Effect of glibenclamide on antinociceptive effects of antidepressants Hajhashemi V and Amin B CLINICS 2011;66(2):321-325 Figure 3 - The antinociceptive effect of i.p. administration of maprotiline and maprotiline plus glibenclamide on licking behavior during phase 2 of formalin test. Bars are mean ¡ SEM for six animals. * significantly different from control group (p,0.001). channels and therefore we do not expect K+ channel blockers alone to exert hyperalgesis or analgesia. As many other experimental works, our work has some limitations. One of them is the use of only one dose (5 mg/kg) of glibenclamide alone for a control group and it would be better to use doses of 10 and 15 mg/kg of this drug. In the present study, glibenclamide could diminish antinociceptive effect produced by amitriptyline a non selec- tive inhibitor of noradrenaline-serotonin and fluvoxamine a selective serotonin reuptake inhibitor and it shows that ATP-dependent K+ channels have some role in antinocicep- tive activity of these antidepressants. Meanwhile inhibition of analgesic effect of fluvoxamine was greater than that of amitriptyline. Glibenclamide even at the highest dose could not inhibit maprotiline-induced analgesia which shows that ATP-dependent K+ channels do not mediate its analgesia. Although Casis et al. showed that maprotiline block delayed rectifier potassium current in ventricular myocytes, but further studies are needed to clarify the exact role of these currents in neuronal pathways affected by maprotiline.27 It has been shown that different mechanisms are responsible for analgesic effects observed with antidepres- sants. The main action seems to be an increase in content of noradrenalin and serotonin in synaptic space followed by increased activity on their receptors. Serotonin is a neurotransmitter with complex actions that causes both inhibition and augmentation of pain perception depending on the subtype of receptor which is stimulated. Until now different subtypes of 5-HT receptors have been known, including 5-HT1 to 5-HT7. Earlier investigations have indicated that stimulation of 5-HT1A receptor, a Gi-protein- coupled receptor which is located throughout of central nervous system (CNS) especially dorsal raphe nucleus contributes in antinociception by descending pathways.28- 31 Stimulation of this receptor by 5-HT leads to increase in potassium current and finally decrease in intracellular cAMP content.28 Robels and coworkers indicated involve- ment of ATP sensitive potassium channels in analgesic action of 5-HT1A agonists.32 With respect to our results and previous data,15 we can suppose that stimulation of 5-HT1A 324 receptors by elevated 5-HT in synaptic space by antide- pressants acting on reuptake of 5-HT, might partially participate in analgesic activity of these drugs through affecting on ATP dependent potassium channels. Therefore opening of these channels have a major role in antinocicep- tive effects of them. Further work by applying 5HT1A agonists and antagonists could help to have a better understanding of these pathways in antinociceptive effect of antidepressants. It is also concluded that ATP-sensitive potassium chan- nels may have no role in antinociceptive effect of maproti- line as a selective reuptake inhibitor because it has not been affected by a potassium channel blocker glibencla- mide. ACKNOWLEDGEMENTS This research was supported by research council of the Isfahan University of Medical Sciences, Isfahan, Iran REFERENCES 1. D’Mello R, Dickenson AH. Spinal cord mechanisms of pain. Br J Anaesth. 2008;101:8–16. 2. Chong MS, Brandner B. Neuropathic agents and pain. New strategies. Biomed Pharmacother. 2006;60:318–22. 3. Mochizucki D. Serotonin and noradrenaline reuptake inhibitors in animal models of pain. Hum Psychopharmacol Clin Exp. 2004;19:15–9. 4. Richeimer SH, Bajwa ZH, Kahraman SS, Ransil BJ, Warfield CA. Utilisation patterns of tricyclic antidepressants in a multidisciplinary pain clinic: a survey. Clin J Pain. 1997;13:324–9. 5. Acton J, Mckenna JE, Melzack R. Amitriptyline produces analgesia in the formalin pain test. Exp Neurol. 1992;117:94–6. 6. Mico JA, Ardid D, Berrocoso E, Eschalier A. Antidepressants and pain. Trends Pharmacol Sci. 2006;27:348–54. 7. Yoshimura M, Furue H. Mechanisms for the anti-nociceptive actions of the descending noradrenergic and serotonergic systems in the spinal cord. J Pharmacol Sci. 2006;101:107–17. 8. Sawynok J. Adenosine receptor activation and nociception. Eur J Pharmacol. 1998;347:1-11. 9. Pareek SS, Chopde CT, Thahur Desai PA. Adenosine enhances analgesic effect of tricyclic antidepressants. Indian J Pharmacol. 1994;26:159-61. 10. Pancrazio JJ, Kamatchi GL, Roscoe AK, Lynch CIII. Inhibition of neuronal Na+ channels by antidepressant drugs. J Pharmacol Exp. 1998;284:208–14.