Skip to main content

Advertisement

Log in

Interactions between morphine and nitric oxide in various organs

  • Review Article
  • Published:
Journal of Anesthesia Aims and scope Submit manuscript

Abstract

Nitric oxide (NO) plays obligatory roles as an important intercellular messenger in the control of physiological functions and it also participates in pathophysiological interventions. This labile, gaseous molecule is also involved in mechanisms underlying the beneficial and untoward actions of therapeutic agents. Endogenous NO is formed by endothelial and neurogenic NO synthases that are constitutively present mainly in the endothelium and nervous system, respectively, and is induced by lipopolysaccharides or cytokines mainly in mitochondria, glial cells, and vascular smooth muscle cells. NO modulates the effects of morphine on processes involving the central nervous system, such as learning, memory, convulsion, thermoregulation, and penile erection. This molecule is also involved in the modification of morphine actions on the cardiovascular, digestive, and respiratory systems. Morphine regulates NO bioavailability in various organs. NO formed by inducible NO synthase participates in some morphine actions in the immune system. Information concerning interactions between NO and morphine and other opioids in a variety of organs and tissues is quite useful in establishing new strategies for minimizing the noxious and unintended reactions that are frequently encountered during analgesic therapy.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead G, Naylor AM, Osterloch IH, Gengell C. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res. 1996;8:47–52.

    CAS  PubMed  Google Scholar 

  2. Toda N, Ayajiki K, Okamura T. Nitric oxide and penile erectile function. Pharmacol Ther. 2005;106:233–266.

    Article  CAS  PubMed  Google Scholar 

  3. Toda N, Kishioka S, Hatano Y, Toda H. Modulation of opioid actions by nitric oxide signaling. Anesthesiology. 2009;110:166–181.

    Article  CAS  PubMed  Google Scholar 

  4. Bredt DS, Snyder SH. Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci U S A. 1990;87:682–685.

    Article  CAS  PubMed  Google Scholar 

  5. Förstermann U, Pollock JS, Schmidt HH, Heller M, Murad F. Calmodulin-dependent endothelium-derived relaxing factor/nitric oxide synthase activity is present in the particulate and cytosolic fractions of bovine aortic endothelial cells. Proc Natl Acad Sci U S A. 1991;88:1788–1792.

    Article  PubMed  Google Scholar 

  6. Palmer RMJ, Rees DD, Ashton DS, Moncada S. L-Arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochem Biophys Res Commun. 1988;153:1251–1256.

    Article  CAS  PubMed  Google Scholar 

  7. Rees DD, Palmer RMJ, Schulz R, Hodson HF, Moncada S. Characterization of three inhibitors of endothelial nitric oxide synthase in vivo and in vitro. Br J Pharmacol. 1990;101:746–752.

    CAS  PubMed  Google Scholar 

  8. Toda N, Minami Y, Okamura T. Inhibitory effects of L-NG-nitro-arginine on the synthesis of EDRF and the cerebroarterial response to vasodilator nerve stimulation. Life Sci. 1990;47:345–351.

    Article  CAS  PubMed  Google Scholar 

  9. Vallance P, Leone A, Calver A, Collier J, Moncada S. Endogenous dimethylarginine as an inhibitor of nitric oxide synthesis. J Cardiovasc Pharmacol. 1992;20(Suppl 12):S60–S62.

    CAS  PubMed  Google Scholar 

  10. Moore PK, Babbedge RC, Wallace P, Gaffen ZA, Hart SL. 7-Nitroindazole, an inhibitor of nitric oxide synthase, exhibits antinociceptive activity in the mouse without increasing blood pressure. Br J Pharmacol. 1993;108:296–297.

    CAS  PubMed  Google Scholar 

  11. Griffiths MJ, Messent M, MacAllister RJ, Evans TW. Aminoguanidine slectively inhibits inducible nitric oxide synthase. Br J Pharmacol. 1993;110:963–968.

    CAS  PubMed  Google Scholar 

  12. Garthwaite J, Southam E, Boulton CL, Nielsen EB, Schmidt K, Mayer B. Potent and selective inhibition of nitric oxide sensitive guanylate cyclase by 1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. Mol Pharmacol. 1995;48:184–188.

    CAS  PubMed  Google Scholar 

  13. Toda N, Okamura T. Possible role of nitric oxide in transmitting information from vasodilator nerve to cerebral arterial muscle. Biochem Biophys Res Commun. 1990;170:308–313.

    Article  CAS  PubMed  Google Scholar 

  14. Bult H, Boeckxstaens GE, Pelckmans PA, Jordaens FH, Van Maercke YM, Herman AG. Nitric oxide as an inhibitory nonadrenergic non-cholinergic neurotransmitter. Nature. 1990;345:346–347.

    Article  CAS  PubMed  Google Scholar 

  15. Toda N, Baba H, Okamura T. Role of nitric oxide in nonadrenergic, non-cholinergic nerve-mediated relaxation in dog duodenal longitudinal muscle strips. Jpn J Pharmacol. 1990;53:281–284.

    Article  CAS  PubMed  Google Scholar 

  16. Tucker JF, Brave SR, Charalambopus L, Hobbs AJ, Bibson A. L-NG-nitro arginine inhibits non-adrenergic, non-cholinergic relaxation of guinea-pig isolated tracheal smooth muscle. Br J Pharmacol. 1990;100:663–664.

