Role of ATP-sensitive K + channels in the antinociception induced by non-steroidal anti-inflammatory drugs in streptozotocin-diabetic and non-diabetic rats Mario I. Ortiz a, b, ⁎, Gilberto Castañeda-Hernández c , Jeannett A. Izquierdo-Vega a , Manuel Sánchez-Gutiérrez a , Héctor A. Ponce-Monter a , Vinicio Granados-Soto d a Área Académica de Medicina del Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Pachuca, Hidalgo, Mexico b Servicio de Investigación del Hospital del Niño DIF, Pachuca, Hidalgo, Mexico c Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México, D.F., Mexico d Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados (Cinvestav), Sede Sur, México, D.F., Mexico abstract article info Article history: Received 1 November 2011 Received in revised form 16 March 2012 Accepted 24 March 2012 Available online 21 April 2012 Keywords: Diclofenac Indomethacin Lumiracoxib Meloxicam Metamizol K + channels Glibenclamide Glipizide Streptozotocin-diabetic rat Formalin test There is evidence that systemic sulfonylureas block diclofenac-induced antinociception in normal rat, suggesting that diclofenac activates ATP-sensitive K + channels. However, there is no evidence for the sys- temic interaction between different non-steroidal anti-inflammatory drugs (NSAIDs) and sulfonylureas in streptozotocin (STZ)-diabetic rats. Therefore, this work was undertaken to determine whether two sulfonyl- ureas, glibenclamide and glipizide, have any effect on the systemic antinociception that is induced by diclofenac (30 mg/kg), lumiracoxib (56 mg/kg), meloxicam (30 mg/kg), metamizol (56 mg/kg) and indo- methacin (30 mg/kg) using the non-diabetic and STZ-diabetic rat formalin test. Systemic injections of NSAIDs produced dose-dependent antinociception during the second phase of the test in both non-diabetic and STZ- diabetic rats. Systemic pretreatment with glibenclamide (10 mg/kg) and glipizide (10 mg/kg) blocked diclofenac-induced systemic antinociception in the second phase of the test (P b 0.05) in both non-diabetic and STZ-diabetic rats. In contrast, pretreatment with glibenclamide or glipizide did not block lumiracoxib-, meloxicam-, metamizol-, and indomethacin-induced systemic antinociception (P > 0.05) in both groups. Re- sults showed that systemic NSAIDs are able to produce antinociception in STZ-diabetic rats. Likewise, data suggest that diclofenac, but not other NSAIDs, activated K + channels to induce its systemic antinociceptive effect in the non-diabetic and STZ-diabetic rat formalin test. © 2012 Elsevier Inc. All rights reserved. 1. Introduction More than 20 years ago, Ocaña et al. (1990) demonstrated that the ATP sensitive K + channels inhibitor glibenclamide blocked the antinociceptive effect induced by morphine in mice. Since then, in- vestigations have attempted to show the role of these channels in antinociceptive and antihyperalgesic activities of non-steroidal anti- inflammatory drugs (NSAIDs), antidepressants, opioids, anticonvul- sants and other analgesic drugs (Ocaña et al., 2004). In this regard, it was found that the NSAIDs diclofenac and lumiracoxib are able to activate ATP sensitive K + channels to produce an antinociceptive ef- fect at peripheral level in the rat (Ortiz et al., 2002, 2003a; Alves et al., 2004; Lozano-Cuenca et al., 2005). Likewise, our group evidenced that sulfonylureas did not block the peripheral antinociceptive activ- ity of the NSAIDs meloxicam, indomethacin and metamizol (Ortiz et al., 2003a, 2003b, 2005), demonstrating the lack of participation at peripheral level of the ATP sensitive K + channels. With respect to the probable participation of ATP-sensitive K + channels at systemic level, it was revealed that the antinociceptive effects of oral diclofenac in the rat were abolished by spinal administration of glibenclamide (Ortiz et al., 2008). These results suggest that oral diclofenac achieves sufficient concentrations to induce antinociceptive effects involving the ATP-sensitive K + channel in the spine. Finally, systemically deliv- ered glibenclamide has been shown to reverse the antinociceptive and antihyperalgesic effects that are produced by systemic administration of diclofenac, suggesting that ATP-sensitive K + channels participate in these effects (Ortiz and Castañeda-Hernández, 2006; León-Reyes et al., 2009). However, the probable participation of ATP-sensitive K + channels in the systemic antinociceptive effects of other NSAIDs has not been evaluated. Mellitus Diabetes (MD) is a chronic disease that occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces (Campbell, 2009). Hyperglyce- mia is a common effect of uncontrolled diabetes and over time leads to serious damage to many of the body's systems, especially nerves and blood vessels (Guastella and Mick, 2009). The treatment of Pharmacology, Biochemistry and Behavior 102 (2012) 163–169 ⁎ Corresponding author at: Laboratorio de Farmacología, Área Académica de Medicina del Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Eliseo Ramírez Ulloa 400, Col. Doctores, Pachuca, Hgo., 42090, Mexico. Tel./fax: +52 77 1717 2000x2361. E-mail address: mario_i_ortiz@hotmail.com (M.I. Ortiz). 0091-3057/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pbb.2012.03.032 Contents lists available at SciVerse ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh