Spinal effect of the cholecystokinin-B receptor antagonist CI-988 on hyperalgesia, allodynia and morphine-induced analgesia in diabetic and mononeuropathic rats

Abstract

Since evidence points to the involvement of cholecystokinin (CCK) in nociception, we examined the effect of intrathecal CI-988, an antagonist of the CCK-B receptors, on mechanical hyperalgesia and allodynia in normal, mononeuropathic and diabetic rats,. Owing to the anti-opioid activity of CCK, it has been suggested that hyperactivity in the spinal CCK system is responsible for the low sensitivity of neuropathic pain to opioids. We therefore also evaluated the effect of the combination of i.t. CI-988+i.v. morphine on mechanical hyperalgesia in diabetic and mononeuropathic rats using isobolographic analysis. Although ineffective in normal rats, CI-988 induced antinociceptive effects in diabetic (290±20 g with a cut-off of 750 g) and mononeuropathic (117±16 g; cut-off 750 g) rats, suggesting an involvement of the CCKergic system in neurogenic pain conditions. The combination of CI-988 and morphine showed a superadditive interaction in the diabetic rats only (477±16 g; cut-off 750 g), in comparison with the antinociceptive effect of each drug. In addition, CI-988 exhibited a weak anti-allodynic effect in mononeuropathic rats, and no anti-allodynic effect in diabetic rats. These results show the CCK-B receptor blockade-mediated antinociceptive effects and reveals the antinociceptive action of morphine in diabetic rats after CCKergic system inhibition.