Volume 20, Issue 6 (Iranian South Medical Journal 2018)                   Iran South Med J 2018, 20(6): 527-539 | Back to browse issues page

XML Persian Abstract Print


Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Ghasemloo K, Manaheji H, Dargahi L, pandamooz S. The Role of Spinal PKCγ in Tolerance and Hyperalgesia Induced by Repeated Morphine Administration in Male Rats. Iran South Med J 2018; 20 (6) :527-539
URL: http://ismj.bpums.ac.ir/article-1-904-en.html
1- Department of Physiology, Shahid Beheshti University of Medical Sciences. Tehran, Iran
2- Department of Physiology, Shahid Beheshti University of Medical Sciences. Tehran, Iran
Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences. Tehran, Iran , manahejih@sbmu.ac.ir
3- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences. Tehran, Iran
Abstract:   (3788 Views)
Background: The aim of this study was to investigate the possible role of Protein Kinase Cᵧ (PKCᵧ) in morphine tolerance and induced hyperalgesia following repeated morphine administration in male rats.
Material and Methods: Rats were divided into 4 groups for testing. The groups consisted of control (saline), morphine tolerance and hyperalgesia, metformin, morphine tolerance and hyperalgesia + metformin. First morphine (10mg/kg, s.c) administrated daily up to 14 days subcutaneously. Hargreaves' behavioral test was performed to evaluate morphine tolerance. The test was ececuted before morphin injection and the results considered as “control” .Then the test repeated  after the first dose of morphine on the first day and then on day14th after the last injection. To consider morphine hyperalgesia PWL (Paw Withdrawal Latency) was measured by Hargreaves test before and after first morphine injection on the first day and then on day 14th before the last injection of morphine and on day16th two days after the last injection of morphine. The expression of spinal PKCᵧ measured on day 14th and 16th. Metformin 100mg/kg, co-administrated with morphine daily up to 14 days then PWL and PKCᵧ expression were assessed as mentioned above.
Results: The results showed a significant tolerance and hyperalgesia on day 14th and 16th compareed to control. PKCᵧ expression also increased significantly on day 14th and 16th compareed to control. However, there was no significant difference in comparison between day 14th and day 16th. Co-administration of metformin and morphine up to 14 days increased PWL in morphine tolerance and reduced hyperalgesia and PKCᵧ expression.
Conclusion: The results showed that increasing of spinal PKCᵧ expression in chronic morphine administration might be involved in morphine tolerance mechanism and induced hyperalgesia.
Full-Text [PDF 1145 kb]   (886 Downloads)    
Type of Study: Original | Subject: Pharmacology
Received: 2017/02/7 | Accepted: 2017/07/23 | Published: 2018/01/7

