COMPARATIVE STUDY OF THE ANTINOCICEPTIVE ACTION OF AMITRIPTYLINE WITH FLUOXETINE AND EVALUATION OF THEIR PROBABLE MECHANISM OF THIS ACTION IN ALBINO MICE
Objective: The aim of our study was to compare the anti-nociceptive action of amitriptyline with fluoxetine and evaluation of their probable mechanism of anti-nociceptive action by observing their individual interactions with morphine, naloxone, yohimbine, and ondansetron.
Methods: Albino mice weighing 25-35 grams were taken and divided into 12 groups. Group A-Control(distilled water), Group B-amitriptyline 20 mg/kg, Group C-fluoxetine 20 mg/kg, Group D-morphine 5 mg/kg, Group E-amitriptyline 20 mg/kg+ morphine 5 mg/kg, Group F-amitriptyline 20 mg/kg+ naloxone 3 mg/kg, Group G-amitriptyline 20 mg/kg+ yohimbine 2 mg/kg, Group H-amitriptyline 20 mg/kg+ ondansetron 0.1 mg/kg, Group I-fluoxetine 20 mg/kg+morphine 5 mg/kg, Group J-fluoxetine 20 mg/kg+ naloxone 3 mg/kg, Group K-fluoxetine 20 mg/kg+ yohimbine 2 mg/kg and Group L-fluoxetine 20 mg/kg+ ondansetron 0.1 mg/kg. Hot plate method and acetic acid writhing test were used to assess central and peripheral analgesic activity respectively.
Results: Both the amitriptyline and fluoxetine-treated animals showed significantly increased reaction time in a hot plate (p<0.05) and a significant decrease in the number of wriths in acetic acid writhing test (p<0.05), when compared with control. Animals in amitriptyline group showed significantly higher reaction time and less number of wriths when compared to fluoxetine group. Morphine increased, while naloxone, yohimbine and ondansetron decreased the reaction time in a hot plate. In the acetic acid writhing test, a number of wriths significantly decreased when co-treated with morphine and increased when co-treated with naloxone, yohimbine and ondansetron.
Conclusion: It is concluded that amitriptyline is a better antinociceptive agent than fluoxetine. Their central and peripheral mechanism of antinociception both involve opioidergic, serotonergic and noradrenergic pathway.
2. Guyton AC, Hall JE. eds. Somatic Sensations: II. Pain, Headache, and Thermal Sensations. Textbook of medical Physiology. 11th ed. Noida: Elsevier Saunders; 2008. p. 598-609.
3. Rang HP, Dale MM, Ritter JM, Flower RJ. editors. Analgesic Drugs. Rang and Dale's Pharmacology. 6th ed. China: Churchill livingstone; 2009. p. 588-609.
4. Pertovaara A. Noradrenergic pain modulation. Prog Neurobiol 2006;80:53-83.
5. Paul D, Yao D, Zhu P, Minor LD. 5-hydroxytryptamine 3 (5-HT3) receptors mediate spinal 5-HT antinociception: an antisense approach. J Pharmacol Exp Ther 2001;298:674-8.
6. Bardin L, Lavarenne J, Eschalier A. Serotonin receptor subtypes involved in the spinal antinociceptive effect of 5-HT in rats. Pain 2000;86:11-8.
7. Kesim M, Duman EN, Kadioglu M. The different roles of 5-HT2, and 5-HT3 receptors on the antinociceptive effect of paroxetine in chemical stimuli in mice. J Pharmacol Sci 2005;97:61-6.
8. Gray AM, Pache DM, Sewel RD. Do alpha2-adrenoreceptors play an integral role in the antinociceptive mechanism of action of antidepressant compounds. Eur J Pharmacol 1999;378:161-8.
9. Schreiber S, Pick CG. From selective to highly selective SSRIs; a comparision of the antinociceptive properties of Fluoxetine, Fluvoxamine, Citalopram and Escitalpram. Eur Neuropsychopharmacol 2006;16:464-8.
10. Rani PU, Naidu MU, Prasad VB. An evaluation of antidepressants in rheumatic pain conditions. Anaesth Anal 1996;83:371-5.
11. Michael N, Bharti Chogtu B, Eesha BR. Comparing the antinociceptive effects of Amitriptiline and Fluoxetine in rats. Indian J Pharmacol 2011;43 Suppl:128-9.
12. Rathmell JP, Fields HL. Pain: pathophysiology and management. In: LongoHarrison's principles of Internal Medicine. Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. editors. Harrison's principles of Internal Medicine. 18th ed. New Delhi: McGrawHill; 2012. p. 93-101.
13. Paudel KR, Das BP, Rauniar GP. Antinociceptive effect of amitrptyline in mice in acute pain models. Indian J Exp Biol 2007;45:529-31.
14. Ghelardini C, Galeotti N, Bartolini A. Antinociception induced by Amitriptyline and Imipramine is mediated by alpha-2A-adrenoceptors. Japan J Pharmacol 2000;82:130-7.
15. Singh VP, Jain NK, Kulkarni SK. On the antinociceptive effect of Fluoxetine, a selective serotonin reuptake inhibitor. Brain Res 2001;915:218-26.
