Anesth Pain Med.  2016 Jan;11(1):23-27. 10.17085/apm.2016.11.1.23.

The effects of hydromorphone on astrocytic responses in cerebral ischemia

• Lee CH
• Park YC
• Kim JH
• Kim WY
• Lee YS
• Kim YH
• Min TJ

• KMID: 2169064
• DOI: http://doi.org/10.17085/apm.2016.11.1.23

Abstract

BACKGROUND
Ischemic insult during operation could cause ischemic-reperfusion injuries in brain and memory impairments. Total intravenous anesthesia (TIVA) is preferred in brain surgery to promote the use of motor evoked potential monitoring and the use of opioids is common in TIVA. However there were few studies about ischemic protective effect of opioids to astrocytes.
METHODS
We used astrocytes, which were derived from human brain. We divided groups by conditioning period; i) pre-culture, ii) post-culture, or iii) pre + post-culture. All groups were treated 100 nM hydromorphone. We measured reactive oxygen species (ROS) by flow cytometry with 2',7'-dichloroflurorescin diacetate. Then ROS in astrocytes which treated by opioid receptor antagonist were measured after treating 100 nM hydromorphone.
RESULTS
ROS was reduced in hydromorphone treated group, as compared to the control group (only tert-butyl hydroperoxide [TBH] treated). There was no difference in pre-conditioned group and post-conditioned group. However, ROS was much more reduced in pre + post-conditioned group compared to pre-conditioned only or post-conditioned only group. Furthermore each selective micro-, delta- and kappa-opioid receptor antagonists partially negated the effect of hydromorphone.
CONCLUSIONS
This study provides evidence that hydromorphone has both preconditioning and postconditioning effects on TBH-induced oxidative stress. Furthermore we proved each micro-, delta- and kappa-opioid receptor relates to protective mechanism of hydromorphone to astrocytes.

Keyword

Astrocytes; Cerebral ischemia; Hydromorphone

MeSH Terms

Analgesics, Opioid
Anesthesia, Intravenous
Astrocytes
Brain
Brain Ischemia*
Evoked Potentials, Motor
Flow Cytometry
Humans
Hydromorphone*
Memory
Oxidative Stress
Reactive Oxygen Species
Receptors, Opioid
tert-Butylhydroperoxide
Analgesics, Opioid
Hydromorphone
Reactive Oxygen Species
Receptors, Opioid
tert-Butylhydroperoxide

Figure

• 

  Fig. 1 Experimental protocol. Experimental design. TBH: tert-butyl hydroperoxide, DCF-DA: 2’,7’-dichloroflurorescin diacetate, OR antagonist: one of selective μ-, δ- and κ-opioid receptor antagonists (naltrindole, nor-binaltorphimine, and CTOP), respectively.

• 

  Fig. 2 Detection of intracellular ROS. Detection of intracellular ROS products. This graph shows the protective effect of hydromorphone on TBH induced toxicity in primary human glial cell cultures. The ROS level was measured with using FACS (DCF-DA) in the 100 nM hydromorphone i) pre-conditioned ii) post-conditioned iii) pre+post-conditioned primary human glial cells. *< 0.05 versus control group. †< 0.05 versus preconditioned group. ‡< 0.05 versus post-conditioned group.

• 

  Fig. 3 Detection of intracellular ROS. Effects of opioid receptor antagonists on ROS products. This graph shows that selective opioid receptor antagonists reverse the attenuation of the ROS induced by hydromorphone (pre + post-conditioned). The ROS level was measured with using FACS (DCF-DA) in the cells treated only TBH (control group), and the cells treated with TBH, hydromorphone and/or one of selective μ-, δ- and κ-opioid receptor antagonists (naltrindole, nor-binaltorphimine, and CTOP), respectively. *< 0.05 versus control group. †< 0.05 versus hydromorphone group.

Reference

1. Vicente E, Degerone D, Bohn L, Scornavaca F, Pimentel A, Leite MC, et al. Astroglial and cognitive effects of chronic cerebral hypoperfusion in the rat. Brain Res. 2009; 1251:204–12. DOI: 10.1016/j.brainres.2008.11.032. PMID: 19056357.

2. Bilotta F, Gelb AW, Stazi E, Titi L, Paoloni FP, Rosa G. Pharmacological perioperative brain neuroprotection: a qualitative review of randomized clinical trials. Br J Anaesth. 2013; 110(Suppl 1):i113–20. DOI: 10.1093/bja/aet059. PMID: 23562933.