References
1. .Lim G, Wang S, Mao J. cAMP and protein kinase A contribute to the downregulation of spinal glutamate transporters after chronic morphine. Neuroscience letters. 2005;376(1):9-13. [PubMed] [Google Scholar]
2. Mayer DJ, Mao J, Price DD. The development of morphine tolerance and dependence is associated with translocation of protein kinase C. Pain.1995;61(3):365-74. [PubMed] [Google Scholar]
3. Xu T, Chen M, Zhou Q, et al. Antisense oligonucleotide knockdown of mGlu 5 receptor attenuates the antinociceptive tolerance and upregulated expression of spinal protein kinase C associated with chronic morphine treatment. European journal of pharmacology. 2012;683(1):78-85. [Google Scholar]
4. Shokoofeh S, Homa M, Leila D, Samira D. Expression of spinal cord GABA transporter 1 in morphine-tolerant male Wistar rats. European journal of pharmacology. 2015;767:77-81. [PubMed] [Google Scholar]
5. Angst MS, Clark JD. Opioid-induced Hyperalgesia. A Qualitative Systematic Review. The Journal of the American Society of Anesthesiologists.2006;104(3):570-587. [PubMed] [Google Scholar]
6. Drdla R, Gassner M, Gingl E, Sandkühler J. Induction of synaptic long-term potentiation after opioid withdrawal. Science. 2009;325(5937):207-210. [PubMed] [Google Scholar]
7. Smith FL, Javed RR, Smith PA, et al. PKC and PKA inhibitors reinstate morphine-induced behaviors in morphine tolerant mice. Pharmacological research. 2006;54(6):474-80. [PubMed] [Google Scholar]
8. DuPen A, Shen D, Ersek M. Mechanisms of opioid induced tolerance and hyperalgesia. Pain Management Nursing. 2007;8(3):113-121. [PubMed] [Google Scholar]
9. Zaringhalam J, Manaheji H, Mghsoodi N, et al. Spinal µ‐opioid receptor expression and hyperalgesia with dexamethasone in chronic adjuvant‐induced arthritis in rats. Clinical and experimental pharmacology and physiology.2008;35(11):1309-1315. [PubMed] [Google Scholar]
10. Nazemi S, Manaheji H, Zaringhalam J, et al. Postinjury repeated administrations of minocycline improve the antinociceptive effect of morphine in chronic constriction injury model of neuropathic pain in rat. Pharmacology Biochemistry and Behavior. 2012;102(4):520-525. [PubMed] [Google Scholar]
11. Hamidi GA, Manaheji H, Janahmadi M, et al. Coadministration of MK-801 and morphine attenuates neuropathic pain in rat. Physiology & Behavior. 2006;88(4-5):628-636. [PubMed] [Google Scholar]
12. 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. Journal of Neuroscience. 1994;14(4):2301-2312. [PubMed] [Google Scholar]
13. Igwe O, Chronwall B. Hyperalgesia induced by peripheral inflammation is mediated by protein kinase C βII isozyme in the rat spinal cord. Neuroscience. 2001;104(3):875-890. [PubMed] [Google Scholar]
14. Yajima Y, Narita M, Shimamura M, et al. Differential involvement of spinal protein kinase C and protein kinase A in neuropathic and inflammatory pain in mice. Brain Research. 2003;992(2):288-293. [PubMed] [Google Scholar]
15. Song L, Wu C, Zuo Y. Melatonin prevents morphine-induced hyperalgesia and tolerance in rats: role of protein kinase C and N-methyl-Daspartate receptors. BMC Anesthesiology.2015;15(12): 1-8. [PubMed] [Google Scholar]
16. Bailey CP, Smith FL, Kelly E, et al. How important is protein kinase C in μ-opioid receptor desensitization and morphine tolerance? Trends in pharmacological sciences. 2006; 27(11):558-565. [PubMed] [Google Scholar]
17. Sjøgren P, Jensen N-H, Jensen TS. Disappearance of morphine-induced hyperalgesia after discontinuing or substituting morphine with other opioid agonists. Pain. 1994;59(2):313-316. [PubMed] [Google Scholar]
18. Mao J. Overview on opioid induced- hyperalgesia. In: first eds; Opioid induced-hyperalgesia. New York: Informa healthcare Inc, 2010, 1-9.
19. Pan Y, Sun X, Jiang L, et al. Metformin reduces morphine tolerance by inhibiting microglialmediated neuroinflammation. Journal of Neuroinflammation. 2016;13)294): 1-12. [PubMed] [Google Scholar]
20. Jin WY, Yu LC. Involvement of protein kinase C in morphine tolerance at spinal levels of rats. ACS Chemical Neuroscience. 2010;1(2):122-128. [PubMed] [Google Scholar]
21. .Gabra BH, Bailey CP, Kelly E, et al. Pre-treatment with a PKCor PKA inhibitor preventsthe development of morphine tolerance but not physical dependence in mice. Brain Research. 2008;1217:70-77. [PubMed] [Google Scholar]
22. .Granados-Soto V, Kalcheva I, Hua XY, et al. Spinal PKC activity and expression: role in tolerance produced by continuous spinal morphine infusion. Pain. 2000;85(3):395-404. [PubMed] [Google Scholar]
23. Hull LC, Llorente J, Gabra BH, Smith FL, et al. The effect of protein kinase C and G protein-coupled receptor kinase inhibition on tolerance induced by μ- opioid agonists of different efficacy. Journal of Pharmacology and Experimental Therapeutics. 2010;332(3):1127-1135. [PubMed] [Google Scholar]
24. Gallo A, Ceolotto G, Pinton P, et al. Metformin prevents glucose-induced protein kinase C-β2 activation in human umbilical vein endothelial cells through an antioxidant mechanism. Diabetes. 2005;54(4):1123-1131. [PubMed] [Google Scholar]
25. Esmaeili‐Mahani S, Shimokawa N, Javan M, et al. Low‐dose morphine induces hyperalgesia through activation of Gαs, protein kinase C, and l‐type Ca2+ channels in rats. Journal of Neuroscience Research.2008;86(2):471-479. [Google Scholar]

Send email to the article author


Rights and Permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

© 2024 CC BY-NC 4.0 | Iranian South Medical Journal

Designed & Developed by: Yektaweb