Neuropharmacology and Analgesia Proglumide enhances the antinociceptive effect of cyclooxygenase inhibitors in diabetic rats in the formalin test Deysi Y. Bermúdez-Ocaña a,b , Hidemi Aguilar-Mariscal c , Teresa Ramón Frías a,c , Jorge L. Blé-Castillo c , Francisco J. Flores-Murrieta d,e , Juan C. Díaz-Zagoya c,f , Vinicio Granados-Soto g , Isela Esther Juárez-Rojop c, ⁎ a División Académica Multidisciplinaria de Comalcalco, Universidad Juárez Autónoma de Tabasco, Comalcalco, Tabasco, Mexico b Hospital de Alta Especialidad “Dr. Gustavo A. Rovirosa Pérez”, Villahermosa, Tabasco, Mexico c Centro de Investigación y Posgrado, División Académica de Ciencias de la Salud, Universidad Juárez Autónoma de Tabasco, Villahermosa, Tabasco, Mexico d Instituto Nacional de Enfermedades Respiratorias, Secretaría de Salud, México, D.F., Mexico e Sección de Estudios de Posgrado e Investigación, Escuela Superior de medicina, Instituto Politécnico Nacional, México, D.F., Mexico f Departamento de Bioquímica, Facultad de Medicina, UNAM, México, D.F., Mexico g Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, Sede Sur, México, D.F., Mexico abstract article info Article history: Received 21 December 2010 Received in revised form 25 March 2011 Accepted 14 April 2011 Available online 1 May 2011 Keywords: Diabetes Meloxicam Ketorolac Cholecystokinin Proglumide The purpose of this study was to assess the effect of the non-selective cholecystokinin receptor antagonist proglumide on the antinociceptive activity of ketorolac and meloxicam in non-diabetic and diabetic rats. Streptozotocin (60 mg/kg) injection caused hyperglycemia which was maintained for 2 weeks. Formalin- evoked flinching was increased in diabetic rats as compared to non-diabetic rats. Local peripheral ipsilateral, but not contralateral, administration of ketorolac and meloxicam produced antinociception in non-diabetic and diabetic rats. However, the antinociceptive effect of both drugs was significantly reduced in diabetic animals. Proglumide was ineffective by itself and it did not affect the antinociception induced by the cyclooxygenase inhibitors in non-diabetic rats. Contrariwise, proglumide reduced formalin-induced nociception and it increased ketorolac- or meloxicam-induced antinociception in diabetic rats. These results suggest that peripheral cholecystokinin plays an important role in diabetes-induced sensitization as well as in the reduction of the antinociceptive effects of ketorolac and meloxicam in diabetic rats. The combination of cholecystokinin receptor antagonists and ketorolac or meloxicam may be a useful strategy to reduce nociception in diabetic patients. © 2011 Elsevier B.V. All rights reserved. 1. Introduction Diabetes mellitus is one of the most common metabolic disorders affecting over 100 million people worldwide (Wild et al., 2008). In this condition, a proportion of diabetic patients describe abnormal sensations such as paresthesia, spontaneous pain, allodynia (pain responses to innocuous stimuli) and hyperalgesia (exaggerated pain responses to noxious stimuli). Anticonvulsants, tricyclic antidepres- sants and opioids have become the mainstay in the treatment of chronic diabetic pain. However, these drugs often have a limited effect or may cause intolerable side effects (Chong and Hester, 2007; O'Connor, 2009). Therefore, other options of treatment are needed. The effect of cyclooxygenase inhibitors in diabetic rats is controversial. There is evidence that intrathecal administration of cyclooxygenase-2 but not cyclooxygenase-1 or cyclooxygenase-3 inhibitors attenuates mechan- ical hyperalgesia in diabetic rats (Matsunaga et al., 2007). However, several studies have reported that cyclooxygenase-1 and cyclooxygenase- 2 inhibitors reduce streptozotocin-induced diabetic hyperalgesia (Bujalska et al., 2008; Kimura and Kontani, 2009). In contrast, it has also been shown that systemic or intrathecal administration of non-selective cyclooxygenase inhibitors did not have an effect on streptozotocin- induced mechanical hyperalgesia (Ahlgren and Levine, 1993; Calcutt and Chaplan, 1997). Thus, it seems that systemic or intrathecal inhibition of cyclooxygenase-2 reduces nociception in diabetic animals. Accordingly, a recent study showed that spinal cyclooxygenase-2 protein levels increased at 4 weeks after streptozotocin injection (Freshwater et al., 2002). The participation of cyclooxygenase-1 is still under investigation. Several pharmacological studies have reported a loss of antinocicep- tive potency of morphine in streptozotocin-treated rats (Courteix et al., 1994, 1998; Gul et al., 2000; Malcangio and Tomlinson, 1998; Raz et al., 1988; Torres-López et al., 2007). Spinal or systemic cholecystokinin diminishes antinociception mediated by morphine (Faris et al., 1983; Noble et al., 1999), whereas cholecystokinin receptor antagonists elicit an enhancement of morphine-induced antinociception at spinal and peripheral levels (Coudoré-Civiale et al., 2000a, 2000b; Dourish et al., 1990; Kamei and Zushida, 2001; O'Neill et al., 1989; Noble et al., 1995; European Journal of Pharmacology 664 (2011) 8–13 ⁎ Corresponding author at: Centro de Investigación y Posgrado, División Académica de Ciencias de la Salud, Universidad Juárez Autónoma de Tabasco, Av. Gregorio Méndez 2838-A, Col. Tamulté, 86150, Villahermosa, Tabasco, Mexico. Tel.: +52 993 3581581, +52 993 3540292. E-mail address: iselajua22@yahoo.com.mx (I.E. Juárez-Rojop). 0014-2999/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2011.04.044 Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar