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Can morphine interfere in the healing process during chronic stress?

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Abstract

Technological advances, constant pressure, increased qualified demand, and other daily activities present in modern society result in increasingly stressful living conditions for the population. In the short term, the release of stress-related hormones can play a key role in the survival of an organism. However, it is well known that chronic exposure to cortisol can lead to many adverse effects. Several findings show immunological changes in response to chronic exposure to cortisol, in particular in skin integrity, which may interfere with the healing process. Morphine is an immunosuppressive drug, and when it is used chronically, it can lead to an increased incidence of infections and a delay in the healing process. The importance of opiates as analgesics in the medical setting is indisputable. However, there are a limited number of studies in this field. These investigations can provide further understanding of the mechanisms involved in the healing process in morphine-dependent individuals under chronic stress, which is a common condition in modern society. Furthermore, medical prescriptions of opiates are common among terminal patients, who frequently develop decubitus ulcers and bacterial infections. This review is aimed to provide a concise analysis of effects of morphine and stress on the healing process.

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References

  1. Adamson WT, Windh RT, Blackford S, Kuhn CM (1991) Ontogeny of m and k-opiate receptor control of the hypothalamic–pituitary–adrenal axis in rats. Endocrinol 129:959–964

    Article  CAS  Google Scholar 

  2. Altemus M, Rao B, Dhabhar FS, Ding W, Granstein RD (2001) Stress-induced changes in skin barrier function in healthy women. J Invest Dermatol 117:309–317

    Article  PubMed  CAS  Google Scholar 

  3. Bayer BM, Brehio RM, Ding XZ, Hernandez MC (1994) Enhanced susceptibility of the immune system to stress in morphine-tolerant rats. Brain Behav Immun 8:173–184

    Article  PubMed  CAS  Google Scholar 

  4. Benedek G, Szikszay M (1985) Sensitization or tolerance to morphine effects after repeated stresses. Prog Neuropsychopharmacol Biol Psychiatry 9:369–380

    Article  PubMed  CAS  Google Scholar 

  5. Bigliardi-Qi M, Sumanovski LT, Buchner S, Rufli T, Bigliardi PL (2004) Mu-opiate receptor and beta-endorphin expression in nerve endings and keratinocytes in human skin. Dermatol 209:183–189

    Article  CAS  Google Scholar 

  6. Brack A, Rittner HL, Machelska H, Leder K, Mousa SA, Schäfer M, Stein C (2004) Control of inflammatory pain by chemokine-mediated recruitment of opioid-containing polymorphonuclear cells. Pain 112:229–238

    Article  PubMed  CAS  Google Scholar 

  7. Broadbent E, Petrie KJ, Alley PG, Booth RJ (2003) Psychological stress impairs early wound repair following surgery. Psychosom Med 65:865–869

    Article  PubMed  Google Scholar 

  8. Broughton G 2nd, Janis JE, Attinger CE (2006) The basic science of wound healing. Plast Reconstr Surg 117:12S–34S

    Article  PubMed  CAS  Google Scholar 

  9. Bryan D, Walker KB, Ferguson M, Thorpe R (2005) Cytokine gene expression in a murine wound healing model. Cytokine 31:429–438

    Article  PubMed  CAS  Google Scholar 

  10. Burnett FE, Scott LV, Weaver MG, Medbak SH, Dinan TG (1999) The effect of naloxone on adrenocorticotropin and cortisol release: evidence for a reduced response in depression. J Affect Disord 53:263–268

    Article  PubMed  CAS  Google Scholar 

  11. Carey AN, Lyons AM, Shay CF, Dunton O, McLaughlin JP (2009) Endogenous kappa opioid activation mediates stress-induced deficits in learning and memory. J Neurosci 29:4293–4300

    Article  PubMed  CAS  Google Scholar 

  12. Carlson KR (1977) Supersensitivity to apomorphine and stress two years after chronic methadone treatment. Neuropharmacology 16:795–798

