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Satureja khuzestanica prevents the development of morphine analgesic tolerance through suppression of spinal glial cell activation in rats

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Abstract

Glial cell activation and oxidative stress are important factors in the induction of opioid side effects such as tolerance and dependence. It has been demonstrated that Satureja khuzistanica extract (SKE) has antioxidative, antinociceptive and anti-inflammatory properties; however, its influences on opioid analgesic tolerance have not yet been clarified. Adult male Wistar rats were rendered analgesic-tolerant by injection of 10 mg/kg morphine twice daily for 8 days. To determine the effect of SKE on the development of morphine tolerance, different doses of SKE (25, 50 and 100 mg/kg i.p.) were injected simultaneously with morphine. The tail-flick test was used to assess the nociceptive threshold. The lumbar spinal cord was assayed to determine glial fibrillary acidic protein (GFAP) and tumor necrosis factor alpha (TNFα) levels by the Western blotting method. Our results showed that chronic morphine produced tolerance to the antinociceptive effect of morphine. However, SKE could prevent, in a dose-dependent manner, morphine tolerance development. In tolerant animals, a significant increase in GFAP and TNFα levels was observed in the lumbar spinal cord, and was reversed to control levels by 100 mg/kg SKE. Our data revealed that Satureja khuzistanica had beneficial effects in preventing opioid tolerance and the underlying mechanisms of those effects may be due, at least in part, to reduce spinal glial cell activation.

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References

  1. Stefano GB, Kream RM, Esch T (2009) Revisiting tolerance from the endogenous morphine perspective. Med Sci Monit 15:189–198

    Google Scholar 

  2. Watkins LR, Hutchinson MR, Milligan ED, Maier SF (2007) “Listening” and “talking” to neurons: implications of immune activation for pain control and increasing the efficacy of opioids. Brain Res Rev 56:148–169

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Raghavendra V, Rutkowski MD, DeLeo JA (2002) The role of spinal neuroimmune activation in morphine tolerance/hyperalgesia in neuropathic and sham-operated rats. J Neurosci 22:9980–9989

    CAS  PubMed  Google Scholar 

  4. Song P, Zhao ZQ (2001) The involvement of glial cells in the development of morphine tolerance. Neurosci Res 39:281–286

    Article  CAS  PubMed  Google Scholar 

  5. DeLeo JA, Tanga FY, Tawfik VL (2004) Neuroimmune activation and neuroinflammation in chronic pain and opioid tolerance/hyperalgesia. Neuroscientist 10:40–52

    Article  CAS  PubMed  Google Scholar 

  6. Raghavendra V, Tanga FY, DeLeo JA (2004) Attenuation of morphine tolerance, withdrawal-induced hyperalgesia, and associated spinal inflammatory immune responses by propentofylline in rats. Neuropsychopharmacology 29:327–334

    Article  CAS  PubMed  Google Scholar 

  7. Ward J, Rosenbaum C, Hernon C, McCurdy CR, Boyer EW (2011) Herbal medicines for the management of opioid addiction: safe and effective alternatives to conventional pharmacotherapy? CNS Drugs 25:999–1007

    Article  CAS  PubMed  Google Scholar 

  8. Zargari A (1990) Medicinal plants. Tehran University Publications, Tehran, pp 42–45

    Google Scholar 

  9. Amanlou M, Dadkhah F, Salehnia A, Farsam H, Dehpour AR (2005) An anti-inflammatory and anti-nociceptive effects of hydroalcoholic extract of Satureja khuzestanica Jamzad extract. J Pharm Pharmaceut Sci 8:102–106

    Google Scholar 

  10. Kaeidi A, Esmaeili-Mahani S, Abbasnejad M, Sheibani V, Rasoulian B, Hajializadeh Z, Pasban-Aliabadi H (2013) Satureja khuzestanica attenuates apoptosis in hyperglycemic PC12 cells and spinal cord of diabetic rats. J Nat Med 67:61–69

