Analgesic effect of α-terpineol on neuropathic pain induced by chronic constriction injury in rat sciatic nerve: Involvement of spinal microglial cells and inflammatory cytokines

Document Type: Original Article

Authors

1 Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

2 Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences

10.22038/ijbms.2019.14028

Abstract

Objective(s): Neuropathic pain is a prevalent and debilitating neurological disorder. Ample evidence indicates that microglial cells and inflammatory cytokines are involved in the pathogenesis of neuropathic pain. Alpha-terpineol is a monoterpenoid alcohol with inhibitory effect on inflammatory cytokines. The main purpose of this study was to evaluate the effect of α-terpineol on neuropathic pain in rats.
Materials and Methods: Chronic constriction injury (CCI) model was utilized to induce neuropathic pain in male Wistar rats. The rats were randomly divided into control, sham, α-terpineol, and gabapentin groups. Normal saline, α-terpineol (25, 50, and 100 mg/kg), and gabapentin (100 mg/kg) were administered intraperitoneally in the above-mentioned groups once daily for 14 days post-CCI. Behavioral tests, including Von Frey, acetone, and Hargreaves were used to assess mechanical allodynia, cold allodynia, and hyperalgesia in rats. Iba1 immunostaining and ELISA procedures were used to assess the activation of microglial cells and inflammatory cytokines level.
Results: The results showed that α-terpineol (50 and 100 mg/kg) significantly attenuated mechanical allodynia, cold allodynia, and hyperalgesia in the neuropathic rats. The analgesic effect of α-terpineol (100 mg/kg) was comparable with that of gabapentin as a standard antineuropathic pain drug. In addition, α-terpineol (25, 50 and 100 mg/kg) significantly decreased the number of Iba1-positive cells and diminished the concentration of IL-1β and TNF-α in the spinal tissue.
Conclusion: It was ultimately attained that α-terpineol attenuates neuropathic pain through the suppression of the microglial cells and reduction of inflammatory cytokine levels in the spinal cord of rats. 

Keywords


1. Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, et al. Neuropathic pain redefinition and a grading system for clinical and research purposes. Neurology 2008; 70: 1630–1635.

2. Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D, et al. Neuropathic pain. Nat Rev Dis Primers 2017; 3: 17002.

3.  Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 2015; 14: 162–173.

4. Kazemi A, Rahmati M, Eslami R, Sheibani V. Activation of neurotrophins in lumbar dorsal root probably contributes to neuropathic pain after spinal nerve ligation. Iran J Basic Med Sci 2017; 20: 29–35.

5. Salter MW, Stevens B. Microglia emerge as central players in brain disease. Nat Med 2017; 23:1018–1027.

6. Kiguchi N, Kobayashi Y, Kishioka S. Chemokines and cytokines in neuroinflammation leading to neuropathic pain. Curr Opin Pharmacol 2012; 12: 55–61.

7. Gui WS, Wei X, Mai CL, Murugan M, Wu LJ, Xin WJ, et al. Interleukin-1β overproduction is a common cause for neuropathic pain, memory deficit, and depression following peripheral nerve injury in rodents. Mol Pain 2016; 12: 1744806916646784.

8. Clark AK, Old EA, Malcangio M. Neuropathic pain and cytokines: current perspectives. J Pain Res 2013; 6: 803–814.

9. Kremer M, Salvat E, Muller A, Yalcin I, Barrot M. Antidepressants and gabapentinoids in neuropathic pain: mechanistic insights. Neuroscience 2016; 338: 183–206.

10. Kanter M. Effects of Nigella sativa and its major constituent, thymoquinone on sciatic nerves in experimental diabetic neuropathy. Neurochem Res 2008; 33: 87–96.

11. Park HJ, Lee HG, Kim YS, Lee JY, Jeon JP, Park C, et al. Ginkgo biloba extract attenuates hyperalgesia in a rat model of vincristine-induced peripheral neuropathy. Anesth Analg 2012; 115: 1228–1233.

12. Gilles M, Zhao J, An M, Agboola S. Chemical composition and antimicrobial properties of essential oils of three Australian Eucalyptus species. Food Chem 2010; 119: 731–737.

13. de Sousa DP, Quintans Jr L, de Almeida RN. Evolution of the anticonvulsant activity of α-terpineol. Pharm Biol 2007; 45: 69–70.

14. Moghimi M, Parvardeh S, Zanjani TM, Ghafghazi S. Protective effect of α-terpineol against impairment of hippocampal synaptic plasticity and spatial memory following transient cerebral ischemia in rats. Iran J Basic Med Sci 2016; 19: 960–969.

15. Parvardeh S, Moghimi M, Eslami P, Masoudi A. α-Terpineol attenuates morphine-induced physical dependence and tolerance in mice: role of nitric oxide. Iran J Basic Med Sci 2016; 19: 201–208.

16. Moreira MR, Cruz GM, Lopes MS, Albuquerque AA, Leal-Cardoso JH. Effects of terpineol on the compound action potential of the rat sciatic nerve. Braz J Med Biol Res 2001; 34: 1337–1340.

17. Quintans-Júnior LJ, Oliveira MG, Santana MF, Santana MT, Guimarães AG, Siqueira JS, et al. α-Terpineol reduces nociceptive behavior in mice. Pharm Biol 2011; 49: 583–586.

18. Safaripour S, Nemati Y, Parvardeh S, Ghafghazi S, Fouladzadeh A, Moghimi M. Role of l‐arginine/SNAP/NO/cGMP/KATP channel signalling pathway in antinociceptive effect of α‐terpineol in mice. J Pharm Pharmacol 2018; 70: 507–515.

19. Tjølsen A, Berge OG, Hunskaar S, Rosland JH, Hole K. The formalin test: an evaluation of the method. Pain 1992; 51: 5–17.

20. de Oliveira MG, Marques RB, de Santana MF, Santos AB, Brito FA, Barreto EO, et al. α-terpineol reduces mechanical hypernociception and inflammatory response. Basic Clin Pharmacol Toxicol 2012; 111: 120–125.

21. Trinh HT, Lee IA, Hyun YJ, Kim DH. Artemisia princeps Pamp. Essential oil and its constituents eucalyptol and α-terpineol ameliorate bacterial vaginosis and vulvovaginal candidiasis in mice by inhibiting bacterial growth and NF-κB activation. Planta Med 2011; 77: 1996–2002.

22. Amin B, Poureshagh E, Hosseinzadeh H. The effect of verbascoside in neuropathic pain induced by chronic constriction injury in rats. Phytother Res 2016; 30: 128–135.

23. de Oliveira MG, Brito RG, Santos PL, Araújo-Filho HG, Quintans JS, Menezes PP, et al. α-Terpineol, a monoterpene alcohol, complexed with β-cyclodextrin exerts antihyperalgesic effect in animal model for fibromyalgia aided with docking study. Chem Biol Interact 2016; 254: 54–62.

24. Naderi Y, Sabetkasaei M, Parvardeh S, Zanjani TM. Neuroprotective effect of minocycline on cognitive impairments induced by transient cerebral ischemia/reperfusion through its anti-inflammatory and anti-oxidant properties in male rat. Brain Res Bull 2017; 131: 207–213.

25. Naderi Y, Sabetkasaei M, Parvardeh S, Zanjani TM. Neuroprotective effect of minocycline on cognitive impairments induced by transient cerebral ischemia/reperfusion through its anti-inflammatory and anti-oxidant properties in male rat. Brain Res Bull 2017; 131: 207–213.

26. Wang J, Li L, Wang Z, Cui Y, Tan X, Yuan T, et al. Supplementation of lycopene attenuates lipopolysaccharide-induced amyloidogenesis and cognitive impairments via mediating neuroinflammation and oxidative stress. J Nutr Biochem 2018; 56:16–25.

27. Jaggi AS, Jain V, Singh N. Animal models of neuropathic pain. Fundam Clin Pharmacol 2011; 25: 1–28.

28. Tsuda M. Microglia in the spinal cord and neuropathic pain. J Diabetes Investig 2016; 7: 17–26.

29. Inoue K, Tsuda M. Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential. Nat Rev Neurosci 2018; 19: 138–152.

30. Wodarski R, Clark AK, Grist J, Marchand F, Malcangio M. Gabapentin reverses microglial activation in the spinal cord of streptozotocin‐induced diabetic rats. Eur J Pain 2009; 13: 807–811.

31. Lee BS, Jun IG, Kim SH, Park JY. Intrathecal gabapentin increases interleukin-10 expression and inhibits pro-inflammatory cytokine in a rat model of neuropathic pain. J Korean Med Sci 2013; 28: 308–314.

32. Aira Z, Buesa I, Salgueiro M, Bilbao J, Aguilera L, Zimmermann M, et al. Subtype-specific changes in 5-HT receptor-mediated modulation of C fibre-evoked spinal field potentials are triggered by peripheral nerve injury. Neuroscience 2010; 168: 831–841.

33. Song Z, Meyerson BA, Linderoth B. Spinal 5-HT receptors that contribute to the pain-relieving effects of spinal cord stimulation in a rat model of neuropathy. Pain 2011; 152: 1666–1673.

34. Mixcoatl-Zecuatl T, Flores-Murrieta FJ, Granados-Soto V. The nitric oxide-cyclic GMP-protein kinase G-K+ channel pathway participates in the antiallodynic effect of spinal gabapentin. Eur J Pharmacol 2006; 531: 87–95.

35. Parvardeh S, Sabetkasaei M, Moghimi M, Masoudi A, Ghafghazi S, Mahboobifard F. Role of L-arginine/NO/cGMP/KATP channel signaling pathway in the central and peripheral antinociceptive effect of thymoquinone in rats. Iran J Basic Med Sci 2018; 21: 625–33.