    Article  PubMed  CAS  Google Scholar 

  13. Christie MJ, Trisdikoon P, Chesher GB (1982) Tolerance and cross tolerance with morphine resulting from physiological release of endogenous opiates. Life Sci 31:839–845

    Article  PubMed  CAS  Google Scholar 

  14. Clark JD, Shi X, Li X, Qiao Y, Liang D, Angst MS, Yeomans DC (2007) Morphine reduces local cytokine expression and neutrophil infiltration after incision. Mol Pain 3:28

    Article  PubMed  Google Scholar 

  15. Coventry TL, Jessop DS, Finn DP, Crabb MD, Kinoshita H, Harbuz MS (2001) Endomorphine and activation of the hypothalamo–pituitary–adrenal axis. J Endocrinol 169:185–193

    Article  PubMed  CAS  Google Scholar 

  16. Cuéllar B, Fernández AP, Lizasoain I, Moro MA, Lorenzo P, Bentura ML, Rodrigo J, Leza JC (2000) Up-regulation of neuronal NO synthase immunoreactivity in opiate dependence and withdrawal. Psychopharmacology (Berl) 148:66–73

    Article  Google Scholar 

  17. Dângelo JG, Fattini CA (1998) Sistema tegumentar. Anatomia humana sistêmica e segmentar: para o estudante de medicina. Ateneu, São Paulo

    Google Scholar 

  18. Delgado AV, McManus AT, Chambers JP (2005) Exogenous administration of substance P enhances wound healing in a novel skin-injury model. Exp Biol Med 230:271–280

    CAS  Google Scholar 

  19. Delle M, Thoren P, Skarphedinsson JO, Hoffman P, Carlsson S, Ricksten S (1990) Differentiated responses of renal and adrenal sympathetic nerve activity to intravenous morphine administration in anesthetized rats. J Pharmacol Exp Ther 253:655–660

    PubMed  CAS  Google Scholar 

  20. Denda M, Tsuchiya T, Elias PM, Feingold KR (2000) Stress alters cutaneous permeability barrier homeostasis. Am J Physiol Regul Integr Comp Physiol 278:367–372

    Google Scholar 

  21. Engin C (1998) Effects of calcitonin gene-related peptide on wound contraction in denervated and normal rat skin: a preliminary report. Plast Reconstr Surg 101:1887–1890

    Article  PubMed  CAS  Google Scholar 

  22. Fitzgerald LW, Ortiz J, Hamedani AG, Nestler EJ (1996) Drugs of abuse and stress increase the expression of GluR1 and NMDAR1 glutamate receptor subunits in the rat ventral tegmental area: common adaptations among cross-sensitizing agents. J Neurosci 16:274–282

    PubMed  CAS  Google Scholar 

  23. Flores LR, Dretchen KL, Bayer BM (1996) Potential role of the autonomic nervous system in the immunosuppressive effects of acute morphine administration. Eur J Pharmacol 318:437–446

    Article  PubMed  CAS  Google Scholar 

  24. Flores LR, Hernandez MC, Bayer BM (1993) Acute immunosuppressive effects of morphine: lack of involvement of pituitary and adrenal factors. J Pharmacol Exp Ther 268:1129–1134

    Google Scholar 

  25. Garg A, Chren MM, Sands LP, Matsui MS, Marenus KD, Feingold KR, Elias PM (2001) Psychological stress perturbs epidermal permeability barrier homeostasis: implications for the pathogenesis of stress-associated skin disorders. Arch Dermatol 137:53–59

    PubMed  CAS  Google Scholar 

  26. Glaser R, Kiecolt-Glaser JK, Marucha PT, MacCallum RC, Laskowski BF, Malarkey WB (1999) Stress-related changes in proinflammatory cytokine production in wounds. Arch Gen Psychiatry 56:450–456