    Article  PubMed  Google Scholar 

  11. Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110

    Article  CAS  PubMed  Google Scholar 

  12. D’Amour FE, Smith DL (1941) A method of determining loss of pain sensation. J Pharmacol Exp Ther 27:74–79

    Google Scholar 

  13. Darvishzadeh-Mahani F, Esmaeili-Mahani S, Komeili G, Sheibani V, Zare L (2012) Ginger (Zingiber officinale Roscoe) prevents the development of morphine analgesic tolerance and physical dependence in rats. J Ethnopharmacol 141:901–907

    Article  CAS  PubMed  Google Scholar 

  14. Zare L, Esmaeili-Mahani S, Abbasnejad M, Rasoulian B, Sheibani V, Sahraei H, Kaeidi A (2012) Oleuropein, chief constituent of olive leaf extract, prevents the development of morphine antinociceptive tolerance through inhibition of morphine-induced L-type calcium channel overexpression. Phytother Res 26:1731–1737

    Article  CAS  PubMed  Google Scholar 

  15. Zhao J, Xin X, Xie GX, Palmer PP, Huang YG (2012) Molecular and cellular mechanisms of the age-dependency of opioid analgesia and tolerance. Mol Pain 8:38

    Article  PubMed Central  PubMed  Google Scholar 

  16. Esmaeili Mahani S, Motamedi F, Javan M, Ahmadiani A (2005) Involvement of hypothalamic pituitary adrenal axis on the effects of nifedipine in the development of morphine tolerance in rats. Pharmacol Biochem Behav 81:152–157

    Article  CAS  PubMed  Google Scholar 

  17. Bryant L, Doyle T, Chen Z, Cuzzocrea S, Masini E, Vinci MC, Esposito E, Mazzon E, Petrusca DN, Petrache I, Salvemini D (2009) Spinal ceramide and neuronal apoptosis in morphine antinociceptive tolerance. Neurosci Lett 463:49–53

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Ueda H, Ueda M (2009) Mechanisms underlying morphine analgesic tolerance and dependence. Front Biosci 14:5260–5272

    Article  CAS  Google Scholar 

  19. Wen YR, Tan PH, Cheng JK, Liu YC, Ji RR (2011) Microglia: a promising target for treating neuropathic and postoperative pain, and morphine tolerance. J Formos Med Assoc 110:487–494

    Article  PubMed Central  PubMed  Google Scholar 

  20. Tai YH, Wang YH, Wang JJ, Tao PL, Tung CS, Wong CS (2006) Amitriptyline suppresses neuroinflammation and up-regulates glutamate transporters in morphine-tolerant rats. Pain 124:77–86

    Article  CAS  PubMed  Google Scholar 

  21. Liu CH, Cherng CH, Lin SL, Yeh CC, Wu CT, Tai YH, Wong CS (2011) N-Methyl-d-aspartate receptor antagonist MK-801 suppresses glial pro-inflammatory cytokine expression in morphine-tolerant rats. Pharmacol Biochem Behav 99:371–380

    Article  CAS  PubMed  Google Scholar 

  22. Shen CH, Tsai RY, Shih MS, Lin SL, Tai YH, Chien CC, Wong CS (2011) Etanercept restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in morphine-tolerant rats. Anesth Analg 112:454–459

    Article  CAS  PubMed  Google Scholar 

  23. Horvath RJ, Romero-Sandoval EA, De Leo JA (2010) Inhibition of microglial P2X4 receptors attenuates morphine tolerance, Iba1, GFAP and mu opioid receptor protein expression while enhancing perivascular microglial ED2. Pain 150:401–413

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Jin H, Li YH, Xu JS, Guo GQ, Chen DL, Bo Y (2012) Lipoxin A4 analog attenuates morphine antinociceptive tolerance, withdrawal-induced hyperalgesia, and glial reaction and cytokine expression in the spinal cord of rat. Neuroscience 208:1–10

    Article  CAS  PubMed  Google Scholar 

  25. Ndengele MM, Cuzzocrea S, Masini E, Vinci MC, Esposito E, Muscoli C, Petrusca DN, Mollace V, Mazzon E, Li D, Petrache I, Matuschak GM, Salvemini D (2009) Spinal ceramide modulates the development of morphine antinociceptive tolerance via peroxynitrite-mediated nitroxidative stress and neuroimmune activation. J Pharmacol Exp Ther 329:64–75