3. Gross GJ, Baker JE, Hsu A, Wu HE, Falck JR, Nithipatikom K. Evidence for a role of opioids in epoxyeicosatrienoic acid-induced cardioprotection in rat hearts. Am J Physiol Heart Circ Physiol. 2010; 298:H2201–7. DOI: 10.1152/ajpheart.00815.2009. PMID: 20400686. PMCID: PMC2886625.

4. Goldsmith JR, Perez-Chanona E, Yadav PN, Whistler J, Roth B, Jobin C. Intestinal epithelial cell-derived mu-opioid signaling protects against ischemia reperfusion injury through PI3K signaling. Am J Pathol. 2013; 182:776–85. DOI: 10.1016/j.ajpath.2012.11.021. PMID: 23291213. PMCID: PMC3589074.

5. Gwak MS, Li L, Zuo Z. Morphine preconditioning reduces lipopolysaccharide and interferon-gamma-induced mouse microglial cell injury via delta 1 opioid receptor activation. Neuroscience. 2010; 167:256–60. DOI: 10.1016/j.neuroscience.2010.02.017. PMID: 20156527. PMCID: PMC2849923.

6. Teo JD, Morris MJ, Jones NM. Hypoxic postconditioning reduces microglial activation, astrocyte and caspase activity, and inflammatory markers after hypoxia-ischemia in the neonatal rat brain. Pediatr Res. 2015; 77:757–64. DOI: 10.1038/pr.2015.47. PMID: 25751571.

7. Scheufler KM, Zentner J. Total intravenous anesthesia for intraoperative monitoring of the motor pathways: an integral view combining clinical and experimental data. J Neurosurg. 2002; 96:571–9. DOI: 10.3171/jns.2002.96.3.0571. PMID: 11883843.

8. Kim EM, Park WY, Choi EM, Choi SH, Min KT. A retrospective analysis of prolonged propofol- remifentanil anesthesia in the neurosurgical patients. Anesth Pain Med. 2008; 3:288–92.

9. Zhang Y, Irwin MG, Lu Y, Mei B, Zuo YM, Chen ZW, et al. Intracerebroventricular administration of morphine confers remote cardioprotection role of opioid receptors and calmodulin. Eur J Pharmacol. 2011; 656:74–80. DOI: 10.1016/j.ejphar.2011.01.027. PMID: 21291882.

10. Rostami F, Oryan S, Ahmadiani A, Dargahi L. Morphine preconditioning protects against LPS-induced neuroinflammation and memory deficit. J Mol Neurosci. 2012; 48:22–34. DOI: 10.1007/s12031-012-9726-4. PMID: 22388653.

11. Iwata-Ichikawa E, Kondo Y, Miyazaki I, Asanuma M, Ogawa N. Glial cells protect neurons against oxidative stress via transcriptional up-regulation of the glutathione synthesis. J Neurochem. 1999; 72:2334–44. DOI: 10.1046/j.1471-4159.1999.0722334.x. PMID: 10349842.

12. Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 1996; 19:312–8. DOI: 10.1016/0166-2236(96)10049-7.

13. Brown GC, Bal-Price A. Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol Neurobiol. 2003; 27:325–55. DOI: 10.1385/MN:27:3:325.

14. Hu Y, Wang S, Wang A, Lin L, Chen M, Wang Y. Antioxidant and hepatoprotective effect of Penthorum chinense Pursh extract against t-BHP-induced liver damage in L02 cells. Molecules. 2015; 20:6443–53. DOI: 10.3390/molecules20046443. PMID: 25867829.

15. Yan LJ. Positive oxidative stress in aging and aging-related disease tolerance. Redox Biol. 2014; 2C:165–9. DOI: 10.1016/j.redox.2014.01.002. PMID: 25460727. PMCID: PMC4297947.

16. Milisav I, Poljsak B, Suput D. Adaptive response, evidence of cross-resistance and its potential clinical use. Int J Mol Sci. 2012; 13:10771–806. DOI: 10.3390/ijms130910771. PMID: 23109822. PMCID: PMC3472714.

17. Das M, Das DK. Molecular mechanism of preconditioning. IUBMB Life. 2008; 60:199–203. DOI: 10.1002/iub.31. PMID: 18344203.