    Article  PubMed  CAS  Google Scholar 

  27. Gosain A, Gamelli RL (2005) A primer in cytokines. J Burn Care Rehabil 26:7–12

    Article  PubMed  Google Scholar 

  28. Guo S, Dipietro LA (2010) Factors affecting wound healing. J Dent Res 89:219–229

    Article  PubMed  CAS  Google Scholar 

  29. Gupta MA (2002) Psychosocial aspects of common skin diseases. Can Fam Physician 48(660–662):668–670

    Google Scholar 

  30. Gupta MA, Gupta AK (1996) Psychodermatology: an update. J Am Acad Dermatol 34:1030–1046

    Article  PubMed  CAS  Google Scholar 

  31. Hyman SM, Fox H, Hong KI, Doebrick C, Sinha R (2007) Stress and drug-cue-induced craving in opioid-dependent individuals in naltrexone treatment. Exp Clin Psychopharmacol 15:134–143

    Article  PubMed  CAS  Google Scholar 

  32. Kahan V, Andersen ML, Tomimori J, Tufik S (2009) Stress, immunity and skin collagen integrity: evidence from animal models and clinical conditions. Brain Behav Immun 23:1089–1095

    Article  PubMed  CAS  Google Scholar 

  33. Kahan V, Andersen ML, Tomimori J, Tufik S (2010) Can poor sleep affect skin integrity? Med Hypotheses 75:535–537

    Article  PubMed  CAS  Google Scholar 

  34. Kiecolt-Glaser JK, Marucha PT, Malarkey WB, Mercado AM, Glaser R (1995) Slowing of wound healing by psychological stress. Lancet 346:1194–1196

    Article  PubMed  CAS  Google Scholar 

  35. Kjartansson J, Dalsgaard CJ (1987) Calcitonin gene-related peptide increases survival of a musculocutaneous critical flap in the rat. Eur J Pharmacol 142:355–358

    Article  PubMed  CAS  Google Scholar 

  36. Klemfuss H, Adler MW (1986) Autonomic mechanisms for morphine and amphetamine mydriasis in the rat. J Pharmacol Exp Ther 238:788–793

    PubMed  CAS  Google Scholar 

  37. Kramer MH, Mangram AJ, Pearson ML, Jarvis WR (1999) Surgical-site complications associated with a morphine nerve paste used for postoperative pain control after laminectomy. Infect Control Hosp Epidemiol 20:183–186

    Article  PubMed  CAS  Google Scholar 

  38. 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  PubMed  CAS  Google Scholar 

  39. Liang D, Shi X, Qiao Y, Angst MS, Yeomans DC, Clark JD (2008) Chronic morphine administration enhances nociceptive sensitivity and local cytokine production after incision. Mol Pain 22(4):7

    Article  Google Scholar 

  40. Liu HC, Anday JK, House SD, Chang SL (2004) Dual effects of morphine on permeability and apoptosis of vascular endothelial cells: morphine potentiates lipopolysaccharide-induced permeability and apoptosis of vascular endothelial cells. J Neuroimmunol 146:13–21

    Article  PubMed  CAS  Google Scholar 

  41. Loomis CW, Cervenko FW, Jhamandas K, Sutak M, Milne B (1985) Analgesia and autonomic function following intrathecal administration of morphine and norepinephrine to the rat. Can J Physiol Pharmacol 63:656–662

    Article  PubMed  CAS  Google Scholar 

  42. Lundberg U (2005) Stress hormones in health and illness: the roles of work and gender. Psychoneuroendocrinology 30:1017–1021

    Article  PubMed  CAS  Google Scholar 

  43. Lysle DT, How T (1999) Endogenous opioids regulate the expression of inducible nitric oxide synthase by splenocytes. J Pharmacol Exp Ther 288:502–508

    PubMed  CAS  Google Scholar 

  44. Magazine HI, Liu Y, Bilfinger TV, Fricchione GL, Stefano GB (1996) Morphine-induced conformational changes in human monocytes, granulocytes, and endothelial cells and in invertebrate immunocytes and microglia are mediated by nitric oxide. J Immunol 156:4845–4850

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  47. Marucha PT, Kiecolt-Glaser JK, Favagehi M (1998) Mucosal wound healing is impaired by examination stress. Psychosom Med 60:362–365

    PubMed  CAS  Google Scholar 

  48. Mellon RD, Bayer BM (1999) The effects of morphine, nicotine and epibatidine on lymphocyte activity and hypothalamic-pituitary-adrenal axis responses. J Pharmacol Exp Ther 288:635–642

    PubMed  CAS  Google Scholar 

  49. Mercado AM, Padgett DA, Sheridan JF, Marucha PT (2002) Altered kinetics of IL-1 alpha, IL-1 beta, and KGF-1 gene expression in early wounds of restrained mice. Brain Behav Immun 16:150–162

    Article  PubMed  CAS  Google Scholar 

  50. Mercado AM, Quan N, Padgett DA, Sheridan JF, Marucha PT (2002) Restraint stress alters the expression of interleukin-1 and keratinocyte growth factor at the wound site: an in situ hybridization study. J Neuroimmunol 129:74–83

    Article  PubMed  CAS  Google Scholar 

  51. Molina VA, Heyser CJ, Spear LP (1994) Chronic variable stress or chronic morphine facilitates immobility in a forced swim test: reversal by naloxone. Psychopharmacology 114:433–440

    Article  PubMed  CAS  Google Scholar 

  52. Nikolarakis KE, Pfeiffer A, Stalla GK, Herz A (1989) Facilitation of ACTH secretion by morphine is mediated by activation of CRF releasing neurons and sympathetic neuronal pathways. Brain Res 498:385–388

    Article  PubMed  CAS  Google Scholar 

  53. Padgett DA, Marucha PT, Sheridan JF (1998) Restraint stress slows cutaneous wound healing in mice. Brain Behav Immun 12:64–73

    Article  PubMed  CAS  Google Scholar 

  54. Patel J, Manjappa N, Bhat R, Mehrotra P, Bhaskaran M, Singhal PC (2003) Role of oxidative stress and heme oxygenase activity in morphine-induced glomerular epithelial cell growth. Am J Physiol Renal Physiol 285:861–869

    Google Scholar 

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

    Article  PubMed  Google Scholar 

  56. Price RK, Risk NK, Haden AH, Lewis CE, Spitznagel EL (2004) Post-traumatic stress disorder, drug dependence, and suicidality among male Vietnam veterans with a history of heavy drug use. Drug Alcohol Depend 76:31–43

    Article  Google Scholar 

  57. Proksch E, Jensen JM, Elias PM (2003) Skin lipids and epidermal differentiation in atopic dermatitis. Clin Dermatol 21:134–144

    Article  PubMed  Google Scholar 

  58. Rapp SE, Ready LB, Nessly ML (1995) Acute pain management in patients with prior opioid consumption: a case-controlled retrospective review. Pain 61:195–201

    Article  PubMed  CAS  Google Scholar 

  59. Report of the International Narcotics Control Board for 1995. Viena, United Nations, 1996. http://www.incb.org/pdf/e/ar/1995/suppl1en.pdf

  60. Report of the International Narcotics Control Board for 2008. New York, United Nations, 2009. http://www.incb.org/pdf/annual-report/2008/en/AR_08_English.pdf

  61. Rojas IG, Padgett DA, Sheridan JF, Marucha PT (2002) Stress-induced susceptibility to bacterial infection during cutaneous wound healing. Brain Behav Immun 16:74–84

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  63. Rook JM, McCarson KE (2007) Delay of cutaneous wound closure by morphine via local blockade of peripheral tachykinin release. Biochem Pharmacol 74:752–757

    Article  PubMed  CAS  Google Scholar 

  64. Rostenberg A Jr (1960) The role of psychogenic factors in skin diseases. Arch Dermatol 81:81–86

    Article  PubMed  Google Scholar 

  65. Roy S, Khanna S, Yeh PE, Rink C, Malarkey WB, Kiecolt-Glaser J, Laskowski B, Glaser R, Sen CK (2005) Wound site neutrophil transcriptome in response to psychological stress in young men. Gene Exp 12:273–287