    CAS  PubMed  Google Scholar 

  17. Ignarro LJ, Bush PA, Buga GM, Wood KS, Fukuto JM, Rajfer J. Nitric oxide and cyclic GMP formation upon electrical field stimulation causes relaxation of corpus cavernosum smooth muscle. Biochem Biophys Res Commun. 1990;170:843–850.

    Article  CAS  PubMed  Google Scholar 

  18. Kiss JP, Vizi ES. Nitric oxide: a novel link between synaptic and nonsynaptic transmission. Trends Neurosci. 2001;24:211–215.

    Article  CAS  PubMed  Google Scholar 

  19. Leza JC, Lizasoain I, San-Martin-Clark O, Lorenzo P. Morphine-induced changes in cerebral and cerebellar nitric oxide synthase activity. Eur J Pharmacol. 1995;285:95–98.

    Article  CAS  PubMed  Google Scholar 

  20. Zhu W, Ma Y, Bell A, Esch T, Guarna M, Bilfinger TV, Bianchi E, Stefano GB. Presence of morphine in rat amygdala: evidence for the μ3 opiate receptor subtypes via nitric oxide release in limbic structures. Med Sci Monit. 2004;10:BR433–BR439.

    CAS  PubMed  Google Scholar 

  21. Yoo JH, Cho JH, Lee SY, Lee S, Loh HH, Ho IK, Jang CG. Differential effects of morphine- and cocaine-induced nNOS immunoreactivity in the dentate gyrus of hippocampus of mice lacking μ-opioid receptors. Neurosci Lett. 2006;395:98–102.

    Article  CAS  PubMed  Google Scholar 

  22. Dyuizen IV, Motavkin PA, Shorin VV. Dynamics of NADPH diaphorase activity in raphe neurons during chronic treatment with opiates. Bull Exp Biol Med. 2001;132:918–920.

    Article  CAS  PubMed  Google Scholar 

  23. Khavandgar S, Homayoun H, Zarrindast MR. The effect of L-NAME and L-arginine on impairment of memory formation and state-dependent learning induced by morphine in mice. Psychopharmacology (Berl). 2003;167:291–296.

    CAS  Google Scholar 

  24. Sahraei H, Poorheidari G, Foadaddini M, Khoshbaten A, Asgari A, Noroozzadeh A, Ghoshooni H, Firoozabadi SH, Zarrindast MR. Effects of nitric oxide on morphine self-administration in rat. Pharmacol Biochem Behav. 2004;77:111–116.

    Article  CAS  PubMed  Google Scholar 

  25. Rezayof A, Amini R, Rassouli Y, Zarrindast MR. Influence of nitric oxide on morphine-induced amnesia and interactions with dopaminergic receptor agents. Physiol Behav. 2006;88:124–131.

    Article  CAS  PubMed  Google Scholar 

  26. Stefano GB, Salzet B, Rialas CM, Pope M, Kustka A, Neenan K, Pryor S, Salzet M. Morphine- and anandamide-stimulated nitric oxide production inhibits presynaptic dopamine release. Brain Res. 1997;763:63–68.

    Article  CAS  PubMed  Google Scholar 

  27. Shin IC, Kim HC, Swanson J, Hong JT, Oh KW. Anxiolytic effects of acute morphine can be modulated by nitric oxide systems. Pharmacology. 2003;68:183–189.

    Article  CAS  PubMed  Google Scholar 

  28. Sakurada T, Komatsu T, Kuwahata H, Watanabe C, Orito T, Sakurada C, Tsuzuki M, Sakurada S. Intrathecal substance P (1–7) prevents morphine-evoked spontaneous pain behavior via spinal NMDA-NO cascade. Biochem Pharmacol. 2007;74:758–767.

    Article  CAS  PubMed  Google Scholar 

  29. Calignano A, Persico P, Mancuso F, Sorrentino L. Endogenous nitric oxide modulates morphine-induced changes in locomotion and food intake in mice. Eur J Pharmacol. 1993;231:415–419.

    Article  CAS  PubMed  Google Scholar 

  30. Zarrindast MR, Askari E, Khalizaden A, Nouraei N. Morphine state-dependent learning sensitization and interaction with nitric oxide. Pharmacology. 2006;78:66–71.

    Article  CAS  PubMed  Google Scholar 

  31. Boethcher C, Fellermeier M, Boettcher C, Dragger B, Zenk MH. How human neuroblastoma cells make morphine. Proc Natl Acad Sci U S A. 2005;102:8495–8500.

    Article  CAS  Google Scholar 

  32. Pak T, Cadet P, Mantione KJ, Stefano GB. Morphine via nitric oxide modulates β-amyloid metabolism: a novel protective mechanism for Alzheimer’s disease. Med Sci Monit. 2005;11:BR357–BR366.

    CAS  PubMed  Google Scholar 

  33. Stefano GB, Goumon Y, Casares F, Cadet P, Fricchione GL, Rialas C, Peter D, Sonetti D, Guarna M, Welters ID, Bianchi E. Endogenous morphine. Trends Neurosci. 2000;23:436–442.

    Article  CAS  PubMed  Google Scholar 

  34. Esch T, Stefano GB, Fricchione GL, Benson H. Stress-related diseases—a potential role for nitric oxide. Med Sci Monit. 2002;8:RA103–PA118.

