Antihyperalgesic Effects of Clomipramine and Tramadol in a Model of Posttraumatic Trigeminal Neuropathic Pain in Mice

Aims: To develop a behavioral model in mice that is capable of mimicking some distinctive symptoms of human posttraumatic trigeminal neuropathic pain such as spontaneous pain, cold allodynia, and chemical/inflammatory hyperalgesia, and to use this model to investigate the antinociceptive effects of clomipramine and tramadol, two drugs used for the treatment of neuropathic pain. Methods: A partial tight ligature of the right infraorbital nerve by an intraoral access or a sham procedure was performed. Fourteen days later, mice were subcutaneously injected with saline or drugs and the spontaneous nociceptive behavior, as well as the responses to topical acetone and to formalin or capsaicin injected into the ipsilateral vibrissal pad, were assessed. Data were analyzed by ANOVA. Results: Neuropathic mice exhibited an increased spontaneous rubbing/scratching of the ipsilateral vibrissal pad, together with enhanced responses to cooling (acetone) and the chemical irritants (formalin, capsaicin). Clomipramine and tramadol produced an antihyperalgesic effect on most of these nociceptive responses, but tramadol was ineffective on capsaicin-induced hyperalgesia. Conclusion: Nociceptive responses in this neuropathic pain model in mice exhibited a pattern consistent with the pain described by posttraumatic trigeminal neuropathic patients. The selective antihyperalgesic effect obtained with two commonly used drugs for treating neuropathic pain confirms the validity of this preclinical model.

clomipramine;infraorbital nerve ligation;mice;neuropathic trigeminal pain;tramadol

1. Macfarlane TV, Blinkhorn AS, Davies RM, Kincey J, Worthington HV. Oro-facial pain in the community: Prevalence and associated impact. Community Dent Oral Epidemiol 2002; 30:52–60.

2. Koopman JS, Dieleman JP, Huygen FJ, de Mos M, Martin CG, Sturkenboom MC. Incidence of facial pain in the general population. Pain 2009;147:122–127.

3. Bennett GJ. Neuropathic pain in the orofacial region: Clinical and research challenges. J Orofac Pain 2004;18:281–286.

4. Zakrzewska JM. Medical management of trigeminal neuropathic pains. Expert Opin Pharmacother 2010;11:1239–1254.

5. Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988;33:87–107.

6. Eide PK, Rabben T. Trigeminal neuropathic pain: Pathophysiological mechanisms examined by quantitative assessment of abnormal pain and sensory perception. Neurosurgery 1998;43: 1103–1110.

7. Rodríguez-Lozano FJ, Sanchez-Pérez A, Moya-Villaescusa MJ, Rodríguez-Lozano A, Sáez-Yuguero MR. Neuropathic orofacial pain after dental implant placement: Review of the literature and case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;109:e8–12.

8. Svensson P, Baad-Hansen L, Thygesen T, Juhl GI, Jensen TS. Overview on tools and methods to assess neuropathic trigeminal pain. J Orofac Pain 2004;18:332–338.

9. Baad-Hansen L, List T, Jensen TS, Svensson P. Increased pain sensitivity to intraoral capsaicin in patients with atypical odontalgia. J Orofac Pain 2006;20:107–114.

10. Attal N, Cruccu G, Haanp;138;;138; M, et al. EFNS guidelines on pharmacological treatment of neuropathic pain. Eur J Neurol 2006;13:1153–1169.

11. Mattia C, Coluzzi F. Tramadol. Focus on musculoskeletal and neuropathic pain. Minerva Anestesiol 2005;71:565–584.

12. Raboisson P, Dallel R. The orofacial formalin test. Neurosci Biobehav Rev 2004;28:219–226.

13. Pelissier T, Pajot J, Dallel R. The orofacial capsaicin test in rats: Effects of different capsaicin concentrations and morphine. Pain 2002;96:81–87.

14. Chichorro JG, Zampronio AR, Souza GE, Rae GA. Orofacial cold hyperalgesia due to infraorbital nerve constriction injury in rats: Reversal by endothelin receptor antagonists but not non-steroidal anti-inflammatory drugs. Pain 2006;123:64–74.

15. Kobayashi A, Shinoda M, Sessle BJ, et al. Mechanisms involved in extraterritorial facial pain following cervical spinal nerve injury in rats. Mol Pain 2011;7:12.

16. 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.

17. Imamura Y, Kawamoto H, Nakanishi O. Characterization of heat-hyperalgesia in an experimental trigeminal neuropathy in rats. Exp Brain Res 1997;116:97–103.