    Article  CAS  Google Scholar 

  66. Ruiz FS, Andersen ML, Martins RC, Zager A, Lopes JD, Tufik S (2012) Immune alterations after selective rapid eye movement or total sleep deprivation in healthy male volunteers. Innate Immun 18:44–54

    Article  PubMed  CAS  Google Scholar 

  67. Ruiz FS, Andersen ML, Zager A, Martins RC, Tufik S (2007) Sleep deprivation reduces the lymphocyte count in a non-obese mouse model of type 1 diabetes mellitus. Braz J Med Biol Res 40:633–637

    Article  PubMed  CAS  Google Scholar 

  68. Sato Y, Ohshima T (2000) The expression of mRNA of proinflammatory cytokines during skin wound healing in mice: a preliminary study for forensic wound age estimation (II). Int J Legal Med 113:140–145

    Article  PubMed  CAS  Google Scholar 

  69. Singhal PC, Pamarthi M, Shah R, Chandra D, Gibbons N (1994) Morphine stimulates superoxide formation by glomerular mesangial cells. Inflammation 18:293–299

    Article  PubMed  CAS  Google Scholar 

  70. Sinha R, Kimmerling A, Doebrick C, Kosten TR (2007) Effects of lofexidine on stress-induced and cue-induced opioid craving and opioid abstinence rates: preliminary findings. Psychopharmacology 190:569–574

    Article  PubMed  CAS  Google Scholar 

  71. Sulowska Z, Majewska E, Tchorzewski H, Klink M (2003) Effect of exogenous opioid peptides on TNF-alpha-induced human neutrophil apoptosis in vitro. Arch Immunol Ther Exp (Warsz) 51:267–272

    CAS  Google Scholar 

  72. Tausk FA, Nousari H (2001) Stress and the skin. Arch Dermatol 137:78–82

    PubMed  CAS  Google Scholar 

  73. Van Bockstaele EJ, Reyes BA, Valentino RJ (2010) The locus coeruleus: a key nucleus where stress and opioids intersect to mediate vulnerability to opiate abuse. Brain Res 16(1314):162–174

    Article  Google Scholar 

  74. Weiss F, Ciccocioppo R, Parsons LH, Katner S, Liu X, Zorrilla EP, Valdez GR, Ben-Shahar O, Angeletti S, Richter RR (2001) Compulsive drug-seeking behavior and relapse. Ann NY Acad Sci 937:1–26

    Article  PubMed  CAS  Google Scholar 

  75. Zager A, Andersen ML, Ruiz FS, Antunes IB, Tufik S (2007) Effects of acute and chronic sleep loss on immune modulation of rats. Am J Physiol Regul Integr Comp Physiol 293:504–509

    Article  Google Scholar 

  76. Zhang YT, Zheng QS, Pan J, Zheng RL (2004) Oxidative damage of biomolecules in mouse liver induced by morphine and protected by antioxidants. Basic Clin Pharmacol Toxicol 95:53–58

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants from Associação Fundo de Incentivo a Pesquisa (AFIP), CNPq, and Fundação de Amparo à Pesquisa do Estado de São Paulo-FAPESP (#11/14462 to F.E.; #07/55445-6 to F.R.S. and CEPID #98/14303-3 to S.T.). M.L.A. and S.T. are recipients of the CNPq fellowship.

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Authors and Affiliations

  1. Departamento de Psicobiologia, Universidade Federal de São Paulo (UNIFESP), Rua Napoleão de Barros, 925, Vila Clementino, São Paulo, SP, 04024-002, Brazil

    F. Egydio, F. S. Ruiz, S. Tufik & Monica Levy Andersen

  2. Departamento de Dermatologia, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil

    J. Tomimori

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  1. F. Egydio
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  2. F. S. Ruiz
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  4. S. Tufik
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  5. Monica Levy Andersen
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Correspondence to Monica Levy Andersen.

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Egydio, F., Ruiz, F.S., Tomimori, J. et al. Can morphine interfere in the healing process during chronic stress?. Arch Dermatol Res 304, 413–420 (2012). https://doi.org/10.1007/s00403-012-1261-1

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