    CAS  PubMed  Google Scholar 

  35. Benson H, Beary HF, Carol MP. The relaxation response. Psychiatry. 1974;37:37–46.

    CAS  PubMed  Google Scholar 

  36. Stefano GB, Fricchione GL, Esch T. Relaxation: molecular and physiological significance. Med Sci Monit. 2006;12:HY21–31.

    CAS  PubMed  Google Scholar 

  37. Kivastik T, Rutkauskaite J, Zharkovsky A. Nitric oxide synthesis inhibition attenuates morphine-induced place preference. Pharmacol Biochem Behav. 1996;53:1013–1015.

    Article  CAS  PubMed  Google Scholar 

  38. Karami M, Zarrindast MR, Sepehri H, Sahraei H. Role of nitric oxide in the rat hippocampal CA1 area on morphine-induced conditioned place preference. Eur J Pharmacol. 2002;449:113–119.

    Article  CAS  PubMed  Google Scholar 

  39. Zarrindast MR, Karami M, Sepehri H, Sahraei H. Influence of nitric oxide on morphine-induced conditioned place preference in the rat central amygdala. Eur J Pharmacol. 2002;453:81–89.

    Article  CAS  PubMed  Google Scholar 

  40. Gholami A, Haeri-Rohani A, Sahraei H, Zarrindast MR. Nitric oxide mediation of morphine-induced place preference in the nucleus accumbens of rat. Eur J Pharmacol. 2002;449:269–277.

    Article  CAS  PubMed  Google Scholar 

  41. Sahraei H, Zarei F, Eidi A, Oryan S, Shams J, Khoshbaten A, Zarrindast MR. The role of nitric oxide within the nucleus accumbens on the acquisition and expression of morphineinduced place preference in morphine sensitized rats. Eur J Pharmacol. 2007;556:99–106.

    Article  CAS  PubMed  Google Scholar 

  42. Gholami A, Zarrindast MR, Sahaei H, Haerri-Rohani A. Nitric oxide within the ventral tegmental area is involved in mediating morphine reward. Eur J Pharmacol. 2003;458:119–128.

    Article  CAS  PubMed  Google Scholar 

  43. Manzanedo C, Aguilar MA, Rodriguez-Arias M, Navarro M, Minarro J. 7-Nitroindazole blocks conditioned place preference but not hyperactivity induced morphine. Behav Brain Res. 2004;150:73–82.

    Article  CAS  PubMed  Google Scholar 

  44. Langroudi RM, Khoshnoodi MA, Abadi NY, Fahadan PT, Ghahremani MH, Dehpour AR. Effect of cyclosporine A on morphine-induced place conditioning in mice: involvement of nitric oxide. Eur J Pharmacol. 2005;507:107–115.

    Article  CAS  PubMed  Google Scholar 

  45. Homayoun H, Khavandgar S, Namiranian K, Gaskari SA, Dehpour AR. The role of nitric oxide in anticonvulsant and proconvulsant effects of morphine in mice. Epilepsy Res. 2002;48:33–41.

    Article  CAS  PubMed  Google Scholar 

  46. Yahyavi-Firouz-Abadi N, Tahsili-Fahadan P, Riazi K, Ghahremani MH, Dehpour AR. Melatonin enhances the anticonvulsant and proconvulsant effects of morphine in mice: role for nitric oxide signaling pathway. Epilepsy Res. 2007;75:138–144.

    Article  CAS  PubMed  Google Scholar 

  47. Homayoun H, Khavandgar S, Dehpour AR. The involvement of endogenous opioids and nitricoxidergic pathway in the anticonvulsant effects of foot-shock stress in mice. Epilepsy Res. 2002;49:131–142.

    Article  CAS  PubMed  Google Scholar 

  48. Khavandgar S, Homayoun H, Dehpour AR. Mediation of nitric oxide in inhibitory effect of morphine against electroshock-induced convulsions in mice. Pharmacol Biochem Behav. 2003;74:795–801.

    Article  CAS  PubMed  Google Scholar 

  49. Handler CM, Celler EB, Adler MW. Effect of μ-, κ- and δ-selective opioid agonists on thermoregulation in the rat. Pharmacol Biochem Behav. 1992;43:1209–1216.

    Article  CAS  PubMed  Google Scholar 

  50. Xin L, Zhao SF, Celler EB, McCafferty MR, Sterling GH, Adler MW. Involvement of β-endorphine in the preoptic anterior hypothalamus during interleukin-1β-induced fever in rats. Ann New York Acad Sci. 1997;813:324–326.

    Article  CAS  Google Scholar 

  51. Moncada S, Palmer RMJ, Higgs EA. Nitric oxide physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991;43:109–142.

    CAS  PubMed  Google Scholar 

  52. Branco LG, Carnio EC, Barros RC. Role of the nitric oxide pathway in hypoxia-induced hypothermia of rats. Am J Physiol. 1997;273:R967–R971.

    CAS  PubMed  Google Scholar 

  53. Lin JH, Lin MT. Nitric oxide synthase-cyclooxygenase pathways in organum vasculosum laminae terminalis: possible role in pyrogenic fever in rabbits. Br J Pharmacol. 1996;118:179–185.

