wound healing model: influence of morphine and solid lipid nanoparticles. J Biotechnol 2010; 148: 24-30.
216. Lindblad WJ. Considerations for selecting the correct animal model for dermal wound-healing studies. J Biomat Sci-Polym E 2008; 19: 1087-96.
217. Davidson JM. Animal models for wound repair. Arch Dermatol Res 1998; 290: S1-S11.
218. Fang Y, Gong SJ, Wang Y, Xu YH, Bao SS. [Effect of GMCSFabsence on neovascularization during wound healing]. Zhonghua Zheng Xing Wai Ke Za Zhi 2007; 23: 233-5.
219. Stein C, Millan MJ, Shippenberg TS, Herz A. Peripheral effect of fentanyl upon nociception in inflamed tissue of the rat. Neuroscience Letters 1988; 84: 225-8.
220. Stein C, Millan MJ, Shippenberg TS, Peter K, Herz A. Peripheral opioid receptors mediating antinociception in inflammation. Evidence for involvement of mu, delta and kappa receptors. J Pharmacol Exp Ther 1989; 248: 1269-75.
221. Likar R, Kapral S, Steinkellner H, Stein C, Schäfer M. Dosedependency of intra-articular morphine analgesia. Br J Anaesth 1999; 83: 241-4.
222. Likar R, Koppert W, Blatnig H, et al. Efficacy of peripheral morphine analgesia in inflamed, non-inflamed and perineural tissue of dental surgery patients. J Pain Symptom Manage 2001; 21: 330-7.
223. Bockamp E, Sprengel R, Eshkind L, et al. Conditional transgenic mouse models: from the basics to genome-wide sets of knockouts and current studies of tissue regeneration. Regen Med 2008; 3: 217-35.
224. Flock P. Pilot study to determine the effectiveness of diamorphine gel to control pressure ulcer pain. J Pain Symptom Manag 2003; 25: 547-54.
225. Long TD, Cathers TA, Twillman R, O'Donnell T, Garrigues N, Jones T. Morphine-Infused silver sulfadiazine (MISS) cream for burn analgesia: a pilot study. J Burn Care Rehabil 2001; 22: 118-23.
226. Zeppetella G, Paul J, Ribeiro MD. Analgesic efficacy of morphine applied topically to painful ulcers. J Pain Symptom Manage 2003; 25: 555-8.
227. Zeppetella G, Ribeiro MD. Morphine in intrasite gel applied topically to painful ulcers. J Pain Symptom Manag 2005; 29: 118-9.
228. Bigliardi PL, Buchner S, Rufli T, Bigliardi-Qi M. Specific stimulation of migration of human keratinocytes by mu-opiate receptor agonists. J Recept Signal Transduct Res 2002; 22: 191-9.
229. Küchler S, Radowski MR, Blaschke T, et al. Nanoparticles for skin penetration enhancement--a comparison of a dendritic coremultishell-nanotransporter and solid lipid nanoparticles. European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik eV 2009; 71: 243-50.
230. Poonawala T, Levay-Young BK, Hebbel RP, Gupta K. Opioids heal ischemic wounds in the rat. Wound Repair Regen 2005; 13: 165-74.
231. Lam CF, Chang PJ, Huang YS, et al. Prolonged use of high-dose morphine impairs angiogenesis and mobilization of endothelial progenitor cells in mice. Anesthesia and Analgesia 2008; 107: 686-92.
232. LeBon B, Zeppetella G, Higginson IJ. Effectiveness of topical administration of opioids in palliative care: a systematic review. J Pain Symptom Manage 2009; 37: 913-7.
233. Canbay O, Celebi N, Uzun S, Sahin A, Celiker V, Aypar U. Topical ketamine and morphine for post-tonsillectomy pain. Eur J Anaesth 2008; 25: 287-92.
234. Platzer M, Likar R, Stein C, Beubler E, Sittl R. Topical application of morphine gel in inflammatory mucosal and cutaneous lesions. Schmerz 2005; 19: 296-+.
235. Howdieshell TR, Webb WL, Sathyanarayana, McNeil PL. Inhibition of inducible nitric oxide synthase results in reductions in wound vascular endothelial growth factor expression, granulation tissue formation, and local perfusion. Surgery 2003; 133: 528-37.
236. Schwentker A, Vodovotz Y, Weller R, Billiar TR. Nitric oxide and wound repair: role of cytokines? Nitric Oxide-Biol Ch 2002; 7: 1-10.
237. Noiri E, Peresleni T, Srivastava N, et al. Nitric oxide is necessary for a switch from stationary to locomoting phenotype in epithelial cells. Am J Physiol-Cell Ph 1996; 39: C794-C802.
238. Saric A, Balog T, Sobocanec S, Marotti T. Endomorphin 1 activates nitric oxide synthase 2 activity and downregulates nitric oxide synthase 2 mRNA expression. Neuroscience 2007; 144: 1454-61.
239. Cho CH, Wu KK, Wu S, et al. Morphine as a drug for stress ulcer prevention and healing in the stomach. Eur J Pharmacol 2003; 460: 177-82.