18. Rush GF, Gorski JR, Ripple MG, Sowinski J, Bugelski P, Hewitt WR. Organic hydroperoxide-induced lipid peroxidation and cell death in isolated hepatocytes. Toxicol Appl Pharmacol. 1985; 78:473–83. DOI: 10.1016/0041-008X(85)90255-8.

19. Holownia A, Mroz RM, Wielgat P, Skiepko A, Sitko E, Jakubow P, et al. Propofol protects rat astroglial cells against tert-butyl hydroperoxide-induced cytotoxicity;the effect on histone and cAMP-response-element-binding protein (CREB) signalling. J Physiol Pharmacol. 2009; 60:63–9. PMID: 20065498.

20. Hutchinson MR, Bland ST, Johnson KW, Rice KC, Maier SF, Watkins LR. Opioid-induced glial activation: mechanisms of activation and implications for opioid analgesia, dependence, and reward. ScientificWorldJournal. 2007; 7:98–111. DOI: 10.1100/tsw.2007.230. PMID: 17982582.

21. Madera-Salcedo IK, Cruz SL, Gonzalez-Espinosa C. Morphine decreases early peritoneal innate immunity responses in Swiss- Webster and C57BL6/J mice through the inhibition of mast cell TNF-alpha release. J Neuroimmunol. 2011; 232:101–7. DOI: 10.1016/j.jneuroim.2010.10.017. PMID: 21087796.

22. Askari N, Mahboudi F, Haeri-Rohani A, Kazemi B, Sarrami R, Edalat R, et al. Effects of single administration of morphine on G-protein mRNA level in the presence and absence of inflammation in the rat spinal cord. Scand J Immunol. 2008; 67:47–52. DOI: 10.1111/j.1365-3083.2007.02043.x. PMID: 18052964.

23. Watkins LR, Hutchinson MR, Rice KC, Maier SF. The “toll” of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia. Trends Pharmacol Sci. 2009; 30:581–91. DOI: 10.1016/j.tips.2009.08.002. PMID: 19762094. PMCID: PMC2783351.

24. Ricket A, Mateyoke G, Vallabh M, Owen C, Peppin J. A pilot evaluation of a hydromorphone dose substitution policy and the effects on patient safety and pain management. J Pain Palliat Care Pharmacother. 2015; 29:120–4. DOI: 10.3109/15360288.2015.1035829. PMID: 26095481.

25. Oosten AW, Oldenmenger WH, Mathijssen RH, van der Rijt CC. A systematic review of prospective studies reporting adverse events of commonly used opioids for cancer-related pain: a call for the use of standardized outcome measures. J Pain. 2015; 16:935–46. DOI: 10.1016/j.jpain.2015.05.006. PMID: 26051219.

26. Wirz S, Wartenberg HC, Nadstawek J. Less nausea, emesis, and constipation comparing hydromorphone and morphine? A prospective open-labeled investigation on cancer pain. Support Care Cancer. 2008; 16:999–1009. DOI: 10.1007/s00520-007-0368-y. PMID: 18095008.

27. Guedes AG, Papich MG, Rude EP, Rider MA. Comparison of plasma histamine levels after intravenous administration of hydromorphone and morphine in dogs. J Vet Pharmacol Ther. 2007; 30:516–22. DOI: 10.1111/j.1365-2885.2007.00911.x. PMID: 17991219.

28. Wolf NB, Kuchler S, Radowski MR, Blaschke T, Kramer KD, Weindl G, et al. Influences of opioids and nanoparticles on in vitro wound healing models. Eur J Pharm Biopharm. 2009; 73:34–42. DOI: 10.1016/j.ejpb.2009.03.009. PMID: 19344759.

29. Wu S, Wong MC, Chen M, Cho CH, Wong TM. Role of opioid receptors in cardioprotection of cold-restraint stress and morphine. J Biomed Sci. 2004; 11:726–31. DOI: 10.1007/BF02254356. PMID: 15591768.

30. Jeong S, Kim SJ, Jeong C, Lee S, Jeong H, Lee J, et al. Neuroprotective effects of remifentanil against transient focal cerebral ischemia in rats. J Neurosurg Anesthesiol. 2012; 24:51–7. DOI: 10.1097/ANA.0b013e3182368d70. PMID: 22015431.