Article Data

  • Views 223
  • Dowloads 65

Original Research

Open Access

Antinociceptive Effects of Mirtazapine, Pregabalin, and Gabapentin After Chronic Constriction Injury of the Infraorbital Nerve in Rats

  • Kunihiro Nakai1,2
  • Aya Nakae3,*,
  • Ryota Hashimoto4,5
  • Takashi Mashimo3
  • Ko Hosokawa2

1Department of Plastic & Reconstructive Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan

2Department of Plastic Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan

3Department of Anesthesiology & Intensive Care, Osaka University, Graduate School of Medicine, Osaka, Japan

4Molecular Research Center for Children’s Mental Development, United Graduate School of Child, Osaka University, Osaka, Japan

5Department of Psychiatry, Graduate School of Medicine, Osaka University, Osaka, Japan

DOI: 10.11607/jop.1105 Vol.28,Issue 1,March 2014 pp.61-67

Published: 30 March 2014

*Corresponding Author(s): Aya Nakae E-mail: anakae@anes.med.osaka-u.ac.jp

Abstract

Aims: To clarify the antiallodynic effects of the α2-adrenergic receptor antagonist mirtazapine compared with those of gabapentin and pregabalin in a rat model of orofacial neuropathic pain. Methods: Mirtazapine (10, 30, and 100 µg), gabapentin (10, 30, and 100 µg), and pregabalin (3, 10, and 30 µg) were administered intrathecally to eight male Sprague-Dawley rats with orofacial neuropathic pain induced by chronic constriction injury of the infraorbital nerve that had been carried out 2 weeks previously. Stimulation using von Frey filaments (1.0 to 15.0 g) applied to skin innervated by the injured infraorbital nerve enabled the measurement of mechanical thresholds 0 to 180 minutes after drug injection. Time-course data for the dose-response effects were analyzed using two-way analysis of variance and the post-hoc Tukey-Kramer multiple-comparison test. Results: Intrathecal administration of not only gabapentin and pregabalin but also mirtazapine reversed the lowered mechanical nociceptive thresholds produced by the nerve injury. The ED50 (95% confidence interval) was (in µg) 49.00 (39.71–58.29) for mirtazapine, 54.84 (46.12–63.56) for gabapentin, and 13.47 (11.24–15.69) for pregabalin. Conclusion: Intraspinal administration of either mirtazapine, gabapentin, or pregabalin reverses the lowered facial mechanical thresholds produced in a rat model of trigeminal neuropathic pain.

Keywords

allodynia; gabapentin; mirtazapine; orofacial pain; pregabalin

Cite and Share

Kunihiro Nakai,Aya Nakae,Ryota Hashimoto,Takashi Mashimo,Ko Hosokawa. Antinociceptive Effects of Mirtazapine, Pregabalin, and Gabapentin After Chronic Constriction Injury of the Infraorbital Nerve in Rats. Journal of Oral & Facial Pain and Headache. 2014. 28(1);61-67.

References

1. Benoliel R, Eliav E, Tal M. No sympathetic nerve sprouting in rat trigeminal ganglion following painful and non-painful infraorbital nerve neuropathy. Neurosci Lett 2001;297:151–154.

2. Latremoliere A, Mauborgne A, Masson J, et al. Differential im-plication of proinflammatory cytokine interleukin-6 in the development of cephalic versus extracephalic neuropathic pain in rats. J Neurosci 2008;28:8489–8501.

3. Chung K, Kim HJ, Na SK, Park MJ, Chung JM. Abnormalities of sympathetic innervation in the area of an injured peripheralnerve in a rat model of neuropathic pain. Neurosci Lett 1993;162:85–88.

4. McLachlan EM, Jänig W, Devor M, Michaelis M. Peripheral nerve injury triggers noradrenergic sprouting within dorsal rootganglia. Nature 1993;363:543–546.

5. Ramer MS, Bisby MA. Rapid sprouting of sympathetic axons in dorsal root ganglia of rats with a chronic constriction injury. Pain 1997;70:237–244.

6. Bongenhielm U, Boissonade FM, Westermark A, Robinson PP, Fried K. Sympathetic nerve sprouting fails to occur in the trigeminal ganglion after peripheral nerve injury in the rat. Pain 1999;82:283–288.

7. Matthews B. Autonomic mechanisms in oral sensations. Proc Finn Dent Soc 1989;85:365–373.

8. Swerdlow M. Anticonvulsivant drugs and chronic pain. Clin Neuropharamacol 1984;7:51–82.

9. Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010;17:1113–1123.

10. Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: Evidence-based recommendations. Pain 2007;132:237–251.

11. Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain 2010;150: 573–581.

12. Richelson E, Pfenning M. Blockage by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes: Most antidepressants selectively block norepinephrine uptake. Eur J Pharmacol 1984;104:277–286.

13. Yokogawa F, Kiuchi Y, Ishikawa Y, et al. An investigation of monoamine receptors involved in antinociceptive effects of antidepressants. Anesth Analg 2002;95:163–168.

14. Hwang AS, Wilcox GL. Analgesic properties of intrathecally administered heterocyclic antidepressants. Pain 1987;28:343–355.

15. Sawyok J, Esser MJ, Reid AR. Peripheral antinociceptive actions of desipramine and fluoxetine in an inflammatory and neuropathic pain test in the rat. Pain 1999;82:149–158.

16. Wang H, Xie YF, Chiang CY, Dostrovsky JO, Sessle BJ. Centrala- adrenoceptors contribute to mustard oil-induced central sensitization in the rat medullary dorsal horn. Neuroscience 2013;236:244–252.

17. Puzantian T. Mirtazapine, an antidepressant. Am J Health Syst Pharm 1998;55:44–49.

18. Davis MP, Dickerson ED, Pappagallo M, Benedetti C, Grauer PA, Lycan J. Mirtazapine: Heir apparent to amitriptyline? Am J Hosp Palliat Care 2001;18:42–46.

19. deBoer TD. The pharmacologic profile of mirtazapine. J Clin Psychiatry 1996;57:19–25.

20. Gorman JM. Mirtazapine: Clinical overview. J Clin Psychiatry 1999;60:9–13.

21. Yaksh TL, Progrel JW, Lee YW, Chaplan SR. Reversal of nerve ligation-induced allodynia by spinal alpha-2 adrenoceptor agonists. J Pharmacol Exp Ther 1995;272:207–214.

22. Obata H, Saito S, Sasaki M, Ishizaki K, Goto F. Antiallodynic effect of intrathecally administered 5-HT2 agonists in rats with nerve ligation. Pain 2001;90:173–179.

23. Nakai K, Nakae A, Oba S, Mashimo T, Ueda K. 5-HT2C receptor agonists attenuate pain-related behavior in a rat model of trigeminal neuropathic pain. Eur J Pain 2010;14:999–1006.

24. Hwang JH, Yaksh TL. Effect of subarachnoid gabapentin on tactile-evoked allodynia in a surgically induced neuropathic pain model in the rat. Reg Anesth 1997;22:249–256.

25. Kayser V, Christensen D. Antinociceptive effect of systemic gabapentin in mononeuropathic rats, depends on stimulus characteristics and level of test integration. Pain 2000;88:53–60.

26. Chen SR, Xu Z, Pan HL. Stereospecific effect of pregabalin on ectopic afferent discharges and neuropathic pain induced by a sciatic nerve ligation in rats. Anesthesiology 2001; 95:1473–1479.

27. Krzyzanowska A, Pittolo S, Cabrerizo M, et al. Assessing nociceptive sensitivity in mouse model of inflammatory and neuropathic trigeminal pain. J Neurosci Methods 2011;201:46–54.

28. Grabow TS, Dougherty PM. Gabapentin produces dose-dependent antinociception in the orofacial formalin test in the rat. Reg Anesth Pain Med 2002;27:277–283.

29. Narita N, Kumar N, Cherkas PS, et al. Systemic pregabalin attenuates sensorimotor responses and medullary glutamate release in inflammatory tooth pain model. Neuroscience 2012;218:359–366.

30. Cao Y, Wang H, Chiang C, Dostrovsky JO, Sessle BJ. Pregabalin suppresses nociceptive behavior and central sensitization in a rat trigeminal neuropathic pain model. J Pain 2013;14:193–204.

31. Shibuta K, Suzuki I, Shinoda M, et al. Organization of hyperactive microglial cells in trigeminal spinal subnucleus caudalis and upper cervical spinal cord associated with orofacial neuropathic pain. Brain Res 2012;1451:74–86.

32. Suzuki I, Tsuboi Y, Shinoda M, et al. Involvement of ERK phosphorylation of trigeminal spinal subnucleus caudalis neurons in thermal hypersensitivity in rats with infraorbital nerve injury. PLoS One 2013;8(2):e57278.

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

34. MacGregor EA, Hackshaw A. Prevalence of migraine on each day of the natural menstrual cycle. Neurology 2004;63:351–353.

35. Nag S, Mokha SS. Activation of a2-adrenoceptors in the trigeminal region produces sexspecific modulation of nociception in the rat. Neuroscience 2006;142:1255–1262.