    CAS  PubMed  Google Scholar 

  54. Scammell TE, Elmquist JK, Saper CB. Inhibition of nitric oxide synthase produces hypothermia and depresses lipopolysaccharide fever. Am J Physiol. 1996;271:R333–R338.

    CAS  PubMed  Google Scholar 

  55. Afify EA, Daabees TT, Gabra BH, Abou Zeit-Har MS. Role of nitric oxide in catalepsy and hyperthermia in morphinedependent rats. Pharmacol Res. 2001;44:533–539.

    Article  CAS  PubMed  Google Scholar 

  56. Benamar K, Xin L, Geller EB, Adler MW. Effect of central and peripheral administration of a nitric oxide synthase inhibitor on morphine hyperthermia in rats. Brain Res. 2001;894:266–273.

    Article  CAS  PubMed  Google Scholar 

  57. Benamar K, Yondorf MZ, Kon D, Geller EB, Adler MW. Role of the nitric-oxide synthase isoforms during morphine-induced hyperthermia in rats. J Pharmacol Exp Ther. 2003;307:219–222.

    Article  CAS  PubMed  Google Scholar 

  58. Ulugol A, Dost T, Dokmeci C, Akpolat M, Karadag CH, Dokmeci I. Involvement of NMDA receptors and nitric oxide in the thermoregulatory effect of morphine in mice. J Neural Transm. 2000;107:515–521.

    Article  CAS  PubMed  Google Scholar 

  59. Mastronicola D, Arcuri E, Arese M, Bacchi A, Mercadante S, Cardelli P, Citro G, Sarti P. Morphine but not fentanyl and methadone affects mitochondrial membrane potential by inducing nitric oxide release in glioma cells. Cell Mol Life Sci. 2004;61:2991–2997.

    Article  CAS  PubMed  Google Scholar 

  60. Brunori M, Giuffre A, Sarti P, Stubauer G, Wilson MT. Nitric oxide and cellular respiration. Cell Mol Life Sci. 1999;56:549–557.

    Article  CAS  PubMed  Google Scholar 

  61. Lim YJ, Zheng S, Zuo Z. Morphine preconditions Purkinje cells against cell death under in vitro stimulated ischemia-reperfusion conditions. Anesthesiology. 2004;100:562–568.

    Article  CAS  PubMed  Google Scholar 

  62. Almeida A, Almeida J, Bolanos JP, Moncada S. Different responses of astrocytes and neurons to nitric oxide: the role of glycolytically generated ATP in astrocyte protection. Proc Natl Acad Sci U S A. 2001;98:15 294–15 299.

    Article  CAS  Google Scholar 

  63. Almeida A, Moncada S, Bolanos JP. Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2-kinase pathway. Nature Cell Biol. 2004;6:45–51.

    Article  CAS  PubMed  Google Scholar 

  64. Ferrari F, Baggio G. Potentiation of the aphrodisiac effect of N-n-propyl-norapomorphine by naloxone. Eur J Pharmacol. 1982;81:321–326.

    Article  CAS  PubMed  Google Scholar 

  65. Argiolas A, Melis MR, Gessa GL. Oxytocin: an extremely potent inducer of penile erection and yawing in male rats. Eur J Pharmacol. 1986;130:265–272.

    Article  CAS  PubMed  Google Scholar 

  66. Gomez-Marrero J, Feria M, Mas M. Simulation of opioid receptors suppresses penile erectile reflexes and seminal emission in rats. Pharmacol Biochem Behav. 1988;31:393–396.

    Article  CAS  PubMed  Google Scholar 

  67. Melis MR, Stancampiano R, Gessa GL, Argiolas A. Prevention by morphine of apomorphine- and oxytocin-induced penile erection and yawing: site of action in the brain. Neuropsychopharmacology. 1992;6:17–21.

    CAS  PubMed  Google Scholar 

  68. Melis MR, Succu S, Argiolas A. Prevention by morphine of N-methyl-D-aspartic acid-induced penile erection and yawing: involvement of nitric oxide. Brain Res Bull. 1997;44:689–694.

    Article  CAS  PubMed  Google Scholar 

  69. Melis MR, Succu S, Iannucci U, Argiolas A. Prevention by morphine of apomorphine- and oxytocin-induced penile erection and yawing: involvement of nitric oxide. Naunyn-Schmiedebergs Arch Pharmacol. 1997;355:595–600.

    Article  CAS  PubMed  Google Scholar 

  70. Melis MR, Succu S, Spano MS, Argiolas A. Morphine injected into the paraventricular nucleus of the hypothalamus prevents noncontact penile erections and impairs copulation: involvement of nitric oxide. Eur J Neurosci. 1999;11:1857–1864.

    Article  CAS  PubMed  Google Scholar 

  71. Succu S, Mascia MS, Melis T, Melis MR, Deghenghi R, Argiolas A. Activation of GABAA and opioid receptors reduces penile erection induced by hexarelin peptides. Pharmacol Biochem Behav. 2003;76:563–570.

    Article  CAS  PubMed  Google Scholar 

  72. Succu S, Mascia MS, Melis T, Sanna F, Boi A, Melis MR, Argiolas A. Morphine reduces penile erection induced by the cannabinoid receptor antagonist SR 141617A in male rats: role of paraventricular glutamic acid and nitric oxide. Neurosci Lett. 2006;404:1–5.