16. Sureshkumar S, Sivakumar T, Chandrasekhar MJN. Investigating the anti-inflammatory and analgesic effect of leaves of wedelia chinensis (osbeck) Merr. In standard experimental animal. Iran J Pharm Res 2006;2:123-9.
17. Sounvoravong S, Nakashima MN, Wada M. Modification of the antiallodynic and antinociceptive effects of morphine by the peripheral and central action of fluoxetine in a neuropathic mice model. Acta Biol Hung 2007;58:369-79.
18. Morales L, Perez Garcia C, Alguacil LF. Effects of yohimbine on the antinociceptive and place conditioning effects of the opioid agonist in rodents. Br J Pharmacol 2001;133:172-8.
19. Ghule RS, Venkatanarayanan SR, Thakre SP. Analgesic activity of Cuscutacampestris Yuncker a parasitic plant grown on neriumindicum mill. J Adv Pharm Educ Res 2011;1:45-51.
20. Tiwari A, Singh A. Synthesis and antinociceptive activity of novel mannich base derivatives of some new fused 3,5-pyrazolidinedione. J Adv Pharm Technol Res 2014;5:41-7.
21. Kulkarni SK. Practical pharmacology and clinical pharmacy. 1st ed. Delhi; Vallabh Prakasan; 2009.
22. Medhi B, Prakash A. Practical manual of experimental and clinical pharmacology. 1st ed. New delhi; Jaypee brothers medical publishers pvt. Ltd; 2010.
23. Ghosh MN. Fundamentals of experimental pharmacology. 5th ed. Kolkata: Hilton and Company; 2011.
24. Singh H, Banerjee S, Karan S, Chatterjee TK. Antinociceptive activity of Freeze dried powdered morinda citrifolia L. fruit. Int J Pharm Pharm Sci 2013;5:608-11.
25. Churruca I, Portillo MP, Zumalabe JM. Fluoxetine alters mu opioid receptor expression in obese Zucker rat extrahypothalamic regions. Int J Neurosci 2006;116:289-98.
26. Tocque B, Albouz S, Boutry JM. Desipramine elicits the expression of opiate receptors and sulfogalactosylceramide synthesis in rat C6 glioma cells. J Neurochem 1984;42:1101-6.
27. Hamon M, Gozlan H, Bourgoin S. Opioid receptors and neuropeptides in the CNS in rats treated chronically with Amoxapine or Amitriptyline. Neuropharmacol 1987;26:531-9.
28. Gray AM, Spancer PSJ, Sewell RDE. The involvement of the opioidergic system in the antinociceptive mechanism of action of antidepressant compounds. Br J Pharmacol 1998;124:669-74.
29. Onali P, Dedoni S, Olianas MC. Direct agonistic activity of tricyclic antidepressants at distinct opioid receptor subtypes. J Pharmacol Exp Ther 2010;332:255-65.
30. Sawynok J, Essar MJ, Reid AR. Antidepressants as analgesics: an overview of central and peripheral mechanisms of action. J Psychiatry Neurosci 2001;26:21-9.
31. Kurlekar PN, Bhatt JD. Study of the antinociceptive activity of fluoxetine and its interaction with morphine and naloxone in mice. Ind J Pharmacol 2004;36:369-72.
32. Sikka P, Kaushik S, Kumar G. Study of antinociceptive activity of SSRIs (fluoxetine and escitaopram) and atypical antidepressants (Venlafaxine and Mirtazepine) and their interaction with morphine and Naloxone in mice. J Pharm Bioallied Sci 2011;3:412-6.
33. Cui M, Feng Y, McAdoo DJ. Periaqueductal grey matter stimulation-induced inhibition of nociceptive dorsal horn neurons in rats is associated with the release of norepinephrine, serotonin, and amino acids. J Pharmacol Exp Ther 1999;289:868-76.
34. Zangen A, Nakash R, Yadid G. Serotonin-mediated increases in the extracellular levels of beta-endorphin in the arcuate nucleus and nucleus accumbens: a microdialysis study. J Neurochem 1999;73:2569-74.
35. Berrocoso E, Sanchez-Blazquez P, Garzon J. Opiates as antidepressants. Curr Pharm Des 2009;15:1612-22.
36. Pran YZ, Li DP, Chen SR. Activation of delta opioid receptor excites spinally projecting Locus ceruleus neurons through inhibiting GABAergic inputs. J Neurophysiol 2002;88:2675-83.
37. Kapitzke D, Vetter I, Cabot PJ. Endogenous opioid analgesia in peripheral tissues and the clinical implications for pain control. Ther Clin Risk Manag 2005;1:279-97.
38. Stein C, Lang LJ. Peripheral mechanisms of opioid analgesia. Curr Opinion Pharmacol Neurosci 2009;9:3-8.
39. Konate K, Zerbo P, Ouedraogo M. Antinociceptive properties in rodents and the possibility of using polyphenol-rich fractions from sidaurens L. (Malvaceae) against of dental caries bacteria. Ann Clin Microbiol Antimicrob 2013;12:4.
40. Salwe K, Mirunalini R, Mano J, Manimekalai K. Evaluation of analgesic activity of murraya koenigii and coriandrum sativum leaves extract in animal model. Asian J Pharm Clin Res 2018;11:328-31.