Modulation of visceral hyperalgesia by morphine and cholecystokinin from the rat rostroventral medial medulla

Abstract

Using a model of visceral nociception, we examined whether cholecystokinin (CCK) acts as an anti-opioid peptide in the rat rostral ventromedial medulla (RVM). Because such interaction may be affected by inflammation, rats with and without inflamed colons were studied. The visceromotor response to noxious colorectal distension (CRD), quantified electromyographically, was recorded before and after intra-RVM administration of CCK, CCK receptor antagonists, and morphine. Either 50% ethanol/saline (vehicle) or 2,4,6-trinitrobenzenesulfonic acid (TNBS), which inflames the colon, was instilled into the colon 5 days before experiments. Intra-RVM morphine dose-dependently attenuated responses to CRD in intracolonic vehicle-treated rats. In TNBS-treated rats with inflamed colons, responses to CRD were significantly increased and 0.3, 3.0 and 6.0 microg doses of intra-RVM morphine reduced responses to control (i.e. were anti-hyperalgesic); the greatest dose tested (30 microg) further reduced responses to 40% control. In intracolonic vehicle-treated rats, intra-RVM pre-treatment with a selective CCK(B) (but not CCK(A)) receptor antagonist dose-dependently and significantly enhanced the effect of a low dose of morphine. Intra-RVM CCK-8 peptide enhanced responses to CRD in intracolonic vehicle-treated, but not TNBS-treated rats. Intra-RVM naloxone was without effect in intracolonic vehicle-or TNBS-treated rats, suggesting an absence of tonic opioid activity in RVM. These results document a CCK-opioid interaction in RVM, suggesting that colon inflammation leads to tonic activity at CCK(B) receptors in RVM.