18. Nakagawa K, Takeda M, Tsuboi Y, et al. Alteration of primary afferent activity following inferior alveolar nerve transection in rats Mol Pain 2010;6:9.

19. Mogil J. Animal models of pain: Progress and challenges. Nat Rev Neurosci 2009;10:283–294.

20. Piao ZG, Cho I-H, Park CK, et al. Activation of glia and microglial p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury. Pain 2006;121:219–231.

21. Seino H, Seo K, Maeda T, Someya G. Behavioural and histological observations of sensory impairment caused by tight liga-tion of the trigeminal nerve in mice. J Neurosci Methods 2009; 181:67–72.

22. Xu M, Aita M, Chavkin C. Partial infraorbital nerve ligation as a model of trigeminal nerve injury in the mouse: Behavioral, neural, and glial reactions. J Pain 2008;9:1036–1048.

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

24. Clavelou P, Dallel R, Orliaguet T, Woda A, Raboisson P. The orofacial formalin test in rats: effects of different formalin concentrations. Pain 1995;62:295–301.

25. Luccarini P, Childeric A, Gaydier AM, Voisin D, Dallel R. The orofacial formalin test in the mouse: A behavioral model for studying physiology and modulation of trigeminal nociception. J Pain 2006;7:908–914.

26. Patapoutian A, Tate S, Woolf CJ. Transient receptor potential channels: Targeting pain at the source. Nat Rev Drug Discov 2009;8:55–68.

27. Eschalier A, Fialip J, Varoquaux O, Makambila MC, Marty H, Bastide P. Pharmacokinetic patterns of repeated administration of antidepressants in animals. I. Implications for antinociceptive action of clomipramine in mice. J Pharmacol Exp Ther 1988;245:963–968.

28. Ardid D, Guilbaud G. Antinociceptive effects of acute and “chronic” injections of tricyclic antidepressant drugs in a new model of mononeuropathy in rats. Pain 1992;49:279–287.

29. Raffa RB, Wild KD, Mosberg HI, Porreca F. Thermodynamic analysis of the temperature dependence of the dissociation constant of naloxone at opioid delta receptors in the mouse isolated vas deferens. J Pharmacol Exp Ther 1992;263: 1030–1035.

30. Ide S, Minami M, Ishihara K, Uhl GR, Sora I, Ikeda K. Mu opioid receptor-dependent and independent components in effects of tramadol. Neuropharmacology 2006;51:651–658.

31. Guneli E, Karabay Yavasoglu NU, Apaydin S, Uyar M, Uyar M. Analysis of the antinociceptive effect of systemic administration of tramadol and dexmedetomidine combination on rat models of acute and neuropathic pain. Pharmacol Biochem Behav 2007;88:9–17.

32. Jähkel M, Oehler J, Schumacher HE. Influence of nootropic and antidepressive drugs on open field and running wheel behavior in spontaneously high and low active mice. Pharmacol Biochem Behav 1994;49:263–269.

33. Pinardi G, Pelissier T, Miranda HF. Interactions in the antinociceptive effect of tramadol in mice: An isobolographic analysis. Eur J Pain 1998;2:343–350.

34. Romero A, Miranda HF, Puig MM. Analysis of the opioidopioid combinations according to the nociceptive stimulus in mice. Pharmacol Res 2010;61:511–518.

35. Carasso RL, Yehuda S, Streifler M. Clomipramine and amitriptyline in the treatment of severe pain. Int J Neurosci 1979;9:191–194.

36. Cabañero D, Campillo A, Célérier E, Romero A, Puig MM. Pronociceptive effects of remifentanil in a mouse model of postsurgical pain: Effect of a second surgery. Anesthesiology 2009; 111:1334–1345.

37. Luhmann HJ, Huston JP, Hasenöhrl RU. Contralateral increase in thigmotactic scanning following unilateral barrelcortex lesion in mice. Behav Brain Res 2005;157:39–43.

38. Choi Y, Yoon YW, Na HS, Kim SH, Chung JM. Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Pain 1994;59:369–376.

39. Mansikka H, Zhao C, Sheth RN, Sora I, Uhl G, Raja SN. Nerve injury induces a tonic bilateral mu-opioid receptor-mediated inhibitory effect on mechanical allodynia in mice. Anesthesiology 2004;100:912–921.

40. LaBuda CJ, Donahue R, Fuchs PN. Enhanced formalin nociceptive responses following L5 nerve ligation in the rat reveals neuropathy-induced inflammatory hyperalgesia. Pain 2001; 94:59–63.

41. Anderson LC, Vakoula A, Veinote R. Inflammatory hypersensitivity in a rat model of trigeminal neuropathic pain. Arch Oral Biol 2003;48:161–169.