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Ren K, Dubner R (2010) Interactions between the immune and nervous systems in pain. Nat Med 16:1267–1276

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Guo RX, Zhang M, Liu W, Zhao CM, Cui Y, Wang CH, Feng JQ, Chen PX (2009) NMDA receptors are involved in upstream of the spinal JNK activation in morphine antinociceptive tolerance. Neurosci Lett 467:95–99

    Article  CAS  PubMed  Google Scholar 

  28. Doyle T, Bryant L, Batinic-Haberle I, Little J, Cuzzocrea S, Masini E, Spasojevic I, Salvemini D (2009) Supraspinal inactivation of mitochondrial superoxide dismutase is a source of peroxynitrite in the development of morphine antinociceptive tolerance. Neuroscience 164:702–710

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Abdel-Zaher AO, Abdel-Rahman MS, ELwasei FM (2010) Blockade of nitric oxide overproduction and oxidative stress by Nigella sativa oil attenuates morphine-induced tolerance and dependence in mice. Neurochem Res 35:1557–1565

    Article  CAS  PubMed  Google Scholar 

  30. Abdollahi M, Salehnia A, Mortazavi SH, Ebrahimi M, Shafiee A, Fouladian F, Keshavarz K, Sorouri S, Khorasani R, Kazemi A (2003) Antioxidant, antidiabetic, antihyperlipidemic, reproduction stimulatory properties and safety of essential oil of Satureja khuzestanica in rat in vivo: a oxicopharmacological study. Med Sci Monit 9:331–335

    Google Scholar 

  31. Vosough-Ghanbari S, Rahimi R, Kharabaf S, Zeinali S, Mohammadirad A, Amini S, Yasa N, Salehnia A, Toliat T, Nikfar S, Larijani B, Abdollahi M (2010) Effects of Satureja khuzestanica on serum glucose, lipids and markers of oxidative stress in patients with type 2 diabetes mellitus: a double-blind randomized controlled trial. Evid Based Complement Altern Med 7:465–470

    Article  Google Scholar 

  32. Rezvanfar M, Sadrkhanlou R, Ahmadi A, Shojaei-Sadee H, Rezvanfar M, Mohammadirad A, Salehnia A, Abdollahi M (2008) Protection of cyclophosphamide-induced toxicity in reproductive tract histology, sperm characteristics, and DNA damage by an herbal source; evidence for role of free-radical toxic stress. Hum Exp Toxicol 27:901–910

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by funds from Razi Herbal Medicines Research Center, Lorestan University of Medical Sciences and Kerman Neuroscience Research Center, Kerman University of Medical Sciences.

Conflict of interest

The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Laboratory of Molecular Neuroscience, Kerman Neuroscience Research Center (KNRC), Kerman University of Medical Sciences, Kerman, Iran

    Saeed Esmaeili-Mahani & Vahid Sheibani

  2. Department of Biology, Faculty of Sciences, Shahid Bahonar University of Kerman, P.O.Box: 76135-133, Kerman, Iran

    Saeed Esmaeili-Mahani, Bahareh Ebrahimi & Mehdi Abbasnejad

  3. Razi Herbal Medicines Research Center, Lorestan University of Medical Sciences, Khoramabad, Iran

    Bahram Rasoulian

Authors
  1. Saeed Esmaeili-Mahani
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  2. Bahareh Ebrahimi
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  4. Bahram Rasoulian
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  5. Vahid Sheibani
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Correspondence to Saeed Esmaeili-Mahani.

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Esmaeili-Mahani, S., Ebrahimi, B., Abbasnejad, M. et al. Satureja khuzestanica prevents the development of morphine analgesic tolerance through suppression of spinal glial cell activation in rats. J Nat Med 69, 165–170 (2015). https://doi.org/10.1007/s11418-013-0796-6

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  • DOI: https://doi.org/10.1007/s11418-013-0796-6

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