36. Vos BP, Strassman AM, Maciewicz, RJ. Behavioral evidence of trigeminal neuropathic pain following chronic constriction injury to the rat’s infraorbital nerve. J Neurosci 1994;14:2708–2723.

37. Marfurt CF, Rajchert DM. Trigeminal primary afferent projections to non-trigeminal areas of the rat central nervous system. J Comp Neurol 1991;303:489–511.

38. Obata H, Saito S, Koizuka S, Nishikawa K, Goto F. The monoamine-mediated antiallodynic effects of intrathecally administered milnacipran, a serotonin noradrenalin reuptake inhibitor, in a rat model of neuropathic pain. Anesth Analg 2005; 100:1406–1410.

39. Boer TD, Nefkens F, Helvoirt AV. The alpha2-adrenoceptor antagonist Org 3770 enhances serotonin transmission in vivo. Eur J Phamacol 1994;253:R5–R6.

40. Baraban JM, Aghajanian GK. Suppression of firing activity of 5- HT neurons in the dorsal raphe by alphaadrenoceptor an-tagonists. Neuropharmacology 1980;19:355–363.

41. Alba-Delgado C, Mico JA, Sanchez-Blazquez P, Berrocoso E. Analgesic antidepressants promote the responsiveness of locus coeruleus neurons to noxious stimulation: Implications for neuropathic pain. Pain 2012;153:1438–1449.

42. Bomholt SF, Mikkelsen JD, Blackburn-Munro G. Antinociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent and neuropathic pain. Neuropharmacology 2005;48:252–263.

43. Schreiber S, Rigai T, Katz Y, Pick CG. The antinociceptive effect of mirtazapine in mice is mediated through serotonergic, noradrenergic and opioid mechanisms. Brain Res Bull 2002; 58:601–605.

44. Gilron I, Flatters SJL. Gabapentin and pregabalin for the treatment of neuropathic pain: A review of laboratory and clinical evidence. Pain Res Manag 2006;11:16A–29A.

45. Fink K, Dooley DJ, Meder WP, et al. Inhibition of neuronal Ca(2+) influx by gabapentin and pregabalin in the human neocortex. Neuropharmacology 2002;42:229–236.

46. Dooley DJ, Mieske CA, Borosky SA. Inhibition of K(+)-evoked glutamate release from rat neocortical and hippocampal slices by gabapentin. Neurosci Lett 2000;280:107–110.

47. Xiao WH, Bennett GJ. Gabapentin has an antinociceptive effect mediated via a spinal site action in a rat model of painful peripheral neuropathy. Analgesia 1996;2:267–273.

48. Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: An evidence based proposal. Pain 2005;118:289–305.

49. Rabe-Jablonska J, Miller A. Links between pain and depression. Psychiatr Pol 2005;39:7–20.

50. Magini G. The use of antidepressants in the treatment of chronic pain: A review of the current evidence. Drugs 1991; 42:730–748.

51. Davis MP, Khawam E, Pozuelo L, Lagman R. Management of symptoms associated with advanced cancer: Olanzapine and mirtazapine. Expert Rev Anticancer Ther 2002;2:365–376.

52. Thase ME. Antidepressant treatment of the depressed patient with insominia. J Clin Psychiatry 1999;60:28–31.

53. Kast KE. Mirtazapine may be useful in treating nausea and insomnia of cancer chemotherapy. Support Care Cancer 2001; 9:469–470.

54. Gelenberg AJ, McGahuey C, Laukes C, et al. Mirtazapine sub-stitution in SSRI-induced sexual dysfunction. J Clin Psychiatry 2000;61:356–360.

55. Hoes MJ, Zeijpveld JH. Mirtazapine as treatment for serotonin syndrome. Pharmacopsychiatry 1996;29:81.

56. Holms KJ, Markham A. Mirtazapine: A review of its use in major depression. Drugs 1999;57:607–631.

57. Freynhagen R, Muth-Selbach U, Lipfert P, et al. The effect of mirtazapine in patients with chronic pain and concomitant depression. Curr Med Res Opin 2006;22:257–264.

58. Brambilla P, Cipriani A, Hotopf M, Barbui C. Side-effect profile of fluoxetine in comparison with other SSRIs, tricyclic and newer antidepressants: A meta-analysis of clinical trial data. Pharmacopsychiatry 2005;38:69–77.

Abstracted / indexed in

Science Citation Index (SCI)

Science Citation Index Expanded (SCIE)

BIOSIS Previews

Scopus

Cumulative Index to Nursing and Allied Health Literature (CINAHL)

Submission Turnaround Time

Conferences

Top