title: Proglumide enhances the antinociceptive effect of cyclooxygenase inhibitors in diabetic rats in the formalin test.
abstract: 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.
authors.affiliation: División Académica Multidisciplinaria de Comalcalco, Universidad Juárez Autónoma de Tabasco, Comalcalco, Mexico.
authors.forename: Deysi Y
authors.initials: DY
authors.lastname: Bermúdez-Ocaña
authors.forename: Hidemi
authors.initials: H
authors.lastname: Aguilar-Mariscal
authors.forename: Teresa Ramón
authors.initials: TR
authors.lastname: Frías
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Blé-Castillo
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Flores-Murrieta
authors.forename: Juan C
authors.initials: JC
authors.lastname: Díaz-Zagoya
authors.forename: Vinicio
authors.initials: V
authors.lastname: Granados-Soto
authors.forename: Isela Esther
authors.initials: IE
authors.lastname: Juárez-Rojop
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004357:Drug Synergism; D005557:Formaldehyde / Q000009:adverse effects*; D020910:Ketorolac / Q000494:pharmacology; D008297:Male; D000077239:Meloxicam; D011377:Proglumide / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors; D013843:Thiazines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D011949:Receptors, Cholecystokinin; D013843:Thiazines; D013844:Thiazoles; D005557:Formaldehyde; D011451:Prostaglandin-Endoperoxide Synthases; D011377:Proglumide; D000077239:Meloxicam; D020910:Ketorolac