Ginger Extract Reduces Chronic Morphine-Induced Neuroinflammation and Glial Activation in Nucleus Accumbens of Rats

Document Type : Original Article


1 Department of Biology, School of Sciences, Shahid Bahonar University of Kerman, Kerman, Iran

2 Department of Biology, School of Sciences, Shahid Bahonar University of Kerman AND Laboratory of Molecular Neuroscience, Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

3 Department of Biology, Payame Noor University, Tehran, Iran

4 Laboratory of Molecular Neuroscience, Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran


Background: Chronic usage of morphine elicits the production of inflammatory factors by glial cells and
induces neuroinflammation. Ginger (Zingiber Officinale Roscoe) is a medicinal herb that has antiinflammatory properties. It has been reported that ginger shows anti-addictive effects against chronic usage
of morphine; however, its influence on morphine-induced neuroinflammation has not yet been clarified.
Methods: Morphine (12 mg/kg) was administrated intraperitoneally for 6 consecutive days. To evaluate the
effect of ginger on morphine-induced neuroinflammation, ginger extract (100 mg/kg) was given orally 30
minutes before morphine. Glial fibrillary acidic protein (GFAP) and P38 mitogen-activated protein kinase
(p38 MAPK) levels were assayed by immunoblotting in the rat nucleus accumbens (NAcc).
Findings: The injection of chronic morphine increased the levels of proteins involved in neuroinflammation
(p38 MAPK and GFAP) in NAcc. Furthermore, the levels of p38 MAPK and GFAP significantly returned to
the control levels by ginger extract.
Conclusion: The results suggest that the ginger extract can reduce morphine-induced neuroinflammation in NAcc.


