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 CCKA and CCKB 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 μg) 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 μg), CCKA receptor antagonist lorglumide (0.1-100 μg) or CCKB receptor antagonist CR-2945 (0.1-100 μg), 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 μg) was significantly reduced by proglumide (100 μg), lorglumide (100 μg), and CR-2945 (100 μg). Results suggest that diabetes-induced peripheral sensitization could be due to a local peripheral release of CCK-8, which in turn would act on CCKB, mainly but also in CCKA, receptors located on the primary afferent neurons.