Neuropharmacology and Analgesia Sildenafil and glyceryl trinitrate reduce tactile allodynia in streptozotocin-injected rats Claudia I. Araiza-Saldaña, Héctor I. Rocha-González, Mónica Ambriz-Tututi, Gabriela Castañeda-Corral, Nadia L. Caram-Salas, Enrique Hong, Vinicio Granados-Soto ⁎ Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados (Cinvestav), Sede Sur, México, D.F., Mexico abstract article info Article history: Received 19 October 2009 Received in revised form 8 December 2009 Accepted 6 January 2010 Available online 13 January 2010 Keywords: Diabetes Tactile allodynia Phosphodiesterase 5 Sildenafil The possible antiallodynic effect of phosphodiesterase 5 inhibitor sildenafil and nitric oxide donor glyceryl trinitrate as well as the changes in phosphodiesterase 5A2 mRNA expression in dorsal root ganglion and spinal cord of allodynic diabetic rats was assessed. Diabetes was induced by streptozotocin (50 mg/kg, i.p.) in male Wistar rats. Streptozotocin injection produced hyperlglycemia, polydipsia, polyphagia and polyuria as well as long-term tactile allodynia (12 weeks) and a reduction of phosphodiesterase 5A2 mRNA expression in spinal cord of diabetic rats. Systemic administration of sildenafil (1–5.6 mg/kg, i.p.) reduced tactile allodynia in a dose-dependent manner in diabetic rats. Likewise, glyceryl trinitrate patches (0.2 mg/h) also reduced tactile allodynia in diabetic rats. Moreover, both drugs reversed streptozotocin-induced phosphodiesterase 5A2 mRNA expression reduction. Our results indicate that glyceryl trinitrate and sildenafil reduce tactile allodynia in diabetic rats suggesting that nitric oxide and cyclic GMP supply is an important step in their mechanism of action of these drugs in diabetic animals. Data suggest that nitric oxide donors (as glyceryl trinitrate) and drugs which increase cyclic GMP levels (as sildenafil) could have a role in the pharmacotherapy of tactile allodynia in diabetic patients. © 2010 Elsevier B.V. All rights reserved. 1. Introduction Diabetes mellitus is one of the most common chronic medical conditions affecting over 100 million people worldwide (Wild et al., 2004). Diabetes leads to several complications including retinopathy, nephropathy and neuropathy. Diabetic neuropathy is the most common complication affecting more than 50% of the diabetic patients. Pain associated with diabetes can occur either spontaneously or as a result of exposure to only mildly painful stimuli (hyperalgesia) or to stimuli not normally perceived as painful (allodynia). The underlying mechanisms of persistent pain in diabetes remain poorly understood. Accordingly, the treatment of pain in diabetic patients is frequently unsatisfactory. Anticonvulsants, tricyclic antidepressants and opioids have become the mainstay in the treatment of diabetic neuropathic pain (Sindrup and Jensen, 1999; Cole, 2007). However, these drugs often have a limited effect or may cause intolerable side effects. Therefore, other options of treatment are needed. There is evidence that glyceryl trinitrate may produce analgesic effects in different pain states in humans. Topical administration of this drug reduces pain in patients with chronic non-insertional Achilles tendinopathy (Kane et al., 2008) and chronic anal fissure (Ahmad et al., 2007). Moreover, transdermal glyceryl trinitrate de- creases pain intensity in women with primary dysmenorrhea (Moya et al., 2000). Of note, glyceryl trinitrate provides a significant im- provement in painful diabetic neuropathy in human beings (Rayman et al., 2003; Agrawal et al., 2007). However, support from animal models of diabetic neuropathy is still missing. On the other hand, sildenafil, an inhibitor of cyclic GMP-specific phosphodiesterase 5, has been shown to be effective in the clinical management of erectile dysfunction in non-diabetic (Langtry and Markham, 1999) and diabetic (Rendell et al., 1999) patients. Previous studies from our laboratory (Mixcotal-Zecuatl et al., 2000; Asomoza- Espinosa et al., 2001; Ambriz-Tututi et al., 2005; Araiza-Saldaña et al., 2005) and others (Jain et al., 2001, 2003; Patil et al., 2003, Patil et al., 2004a,b; Vale et al., 2007; Yoon et al., 2008) have consistently found that sildenafil produces antinociception in several pain models in non-diabetic rats and mice after local peripheral, intrathecal and systemic administration. In addition, there is evidence that sildenafil reduces chemical and mechanical hyperalgesia in diabetic animals (Patil et al., 2004a,b; Araiza-Saldaña et al., 2005). Its efficacy on diabetes-induced tactile allodynia is currently unknown. Therefore, the purpose of this study was to assess the effect of sildenafil (cyclic GMP enhancer) and glyceryl trinitrate (nitric oxide donor) on diabetes-induced tactile allodynia as well as the possible changes in phosphodiesterase 5A2 mRNA expression in diabetic rats. European Journal of Pharmacology 631 (2010) 17–23 ⁎ Corresponding author. Departamento de Famacobiología, Cinvestav, Sede Sur, Calz. Tenorios 235, Col. Granjas Coapa, Deleg. Tlalpan, 14330, México, D.F., Mexico. Tel.: + 52 55 5483 2868; fax: +52 55 5483 2863. E-mail address: vgranados@prodigy.net.mx (V. Granados-Soto). 0014-2999/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2010.01.001 Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar