Association of morphine-induced analgesic tolerance with changes in gene expression of GluN1 and MOR1 in rat spinal cord and midbrain

Document Type: Original Article

Authors

Department of Biological Science, Faculty of Science, University of Kurdistan, Sanandaj, Iran

Abstract

Objective(s): We aimed to examine association of gene expression of MOR1 and GluN1 at mRNA level in the lumbosacral cord and midbrain with morphine tolerance in male Wistar rats.
Materials and Methods: Analgesic effects of morphine administrated intraperitoneally at doses of 0.1, 1, 5 and 10 mg/kg were examined using a hot plate test in rats with and without a history of 15 days morphine (10 mg/kg) treatment. Morphine-induced analgesic tolerance was also assessed on days 1, 5, 10 and 15 of chronic morphine injections. Two groups with history of 15 days injections of saline or morphine (10 mg/kg) were decapitated on day 15 and their lumbosacral cord and midbrain were dissected for evaluating MOR1 and GluN1 gene expression.
Results: The results of the hot plate test showed that morphine (5 and 10 mg/kg) induced significant analgesia in naïve rats but its analgesic effects in rats receiving 15 days injections of morphine (10 mg/kg) was decreased, indicating tolerance to morphine analgesia. The results also showed that the GluN1 gene expression in tolerant rats was decreased by 71 % in the lumbosacral cord but increased by 110 % in the midbrain compared to the control group. However, no significant change was observed for the MOR1 gene expression in both areas.
Conclusion: It can be concluded that tolerance following administration of morphine (10 mg/kg) for 15 days is associated with site specific changes in the GluN1 gene expression in the spinal cord and midbrain but the MOR1 gene expression is not affected.

Keywords


1. Harden RN. Chronic pain and opiates: a call for moderation. Arch Phys Med Rehabil 2008; 89:S72-76.

2. Ravindranathan A, Joslyn G, Robertson M, Schuckit MA, Whistler JL, White RL. Functional characterization of human variants of the mu-opioid receptor gene. Proc Natl Acad Sci U S A 2009; 106:10811-10816.

3. Williams JT, Ingram SL, Henderson G, Chavkin C, von Zastrow M, Schulz S, et al. Regulation of mu-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev 2013; 65:223-254.

4. Chang G, Chen L, Mao J. Opioid tolerance and hyperalgesia. Med Clin North Am 2007; 91:199-211.

5. Dumas EO, Pollack GM. Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective. AAPS J 2008; 10:537-551.

6. Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L. A comprehensive review of opioid-induced hyperalgesia. Pain Physician 2011; 14:145-161.

7. DuPen A, Shen D, Ersek M. Mechanisms of opioid-induced tolerance and hyperalgesia. Pain Manag Nurs 2007; 8:113-121.

8. Prescott SA, Ma Q, De Koninck Y. Normal and abnormal coding of somatosensory stimuli causing pain. Nat Neurosci 2014; 17:183-191.

9. Piomelli D, Sasso O. Peripheral gating of pain signals by endogenous lipid mediators. Nat Neurosci 2014; 17:164-174.

10. Almeida TF, Roizenblatt S, Tufik S. Afferent pain pathways: a neuroanatomical review. Brain Res 2004; 1000:40-56.

11. Lau BK, Vaughan CW. Descending modulation of pain: the GABA disinhibition hypothesis of analgesia. Curr Opin Neurobiol 2014; 29:159-164.

12. Millan MJ. Descending control of pain. Prog Neurobiol 2002; 66:355-474.

13. Ossipov MH, Lai J, King T, Vanderah TW, Porreca F. Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure. Biopolymers 2005; 80:319-324.

14. Ueda H, Inoue M, Matsumoto T. Protein kinase C-mediated inhibition of mu-opioid receptor internalization and its involvement in the development of acute tolerance to peripheral mu-agonist analgesia. J Neurosci 2001; 21:2967-2973.

15. Chen W, Zhang G, Marvizon JC. NMDA receptors in primary afferents require phosphorylation by Src family kinases to induce substance P release in the rat spinal cord. Neuroscience 2010; 166:924-934.

16. Mao J, Price DD, Mayer DJ. Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C. J Neurosci 1994; 14:2301-2312.

17. Trujillo KA, Akil H. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 1991; 251:85-87.

18. Arout CA, Edens E, Petrakis IL, Sofuoglu M. Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations. CNS Drugs 2015; 29:465-486.

19. Ahmadi S, Amiri S, Rafieenia F, Rostamzadeh J. Gene Expression Profile of Calcium/Calmodulin-Dependent Protein Kinase IIalpha in Rat's Hippocampus during Morphine Withdrawal. Basic Clin Neurosci 2013; 4:146-152.

20. Ahmadi S, Karami Z, Mohammadian A, Khosrobakhsh F, Rostamzadeh J. Cholestasis induced antinociception and decreased gene expression of MOR1 in rat brain. Neuroscience 2015; 284:78-86.

21. Jin WY, Yu LC. Involvement of protein kinase C in morphine tolerance at spinal levels of rats. ACS Chem Neurosci 2010; 1:122-128.

22. Dogrul A, Bilsky EJ, Ossipov MH, Lai J, Porreca F. Spinal L-type calcium channel blockade abolishes opioid-induced sensory hypersensitivity and antinociceptive tolerance. Anesth Analg 2005; 101:1730-1735.

23. Hosseini M, Taiarani Z, Hadjzadeh MA, Salehabadi S, Tehranipour M, Alaei HA. Different responses of nitric oxide synthase inhibition on morphine-induced antinociception in male and female rats. Pathophysiology 2011; 18:143-149.

24. Keil GJ, 2nd, Delander GE. Time-dependent antinociceptive interactions between opioids and nucleoside transport inhibitors. J Pharmacol Exp Ther 1995; 274:1387-1392.

25. Ossipov MH, Harris S, Lloyd P, Messineo E, Lin BS, Bagley J. Antinociceptive interaction between opioids and medetomidine: systemic additivity and spinal synergy. Anesthesiology 1990; 73:1227-1235.

26. Marone M, Mozzetti S, De Ritis D, Pierelli L, Scambia G. Semiquantitative RT-PCR analysis to assess the expression levels of multiple transcripts from the same sample. Biol Proced Online 2001; 3:19-25.

27. Ahmadi S, Poureidi M, Rostamzadeh J. Hepatic encephalopathy induces site-specific changes in gene expression of GluN1 subunit of NMDA receptor in rat brain. Metab Brain Dis 2015; 30:1035-1041.

28. Benyamin R, Trescot AM, Datta S, Buenaventura R, Adlaka R, Sehgal N, et al. Opioid complications and side effects. Pain Physician 2008; 11:S105-120.

29. Bannister K. Opioid-induced hyperalgesia: where are we now? Curr Opin Support Palliat Care 2015; 9:116-121.

30. Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain 1995; 62:259-274.

31. Fabian G, Bozo B, Szikszay M, Horvath G, Coscia CJ, Szucs M. Chronic morphine-induced changes in mu-opioid receptors and G proteins of different subcellular loci in rat brain. J Pharmacol Exp Ther 2002; 302:774-780.

32. Ossipov MH, Lai J, Vanderah TW, Porreca F. Induction of pain facilitation by sustained opioid exposure: relationship to opioid antinociceptive tolerance. Life Sci 2003; 73:783-800.

33. Kozela E, Popik P. A complete analysis of NMDA receptor subunits in periaqueductal grey and ventromedial medulla of morphine tolerant mice. Drug Alcohol Depend 2007; 86:290-293.

34. Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain Physician 2008; 11:S133-153.

35. Zhao YL, Chen SR, Chen H, Pan HL. Chronic opioid potentiates presynaptic but impairs postsynaptic N- methyl-D-aspartic acid receptor activity in spinal cords: implications for opioid hyperalgesia and tolerance. J Biol Chem 2012; 287:25073-25085.

36. Kuhar MJ, Joyce A, Dominguez G. Genes in drug abuse. Drug Alcohol Depend 2001; 62:157-162.

37. Mendez IA, Trujillo KA. NMDA receptor antagonists inhibit opiate antinociceptive tolerance and locomotor sensitization in rats. Psychopharmacology (Berl) 2008; 196:497-509.

38. Incontro S, Asensio CS, Edwards RH, Nicoll RA. Efficient, complete deletion of synaptic proteins using CRISPR. Neuron 2014; 83:1051-1057.

39. Zhu H, Brodsky M, Gorman AL, Inturrisi CE. Region-specific changes in NMDA receptor mRNA induced by chronic morphine treatment are prevented by the co-administration of the competitive NMDA receptor antagonist LY274614. Brain Res Mol Brain Res 2003; 114:154-162.

40. Turchan J, Maj M, Przewlocka B. The effect of drugs of abuse on NMDAR1 receptor expression in the rat limbic system. Drug Alcohol Depend 2003; 72:193-196.

41. Zhu H, Jang CG, Ma T, Oh S, Rockhold RW, Ho IK. Region specific expression of NMDA receptor NR1 subunit mRNA in hypothalamus and pons following chronic morphine treatment. Eur J Pharmacol 1999; 365:47-54.

42. Lim G, Wang S, Zeng Q, Sung B, Yang L, Mao J. Expression of spinal NMDA receptor and PKCgamma after chronic morphine is regulated by spinal glucocorticoid receptor. J Neurosci 2005; 25:11145-11154.

43. Ammon-Treiber S, Hollt V. Morphine-induced changes of gene expression in the brain. Addict Biol 2005; 10:81-89.

44. Garzon J, Rodriguez-Munoz M, Sanchez-Blazquez P. Direct association of Mu-opioid and NMDA glutamate receptors supports their cross-regulation: molecular implications for opioid tolerance. Curr Drug Abuse Rev 2012; 5:199-226.

45. Sánchez-Blázquez P, Rodríguez-Muñoz M, Berrocoso E, Garzón J. The plasticity of the association between mu-opioid receptor and glutamate ionotropic receptor N in opioid analgesic tolerance and neuropathic pain. Eur J Pharmacol 2013; 716:94-105.

46. Tian Q, Stepaniants SB, Mao M, Weng L, Feetham MC, Doyle MJ, et al. Integrated genomic and proteomic analyses of gene expression in Mammalian cells. Mol Cell Proteomics 2004; 3:960-969.

47. Jayanthi S, McCoy MT, Chen B, Britt JP, Kourrich S, Yau HJ, et al. Methamphetamine downregulates striatal glutamate receptors via diverse epigenetic mechanisms. Biol Psychiatry 2014; 76:47-56.

48. Priya A, Johar K, Wong-Riley MT. Specificity protein 4 functionally regulates the transcription of NMDA receptor subunits GluN1, GluN2A, and GluN2B. Biochim Biophys Acta 2013; 1833:2745-2756.