    Article  CAS  PubMed  Google Scholar 

  73. Burnett AL, Lowenstein CJ. Bredt DS, Chang TSK, Snyder SH. Nitric oxide: a physiologic mediator of penile erection. Science. 1992;257:401–403.

    Article  CAS  PubMed  Google Scholar 

  74. Matton A, Bollengier F, Finne E, Vanhaelst L. Effect of Nω-nitro-L-arginine methyl ester, a nitric oxide synthesis inhibitor, on stress- and morphine-induced prolactin release in male rats. Br J Pharmacol. 1997;120:268–272.

    Article  CAS  PubMed  Google Scholar 

  75. Lesage J, Bernet F, Montel V, Dupouy JP. Morphine-induced stimulation of pituitary-adrenocortical activity is mediated by activation of nitric oxide in the early stages of postnatal life in the rat. Eur J Endocrinol. 2001;144:441–451.

    Article  CAS  PubMed  Google Scholar 

  76. Schneider GM, Lysle DT. Role of central μ-opioid receptors in the modulation of nitric oxide production by splenocytes. J Neuroimmunol. 1998;89:150–159.

    Article  CAS  PubMed  Google Scholar 

  77. Stefano GB, Hartman A, Bilfinger TV, Magazine HT, Liu Y. Presence of the μ3 opiate receptor in endothelial cells. Coupling to nitric oxide production and vasodilation. J Biol Chem. 1995;270:30 290–30 293.

    CAS  Google Scholar 

  78. Cadet P, Bilfinger TV, Fimiani C, Peter D, Stefano GB. Human vascular and cardiac endothelia express μ opiate receptor transcripts. Endothelium. 2000;7:185–191.

    CAS  PubMed  Google Scholar 

  79. Fimiani C, Mattocks D, Cavani F, Salzet M, Deutsch DG, Pryor S, Bilfinger TV, Stefano GB. Morphine and anandamide stimulate intracellular calcium transients in human arterial endothelial cells: coupling to nitric oxide release. Cell Signal. 1999;11:189–193.

    Article  CAS  PubMed  Google Scholar 

  80. Bilfinger TV, Vosswinkel JA, Cadet P, Rialas CM, Magazine HI, Stefano GB. Direct assessment and diminished production of morphine stimulated NO by diabetic endothelium from saphenous vein. Acta Pharmacol. Sin 2002;23:97–102.

    CAS  PubMed  Google Scholar 

  81. Hayashida K, Takeuchi T, Ozaki T, Shimizu H, Ando K, Miyamoto A, Harada E. Bovine lactoferrin has a nitric oxidedependent hypotensive effect in rats. Am J Physiol. 2004;286:R359–R365.

    CAS  Google Scholar 

  82. Hayashida K, Takeuchi T, Harada E. Lactoferrin enhances peripheral opioid-mediated antinociception via nitric oxide in rats. Eur J Pharmacol. 2004;484:175–181.

    Article  CAS  PubMed  Google Scholar 

  83. Prevot V, Rialas CM, Croix D, Salzet M, Dupouy JP, Poulain P, Beauvillain JC, Stefano GB. Morphine and anandamide coupling to nitric oxide stimulates GnRH and CRF release from rat median eminence: neurovascular regulation. Brain Res. 1998;790:236–244.

    Article  CAS  PubMed  Google Scholar 

  84. Zochodne DW, Sun H, Li XQ. Evidence that nitric oxide- and opioid-containing interneurons innervate vessels in the dorsal horn of the spinal cord of rats. J Physiol. 2001;532:749–758.

    Article  CAS  PubMed  Google Scholar 

  85. Komjati K, Greenberg JH, Reivich M, Sandor P. Interactions between the endothelium-derived relaxing factor/nitric oxide system and the endogenous opiate system in the modulation of cerebral and spinal vascular CO2 responsiveness. J Cereb Blood Flow Metab. 2001;21:937–944.

    Article  CAS  PubMed  Google Scholar 

  86. Toda N, Okamura T. The pharmacology of nitric oxide in the peripheral nervous system of blood vessels. Pharmacol Rev. 2003;55:271–324.

    Article  CAS  PubMed  Google Scholar 

  87. Ozdem SS, Batu O, Tayfun F, Yalcin O, Meiselman HJ, Baskurt OK. The effect of morphine in rat small mesenteric arteries. Vascul Pharmacol. 2005;43:56–61.

    Article  CAS  PubMed  Google Scholar 

  88. Gursoy S, Bagcivan I, Yildirim MK, Berkan O, Kaya T. Vasorelaxant effect of opioid analgesics on the isolated human radial artery. Eur J Anaesth. 2006;23:496–500.

    Article  CAS  Google Scholar 

  89. Namiranian K, Samini M, Mehr SE, Gaskari SA, Rastegar H, Homayoun H, Dehpour AR. Mesenteric vascular bed responsiveness in bile duct-ligated rats: role of opioid and nitric oxide system. Eur J Pharmacol. 2001;423:185–193.

    Article  CAS  PubMed  Google Scholar 

  90. Way WL, Rields HL, Way LW. Opioid analgesics and antagonists. In: Katzung BG, editor. Basic and clinical pharmacology. 7th ed. Norwalk, CT: Appleton & Lange; 1998. p. 496–515.