240. Rook JM, Hasan W, McCarson KE. Temporal effects of topical morphine application on cutaneous wound heating. Anesthesiology 2008; 109: 130-6.
241. Sassani JW, Zagon IS, McLaughlin PJ. Opioid growth factor modulation of corneal epithelium: Uppers and downers. Curr Eye Res 2003; 26: 249-62.
242. Brodin E, Gazelius B, Panopoulos P, Olgart L. Morphine inhibits substance P release from peripheral sensory nerve endings. Acta Physiologica Scandinavica 1983; 117: 567-70.
243. Clark JD, Shi XY, Li XQ, et al. Morphine reduces local cytokine expression and neutrophil infiltration after incision. Mol Pain 2007; 3:-.
244. Adamson R. Role of macrophages in normal wound healing: an overview. J Wound Care 2009; 18: 349-51.
245. Shih B, Garside E, McGrouther DA, Bayat A. Molecular dissection of abnormal wound healing processes resulting in keloid disease. Wound Repair Regen 2010; 18: 139-53.
246. Delgado AV, McManus AT, Chambers JP. Exogenous administration of Substance P enhances wound healing in a novel skin-injury model. Exp Biol Med (Maywood) 2005; 230: 271-80.
247. Engin C. Effects of calcitonin gene-related peptide on wound contraction in denervated and normal rat skin: a preliminary report. Plast Reconstr Surg 1998; 101: 1887-90.
248. da Silva L, Carvalho E, Cruz MT. Role of neuropeptides in skin inflammation and its involvement in diabetic wound healing. Expert Opin Biol Ther 2010; 10: 1427-39.
249. Khalil Z, Helme R. Sensory peptides as neuromodulators of wound healing in aged rats. J Gerontol a-Biol 1996; 51: B354-B61.
250. Rook JM, Hasan W, McCarson KE. Morphine-induced early delays in wound closure: Involvement of sensory neuropeptides and modification of neurokinin receptor expression. Biochem Pharmacol 2009; 77: 1747-55.
251. Rook JM, McCarson KE. Delay of cutaneous wound closure by morphine via local blockade of peripheral tachykinin release. Biochem Pharmacol 2007; 74: 752-7.
252. Rook JM, Hasan W, McCarson KE. Temporal effects of topical morphine application on cutaneous wound healing. Anesthesiology 2008; 109: 130-6.
253. Martin JL, Charboneau R, Barke RA, Roy S. Chronic morphine treatment inhibits LPS-induced angiogenesis: Implications in wound healing. Cell Immunol 2010; 265: 139-45.
254. Martin JL, Koodie L, Krishnan AG, Charboneau R, Barke RA, Roy S. Chronic Morphine Administration Delays Wound Healing by Inhibiting Immune Cell Recruitment to the Wound Site. Am J Pathol 2010; 176: 786-99.
255. Balasubramanian S, Ramakrishnan S, Charboneau R, Wang J, Barke RA, Roy S. Morphine sulfate inhibits hypoxia-induced vascular endothelial growth factor expression in endothelial cells and cardiac myocytes. J Mol Cell Cardiol 2001; 33: 2179-87.
256. Roy S, Balasubramanian S, Wang JH, Chandrashekhar Y, Charboneau R, Barke R. Morphine inhibits VEGF expression in myocardial ischemia. Surgery 2003; 134: 336-44.
257. Zagon IS, Sassani JW, McLaughlin PJ. Reepithelialization of the human cornea is regulated by endogenous opioids. Invest Ophth Vis Sci 2000; 41: 73-81.
258. Zagon IS, Verderame MF, McLaughlin PJ. The biology of the opioid growth factor receptor (OGFr). Brain Research Reviews 2002; 38: 351-76.
259. McLaughlin PJ, Sassani JW, Klocek MS, Zagon IS. Diabetic keratopathy and treatment by modulation of the opioid growth factor (OGF)-OGF receptor (OGFr) axis with naltrexone: A review. Brain Research Bulletin 2010; 81: 236-47.
260. Stiles J, Honda CN, Krohne SG, Kazacos EA. Effect of topical administration of 1% morphine sulfate solution on signs of pain and corneal wound healing in dogs. Am J Vet Res 2003; 64: 813-8.
261. Zagon IS, Wu Y, McLaughlin PJ. The opioid growth factor, [Met(5)]-enkephalin, and the zeta opioid receptor are present in human and mouse skin and tonically act to inhibit DNA synthesis in the epidermis. J Investigative Dermatol 1996; 106: 490-7.
262. Nissen JB, Kragballe K. Enkephalins modulate differentiation of normal human keratinocytes in vitro. Exp Dermatol 1997; 6: 222-9.
263. Wilson RP, McLaughlin PJ, Lang CM, Zagon IS. The opioid growth factor, [Met(5)]-enkephalin, inhibits DNA synthesis during recornification of mouse tail skin. Cell Proliferat 2000; 33: 63-73.
264. Cressey D. Traditional drug-discovery model ripe for reform. Nature 2011; 471: 17-8.