DOI:10.1590/S1807-59322011000200023 CLINICS 2011;66(2):321-325 BASIC RESEARCH Effect of glibenclamide on antinociceptive effects of antidepressants of different classes Valiollah Hajhashemi,I,II Bahareh AminII I Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran. II Department of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran. OBJECTIVES: The purpose of this work was to determine whether the intraperitoneal administration of glibenclamide as a KATP channel blocker could have an effect on the antinociceptive effects of antidepressants with different mechanisms of action. METHODS: Three antidepressant drugs, amitriptyline as a dual-action, nonselective inhibitor of noradrenaline and a serotonin reuptake inhibitor, fluvoxamine as a selective serotonin reuptake inhibitor and maprotiline as a selective noradrenaline reuptake inhibitor, were selected, and the effect of glibenclamide on their antinociceptive activities was assessed in male Swiss mice (25-30 g) using a formalin test. DISCUSSION: None of the drugs affected acute nociceptive responses during the first phase. Amitriptyline (5, 10 mg/ kg), maprotiline (10, 20 mg/kg) and fluvoxamine (20 and 30 mg/kg) effectively inhibited pain induction caused by the second phase of the formalin test. Glibenclamide (5 mg/kg) alone did not alter licking behaviors based on a comparison with the control group. However, the pretreatment of animals with glibenclamide (10 and 15 mg/kg) partially reversed the antinociceptive effects of fluvoxamine but not those of maprotiline. In addition, the highest dose of glibenclamide (15 mg/kg) partially prevented the analgesic effect of amitriptyline. CONCLUSION: Therefore, it seems that adenosine triphosphate-dependent potassium channels have a major role in the analgesic activity of amitriptyline and fluvoxamine. KEYWORDS: Antidepressants; Antinociceptive; ATP dependent K+ channels. Hajhashemi V, Amin B. Effect of glibenclamide on antinociceptive effects of antidepressants of different classes. Clinics. 2011;66(2):321-325. Received for publication on September 9, 2010; First review completed on October 8, 2010; Accepted for publication on November 8, 2010 E-mail: vhajhashemi@gmail.com Tel.: 0098 311 7922630 INTRODUCTION After an annoyance by a noxious stimulus, peripheral nociceptor fibers translate sensory information into the dorsal horn of spinal cord and then through central ascending fibers to brainstem, thalamus and cerebral cortex for processing and perception of pain. With potentiation of descending inhibitory outputs including direct pathways [via gamma aminobutyric acid (GABA), opioids and cannabinoids] and indirect pathways (via 5-Hydroxytrip- tamine, noradrenaline, and acetylcholine) and modulation of sodium and calcium channels, we can overcome and relieve pain syndromes.1,2 For many years antidepressants have been shown to possess analgesic activity in different kinds of pain models in animals. They are frequently used in chronic pain conditions including diabetic neuropathy, post-herpetic neuralgia, headaches, cancer, chronic back pain and phantom limb pain and their effects are unrelated to their Copyright 2011 CLINICS – This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non- commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 321 antidepressant effects because the doses used for analgesic actions are lower than antidepressant effects.3-6 These drugs can increase noradrenaline (NA) and/or 5-hydroxytripta- mine (5-HT) concentration in the extracellular space via inhibition of reuptake by blocking their transporters. Antidepressants are classified into different classes, some of them nonselectively block the reuptake of and 5-HT including tricyclic antidepressants such as amitriptyline, clomipramine and newer ones such as duloxetine and milnacipran. Some of them are selective for (SNRIs) such as maprotiline, or selective for 5-HT (SSRIs) such as fluoxetine, sertraline and fluvoxamine.5-7 However it has been shown that blockade of neurotrans- mitter reuptake is not the only mechanism involved in and there are additional central and peripheral mechanisms that contribute to either their antinociceptive actions or even adverse effects of these drugs. Inhibition of adenosine reup- take is one of the peripheral mechanisms in antinociceptive effects of these drugs.8,9 Other potential mechanisms are inhibiting the functions of several other receptors including 5- HT2C, 5-HT3 and nicotinic acetylcholine receptors and affect- ing ion channels, by blocking the activity of voltage-gated Na+ and Ca2+ channels or opening of K+channels.10-15 It has been shown that antidepressant drugs can potentiate analgesic effect of opioids by increasing the level of opioids.16,17