    Google Scholar 

  91. Jiang X, Shi E, Nakajima Y, Sato S. Inducible nitric oxide synthase mediates delayed cardioprotection induced by morphine in vivo: evidence from pharmacologic inhibition and geneknockout mice. Anesthesiology. 2004;101:82–88.

    Article  CAS  PubMed  Google Scholar 

  92. Jiang X, Shi E, Nakajima Y, Sato S. COX-2 mediates morphineinduced delayed cardioprotection via an iNOS-dependent mechanism. Life Sci. 2006;78:2543–2549.

    Article  CAS  PubMed  Google Scholar 

  93. Shinmura K, Xuan YT, Tang XL, Kodani E, Han H, Zhu Y, Bolli R. Inducible nitric oxide synthase modulates cyclooxygenase-2 activity in the heart of conscious rabbits during the late phase of ischemic preconditioning. Circ Res. 2002;90:602–608.

    Article  CAS  PubMed  Google Scholar 

  94. Xuan YT, Guo Y, Zhu Y, Han H, Langtenback R, Dawn B, Bolli R. Mechanism of cyclooxygenase-2 upregulation in late preconditioning. J Mol Cell Cardiol. 2003;35:525–537.

    Article  CAS  PubMed  Google Scholar 

  95. Stefano GB, Neeman K, Cadet P, Magazine H, Bilfinger TV. Ischemic preconditioningh—an opiate constitutive nitric oxide molecular hypothesis. Med Sci Monit. 2001;7:1357–1375.

    CAS  PubMed  Google Scholar 

  96. Jang Y, Xi J, Wang H, Mueller RA, Norfleet EA, Xu Z. Postconditioning prevents reperfusion injury by activating δ-opioid receptors. Anesthesiology. 2008;108:243–250.

    Article  CAS  PubMed  Google Scholar 

  97. Calignano A, Moncada S, Di Rosa M. Endogenous nitric oxide modulates morphine-induced constipation. Biochem Biophys Res Commun. 1991;181:889–893.

    Article  CAS  PubMed  Google Scholar 

  98. Gustafsson BI, Delbro DS. Neurogenic inhibition of duodenal and jejunal motility in the anaesthetized rat. Eur J Pharmacol. 1994;257:227–233.

    Article  CAS  PubMed  Google Scholar 

  99. Lenard L, Halmai V, Bartho L. Morphine contracts the guinea pig ileal circular muscle by interfering with a nitric oxide mediated tonic inhibition. Digestion. 1999;60:562–566.

    Article  CAS  PubMed  Google Scholar 

  100. Toda N, Herman AG. Gastrointestinal function regulation by nitrergic efferent nerves. Pharmacol Rev. 2005;57:315–338.

    Article  CAS  PubMed  Google Scholar 

  101. Iwata H, Tsuchiya S, Nakamura T, Yano S. Morphine leads to contraction of the ileal circular muscle via inhibition of the nitrergic pathway in mice. Eur J Pharmacol. 2007;574:66–70.

    Article  CAS  PubMed  Google Scholar 

  102. Tucci P, Palmery M, Piccolotti P, Pimpinella G, Valeri P, Romanelli L. Counteracting effect of papaverine on morphine inhibition of gastrointestinal transit in mice. Neurogastroenterol Motil. 2008;20:958–965.

    Article  CAS  PubMed  Google Scholar 

  103. Gyires K. The role of endogenous nitric oxide in the gastroprotective action of morphine. Eur J Pharmacol. 1994;255:33–37.

    Article  CAS  PubMed  Google Scholar 

  104. Stefano GB, Zhu W, Cadet P, Bilfinger TV, Mantione K. Morphine enhances nitric oxide release in the mammalian gastrointestinal tract via the μ3 opiate receptor subtype: a hormonal role for endogenous morphine. J Physiol Pharmacol. 2004;55:279–288.

    CAS  PubMed  Google Scholar 

  105. Abdollahi M, Safarhamidi H. Protection by nitric oxide of morphine-induced inhibition of rat submandibular gland function. Pharmacol Res. 2002;45:87–92.

    Article  CAS  PubMed  Google Scholar 

  106. Kim JS, Lemasters JJ. Opioid receptor-independent protection of ischemic rat hepatocytes by morphine. Biochem Biophys Res Commun. 2006;351:958–964.

    Article  CAS  PubMed  Google Scholar 

  107. Gholipour T, Riazi K, Noorian AR, Jannati A, Honar H, Doratotaj B, Nik HH, Shariftabrizi A, Dehpour AR. Seizure susceptibility alteration following reversible cholestasis in mice: modulation by opioids and nitric oxide. Eur J Pharmacol. 2008;580:322–328.

    Article  CAS  PubMed  Google Scholar 

  108. Gabra BH, Afify EA, Daabees TT, Abou Zeit-Har MS. The role of the NO/NMDA pathways in the development of morphine withdrawal induced by naloxone in vitro. Pharmacol Res. 2005;51:319–327.

    Article  CAS  PubMed  Google Scholar 

  109. Capasso A, Sorrentino L, Pinto A. The role of nitric oxide in the development of opioid withdrawal induced by naloxone after acute treatment with μ- and κ-opioid receptor agonists. Eur J Pharmacol. 1998;359:127–131.

