Involvement of cholecystokinin in peripheral nociceptive sensitization during diabetes in rats as revealed by the formalin response.
The possible pronociceptive role of peripheral cholecystokinin (CCK-8) as well as CCK(A) and CCK(B) receptors in diabetic rats was assessed. Subcutaneous injection of 0.5% formalin induced a greater nociceptive behavior in diabetic than in non-diabetic rats. Moreover, local peripheral injection of CCK-8 (0.1-100 microg) significantly increased 0.5% formalin-induced nociceptive activity in diabetic, but not in non-diabetic, rats. This effect was restricted to the formalin-injected paw as administration of CCK-8 into the contralateral paw was ineffective. Local peripheral administration of CCK-8, in the absence of formalin injection, produced a low level of, but significant increase in, flinching behavior in diabetic compared to non-diabetic rats. In addition, local peripheral administration of the non-selective CCK receptor antagonist proglumide (1-100 microg), CCK(A) receptor antagonist lorglumide (0.1-100 microg) or CCK(B) receptor antagonist CR-2945 (0.1-100 microg), but not vehicle or contralateral administration of CCK receptor antagonists, significantly reduced 0.5% formalin-induced flinching in diabetic rats. CR-2945 was the most effective drug in this condition. These effects were not observed in non-diabetic rats. The local peripheral pronociceptive effect of CCK-8 (100 microg) was significantly reduced by proglumide (100 microg), lorglumide (100 microg), and CR-2945 (100 microg). Results suggest that diabetes-induced peripheral sensitization could be due to a local peripheral release of CCK-8, which in turn would act on CCK(B), mainly but also in CCK(A), receptors located on the primary afferent neurons.
Juárez-Rojop
Isela E
IE
Laboratorio Mecanismos del Dolor, Centro de Investigación y Posgrado, División Académica de Ciencias de la Salud, Universidad Juárez Autónoma de Tabasco, Villahermosa, Tabasco, Mexico.
Granados-Soto
Vinicio
V
Díaz-Zagoya
Juan C
JC
Flores-Murrieta
Francisco J
FJ
Torres-López
Jorge E
JE
D000818:Animals; D048909:Diabetes Complications / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004351:Drug Resistance; D005557:Formaldehyde; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology*; D017288:Pain Threshold / Q000187:drug effects*; D051381:Rats; D043886:Receptor, Cholecystokinin A / Q000378:metabolism*; D043887:Receptor, Cholecystokinin B / Q000378:metabolism*; D012844:Sincalide / Q000008:administration & dosage* / Q000378:metabolism*
D004338:Drug Combinations; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D005557:Formaldehyde; D012844:Sincalide