42. Bach-Rojecky L. Analgesic effect of caffeine and clomipramine: A possible interaction between adenosine and serotonin systems. Acta Pharm 2003;53:33–39.

43. Fasmer OB, Hunskaar S, Hole K. Antinociceptive effects of serotonergic reuptake inhibitors in mice. Neuropharmacology 1989;28:1363–1366.

44. Rosland JH, Hunskaar S, Hole K. Modification of the an-tinociceptive effect of morphine by acute and chronic administration of clomipramine in mice. Pain 1988;33:349–355.

45. Ardid D, Alloui A, Brousse G, et al. Potentiation of the antinociceptive effect of clomipramine by a 5-HT(1A) antagonist in neuropathic pain in rats. Br J Pharmacol 2001;132: 1118–1126.

46. Idänpään-Heikkilä JJ, Guilbaud G. Pharmacological studies on a rat model of trigeminal neuropathic pain: Baclofen, but not carbamazepine, morphine or tricyclic antidepressants, attenuates the allodynia-like behaviour. Pain 1999;79:281–290.

47. McCleane G. Antidepressants as analgesics. CNS Drugs 2008;22:139–156.

48. Ansuategui M, Naharro L, Feria M. Noradrenergic and opioidergic influences on the antinociceptive effect of clomipramine in the formalin test in rats. Psychopharmacology (Berl) 1989;98:93–96.

49. Ardid D, Jourdan D, Mestre C, Villanueva L, Le Bars D, Eschalier A. Involvement of bulbospinal pathways in the antinociceptive effect of clomipramine in the rat. Brain Res 1995; 695:253–256.

50. Eschalier A, Montastruc JL, Devoize JL, Rigal F, Gaillard Plaza G, Pechadre JC. Influence of naloxone and methysergide on the analgesic effect of clomipramine in rats. Eur J Pharmacol 1981;74:1–7.

51. Valverde O, Micó JA, Maldonado R, Mellado M, Gibert Rahola J. Participation of opioid and monoaminergic mechanisms on the antinociceptive effect induced by tricyclic antidepressants in two behavioural pain tests in mice. Prog Neuropsychopharmacol Biol Psychiatry 1994;18: 1073–1092.

52. Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol 2007;151:737–748.

53. Maj J, Stala L, Górka Z, Adamus A. Comparison of the pharmacological actions of desmethylclomipramine and clomipramine. Psychopharmacology (Berl) 1982;78:165–169.

54. Hwang J, Zheng LT, Ock J, et al. Inhibition of glial inflammatory activation and neurotoxicity by tricyclic antidepressants. Neuropharmacology 2008;55:826–834.

55. Okada-Ogawa A, Suzuki I, Sessle BJ, et al. Astroglia in medullary dorsal horn (trigeminal spinal subnucleus caudalis) are involved in trigeminal neuropathic pain mechanisms. J Neurosci 2009;29:11161–11171.

56. Munro G. Pharmacological assessment of the rat formalin test utilizing the clinically used analgesic drugs gabapentin, lamotrigine, morphine, duloxetine, tramadol and ibuprofen: influence of low and high formalin concentrations. Eur J Pharmacol 2009;605:95–102.

57. Oliva P, Aurilio C, Massimo F, et al. The antinociceptive effect of tramadol in the formalin test is mediated by the serotonergic component. Eur J Pharmacol 2002;445:179–185.

58. Christoph T, Kögel B, Strassburger W, Schug SA. Tramadol has a better potency ratio relative to morphine in neuropathic than in nociceptive pain models. Drugs R D 2007;8:51–57.

59. Altis K, Schmidtko A, Angioni C, et al. Analgesic efficacy of tramadol, pregabalin and ibuprofen in menthol-evoked cold hyperalgesia. Pain 2009;147:116–121.

60. Marincsák R, Tóth BI, Czifra G, Szabó T, Kovács L, Bíró T. The analgesic drug, tramadol, acts as an agonist of the transient receptor potential vanilloid-1. Anesth Analg 2008; 106:1890–1896.

61. Wang JT, Chung CC, Whitehead RA, Schwarz SK, Ries CR, MacLeod BA. Effects of local tramadol administration on peripheral glutamate-induced nociceptive behaviour in mice. Can J Anaesth 2010;57:659–663.

62. Raffa RB, Friderichs E, Reimann W, et al. Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol. J Pharmacol Exp Ther 1993;267:331–340.

63. Zhao CS, Tao YX, Tall JM, Donovan DM, Meyer RA, Raja SN. Role of micro-opioid receptors in formalin-induced pain behavior in mice. Exp Neurol 2003;184:839–845.