    Article  CAS  PubMed  Google Scholar 

  110. Pelligrino DA, Laurito CE, VadeBoncouer TR. Nitric oxide synthase inhibition modulates the ventilatory depressant and antinociceptive actions of fourth ventricular infusions of morphine in the awake dogs. Anesthesiology. 1996;85:1367–1377.

    Article  CAS  PubMed  Google Scholar 

  111. Teppema LJ, Berkenbosch A, Olievier CN. Effect of Nω-nitro-L-arginine on ventilatory response to hypercapnia in anesthetized cats. J Appl Physiol. 1997;82:292–297.

    CAS  PubMed  Google Scholar 

  112. Teppema LJ, Sarton E, Dahan A, Olievier CN. The neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI) and morphine act independently on the control of breathing. Br J Anaesth. 2000;84:190–196.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  114. Ni X, Gritman KR, Eisenstein TK, Adler MW, Arfors KE, Tuma RF. Morphine attenuates leukocyte/endothelial interactions. Microvasc Res. 2000;60:121–130.

    Article  CAS  PubMed  Google Scholar 

  115. Pacifici R, Minetti M, Zuccharo P, Pietraforte D. Morphine affects cytostatic activity of macrophages by the modulation of nitric oxide release. Int J Immunopharmacol. 1995;17:771–777.

    Article  CAS  PubMed  Google Scholar 

  116. Fecho K, Maslonek KA, Dykstra LA, Lysle DT. Mechanisms whereby macrophage-derived nitric oxide is involved in morphine-induced suppression of splenic lymphocyte proliferation. J Pharmacol Exp Ther. 1995;272:477–483.

    CAS  PubMed  Google Scholar 

  117. Frenklakh L, Bhat RS, Bhaskaran M, Sharma S, Sharma M, Dinda A, Singhal PC. Morphine-induced degradation of the host defense barrier: role of intestinal mucosal injury. Dig Dis Sci. 2006;51:318–325.

    Article  CAS  PubMed  Google Scholar 

  118. Singhal PC, Sharma P, Kapasi AA, Reddy K, Franki N, Gibbons N. Morphine enhances macrophage apoptosis. J Immunol. 1998;160:1886–1893.

    CAS  PubMed  Google Scholar 

  119. Singh PP, Singal P. Morphine-induced neuroimmunomodulation in murine visceral leishmaniasis: the role(s) of cytokines and nitric oxide. J Neuroimmune Pharmacol. 2007;2:338–351.

    Article  PubMed  Google Scholar 

  120. Lysle DT, How T. Heroin modulates the expression of inducible nitric oxide synthase. Immunopharmacology 2000;46:181–192.

    Article  CAS  PubMed  Google Scholar 

  121. Comert M, Sipahi EY, Ustun H, Isikdemir F, Numanoglu G, Barut F, Altunkaya H, Ozer Y, Niyazi Ayoglu F, Sipahi TH, Tekin IO, Banoglu ZN. Morphine modulates inducible nitric oxide synthase expression and reduces pulmonary oedema induced by α-naphthylthiourea. Eur J Pharmacol. 2005;511:183–189.

    Article  CAS  PubMed  Google Scholar 

  122. Block SC, Tonussi CR. Intrathecally injected morphine inhibits inflammatory paw edema: the involvement of nitric oxide and cyclic-guanosine monophosphate. Anesth Analg. 2008;106:965–971.

    Article  Google Scholar 

  123. Kim MS, Cheong YP, So HS, Lee KM, Kim TY, Oh J, Chung YT, Son Y, Kim BR, Park R. Protective effects of morphine in peroxynitrite-induced apoptosis of primary rat neonatal astrocytes: potential involvement of G protein and phosphatidylinositol 3-kinase (IP3 kinase). Biochem Pharmacol. 2001;61:779–886.

    Article  CAS  PubMed  Google Scholar 

  124. Duan Y, Panoff J, Burrell BD, Sahley CL, Muller KJ. Repair and regeneration of functional synaptic connections: cellular and molecular interactions in the leech. Cell Mol Neurobiol. 2005;25:441–450.

    Article  PubMed  Google Scholar 

  125. Yahyavi-Firouz-Abadi N, Tahsili-Fahadan P, Ostad SN. Effect of μ and κ opioids on injury-induced microglial accumulation in leech CNS: involvement of the nitric oxide pathway. Neuroscience. 2007;144:1075–1086.

    Article  CAS  PubMed  Google Scholar 

  126. Stefano GB, Salzet M, Magazine HI, Bilfinger TV. Antagonism of LPS and IFN-γ induction of iNOS in human saphenous vein endothelium by morphine and anandamide by nitric oxide inhibition of adenylate cyclase. J Cardiovasc Pharmacol. 1998;31:813–820.

    Article  CAS  PubMed  Google Scholar 

  127. Stefano GB, Salzet M, Bilfinger TV. Long-term exposure of human blood vessels to HIV gp120, morphine, and anandamide increases endothelial adhesion of monocytes: uncoupling of nitric oxide release. J Cardiovasc Pharmacol. 1998;31:862–868.

    Article  CAS  PubMed  Google Scholar 

  128. Stefano GB, Salzet M, Hughes TK, Bilfinger TV. Delta opioid receptor subtype on human vascular endothelium uncouples morphine stimulated nitric oxide release. Int J Cardiol. 1998;64(Suppl 1):S43–S51.