Zhu H, Zhou W. Discharge activities of neurons in
the nucleus paragigantocellularis during the
development of morphine tolerance and dependence:
A single unit study in chronically implanted rats. Eur
J Pharmacol 2010; 636(1-3): 65-72.
2. Wang X, Loram LC, Ramos K, de Jesus AJ, Thomas
J, Cheng K, et al. Morphine activates
neuroinflammation in a manner parallel to
endotoxin. Proc Natl Acad Sci USA 2012; 109(16):
3. DeLeo JA, Tanga FY, Tawfik VL. Neuroimmune
activation and neuroinflammation in chronic pain
and opioid tolerance/hyperalgesia. Neuroscientist
2004; 10(1): 40-52.
4. Bachstetter AD, Van Eldik LJ. The p38 MAP kinase
family as regulators of proinflammatory cytokine
production in degenerative diseases of the CNS.
Aging Dis 2010; 1(3): 199-211.
5. Hutchinson MR, Coats BD, Lewis SS, Zhang Y,
Sprunger DB, Rezvani N, et al. Proinflammatory
cytokines oppose opioid-induced acute and chronic
analgesia. Brain Behav Immun 2008; 22(8): 1178-89.
6. Horvath RJ, Landry RP, Romero-Sandoval EA,
DeLeo JA. Morphine tolerance attenuates the
resolution of postoperative pain and enhances spinal
microglial p38 and extracellular receptor kinase
phosphorylation. Neuroscience 2010; 169(2): 843-54.
7. Song P, Zhao ZQ. The involvement of glial cells in
the development of morphine tolerance. Neurosci
Res 2001; 39(3): 281-6.
8. Ridet JL, Malhotra SK, Privat A, Gage FH. Reactive
astrocytes: cellular and molecular cues to biological
function. Trends Neurosci 1997; 20(12): 570-7.
9. Middeldorp J, Hol EM. GFAP in health and disease.
Prog Neurobiol 2011; 93(3): 421-43.
10. Esmaeili-Mahani S, Ebrahimi B, Abbasnejad M,
Rasoulian B, Sheibani V. Satureja khuzestanica
prevents the development of morphine analgesic
tolerance through suppression of spinal glial cell
activation in rats. J Nat Med 2015; 69(2): 165-70.
11. Ward J, Rosenbaum C, Hernon C, McCurdy CR,
Boyer EW. Herbal medicines for the management of
opioid addiction: Safe and effective alternatives to
conventional pharmacotherapy? CNS Drugs 2011;
25(12): 999-1007.
12. Afzal M, Al-Hadidi D, Menon M, Pesek J, Dhami
MS. Ginger: An ethnomedical, chemical and
pharmacological review. Drug Metabol Drug
Interact 2001; 18(3-4): 159-90.
13. Rasmussen P. Ginger--Zingiber officinale Roscoe,
Zingiberaceae. J Prim Health Care 2011; 3(3): 235-6.
14. Rahmani AH, Shabrmi FM, Aly SM. Active
ingredients of ginger as potential candidates in the
prevention and treatment of diseases via modulation
of biological activities. Int J Physiol Pathophysiol
Pharmacol 2014; 6(2): 125-36.
15. Wohlmuth H Phytochemistry and pharmacology of
plants from the ginger family, Zingiberaceae [PhD
Thesis]. Lismore, NSW, Australia: Southern Cross
University; 2008.
16. Ali BH, Blunden G, Tanira MO, Nemmar A. Some
phytochemical, pharmacological and toxicological
properties of ginger (Zingiber officinale Roscoe): A
review of recent research. Food Chem Toxicol 2008;
46(2): 409-20.
17. Grzanna R, Lindmark L, Frondoza CG. Ginger--an
herbal medicinal product with broad antiinflammatory actions. J Med Food 2005; 8(2): 125-32.
18. Torkzadeh-Mahani S, Nasri S, Esmaeili-Mahani S.
Ginger (zingiber officinale roscoe) prevents
?????????? Torkzadeh-Mahani et al.
Addict Health, Spring 2019; Vol 11 , No 2 71, 04 April
morphine-induced addictive behaviors in conditioned
place preference test in rats. Addict Health 2014;
6(1-2): 65-72.
19. Milligan ED, Watkins LR. Pathological and
protective roles of glia in chronic pain. Nat Rev
Neurosci 2009; 10(1): 23-36.
20. Lazriev IL, Kiknadze GI, Kutateladze II, Nebieridze
MI. Effect of morphine on the number and branching
of astrocytes in various regions of rat brain. Bull Exp
Biol Med 2001; 131(3): 248-50.
21. Schwarz JM, Hutchinson MR, Bilbo SD. Early-life
experience decreases drug-induced reinstatement of
morphine CPP in adulthood via microglial-specific
epigenetic programming of anti-inflammatory IL-10
expression. J Neurosci 2011; 31(49): 17835-47.
22. Cooper ZD, Jones JD, Comer SD. Glial modulators:
A novel pharmacological approach to altering the
behavioral effects of abused substances. Expert Opin
Investig Drugs 2012; 21(2): 169-78.
23. Choi DK, Koppula S, Suk K. Inhibitors of microglial
neurotoxicity: Focus on natural products. Molecules
2011; 16(2): 1021-43.
24. Dedov VN, Tran VH, Duke CC, Connor M, Christie
MJ, Mandadi S, et al. Gingerols: A novel class of
vanilloid receptor (VR1) agonists. Br J Pharmacol
2002; 137(6): 793-8.
25. Svensson CI, Marsala M, Westerlund A, Calcutt NA,
Campana WM, Freshwater JD, et al. Activation of
p38 mitogen-activated protein kinase in spinal
microglia is a critical link in inflammation-induced
spinal pain processing. J Neurochem 2003; 86(6):
26. Cui Y, Chen Y, Zhi JL, Guo RX, Feng JQ, Chen PX.
Activation of p38 mitogen-activated protein kinase
in spinal microglia mediates morphine
antinociceptive tolerance. Brain Res 2006; 1069(1):
27. Jung HW, Yoon CH, Park KM, Han HS, Park YK.
Hexane fraction of Zingiberis Rhizoma Crudus
extract inhibits the production of nitric oxide and
proinflammatory cytokines in LPS-stimulated BV2
microglial cells via the NF-kappaB pathway. Food
Chem Toxicol 2009; 47(6): 1190-7.
28. Wang Z, Ma W, Chabot JG, Quirion R. Cell-type
specific activation of p38 and ERK mediates
calcitonin gene-related peptide involvement in
tolerance to morphine-induced analgesia. FASEB J
2009; 23(8): 2576-86.
29. 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(11):
30. Horvath RJ, DeLeo JA. Morphine enhances
microglial migration through modulation of P2X4
receptor signaling. J Neurosci 2009; 29(4):
31. Raghavendra V, Tanga FY, DeLeo JA. Attenuation
of morphine tolerance, withdrawal-induced
hyperalgesia, and associated spinal inflammatory
immune responses by propentofylline in rats.
Neuropsychopharmacology 2004; 29(2): 327-34.