    Article  PubMed  Google Scholar 

  129. Fimiani C, Magazine H, Welters ID, Bilfinger TV, Salsano F, Tonnesen E, Stefano GB. Antagonism of LPS and IFN-γ induced iNOS expression in human atrial endothelia by morphine, anandamide, and estrogen. Acta Pharmacol Sin. 2000;21:405–409.

    CAS  PubMed  Google Scholar 

  130. Stefano GB, Cadet P, Fimiani C, Magazine HI. Morphine stimulates iNOS expression via a rebound from inhibition in human macrophages: nitric oxide involvement. Int J Immunopathol Pharmacol. 2001;14:129–138.

    CAS  PubMed  Google Scholar 

  131. Stefano GB. Autoimmunovascular regulation: morphine and anandamide and ancondamide stimulated nitric oxide release. J Neuroimmunol. 1998;83:70–76.

    Article  CAS  PubMed  Google Scholar 

  132. Kanesaki T, Saki M, Ooi Y, Suematsu M, Matsumoto K, Sakuda M, Saito K, Maeda S. Morphine prevents peroxynitrite-induced death of human neuroblastoma SH-SY5Y cells through a direct scavenging action. Eur J Pharmacol. 1999;372:319–324.

    Article  CAS  PubMed  Google Scholar 

  133. Welters ID, Menzebach A, Goumon Y, Cadet P, Menges T, Hughes TK, Hempelmann G, Stefano GB. Morphine inhibits NF-κB nuclear binding in human neutrophils and monocytes by a nitric oxide-dependent mechanism. Anesthesiology. 2000;92:1 677–1 684.

    Article  CAS  Google Scholar 

  134. Welters ID, Menzebach A, Goumon Y, Langefeld TW, Teschemacher H, Hempelmann G, Stefano GB. Morphine suppresses complement receptor expression, phagocytosis, and respiratory bursts in neutrophils by a nitric oxide and μ3 opiate receptor-dependent mechanism. J Neuroimmunol. 2000;111:139–145.

    Article  CAS  PubMed  Google Scholar 

  135. Zhu W, Cadet P, Baggerman G, Mantione KJ, Stefano GB. Human white blood cells synthesize morphine: CYP2D6 modulation. J Immunol. 2005;175:7357–7362.

    CAS  PubMed  Google Scholar 

  136. Welters ID, Menzebach A, Goumon Y, Langefeld TW, Harbach H, Muhling J, Cadet P, Stefano GB. Morphine inhibits AP-1 activity and CD14 expression in leukocytes by a nitric oxide and opioid receptor-dependent mechanism. Eur J Anaesthesiol. 2007;24:958–965.

    Article  CAS  PubMed  Google Scholar 

  137. Drago F, Panissidi G, Bellomio F, Dal Bello A, Aguglia E, Gorgone G. Effects of opiates and opioids on intraocular pressure of rabbits and humans. Clin Exp Pharmacol Physiol. 1985;12:107–113.

    Article  CAS  PubMed  Google Scholar 

  138. Bonfiglio V, Bucolo C, Camillieri G, Drago F. Possible involvement of nitric oxide in morphine-induced miosis and reduction of intraocular pressure in rabbits. Eur J Pharmacol. 2006;534:227–232.

    Article  CAS  PubMed  Google Scholar 

  139. Dortch-Carnes J, Russell KR. Morphine-induced reduction of intraocular pressure and pupil diameter: role of nitric oxide. Pharmacology. 2006;77:17–24.

    Article  CAS  PubMed  Google Scholar 

  140. Dortch-Carnes J, Russell KR. Morphine-stimulated nitric oxide release in rabbit aqueous humor. Exp Eye Res. 2007;84:185–190.

    Article  CAS  PubMed  Google Scholar 

  141. Budziszewska B, Leskiewicz M, Jaworska-Feil L, Lason W. The effect of N-nitro-L-arginine methyl ester on morphine-induced changes in the plasma corticosterone and testosterone levels in mice. Exp Clin Endocrinol Diabetes. 1999;107:75–79.

    Article  CAS  PubMed  Google Scholar 

  142. Cadet P, Mantione KJ, Zhu W, Kream RM, Sheehan M, Stefano GB. A functionally coupled μ3-like opiate receptor/nitric oxide regulatory pathway in human multi-leakage progenitor cells. J Immunol. 2007;179:5839–5844.

    CAS  PubMed  Google Scholar 

  143. Paris D, Quadros A, Patel N, DelleDonne A, Humphrey J, Mullan M. Inhibition of angiogenesis and tumor growth by β- and γ-secretase inhibitors. Eur J Pharmacol. 2005;514:1–15.

    Article  CAS  PubMed  Google Scholar 

  144. Stefano GB, Kream RM, Mantione KJ, Sheehan M, Cadet P, Zhu W, Bilfinger TV, Esch T. Endogenous morphine/nitric oxide-coupled regulation of cellular physiology and gene expression: implications for cancer biology. Semin Cancer Biol. 2008;18:199–210.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

About this article

Cite this article

Toda, N., Kishioka, S., Hatano, Y. et al. Interactions between morphine and nitric oxide in various organs. J Anesth 23, 554–568 (2009). https://doi.org/10.1007/s00540-009-0793-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00540-009-0793-9

Key words

Navigation