kappa-Opioid receptor agonists modulate visceral nociception at a novel, peripheral site of action

kappa-opioid receptor agonists (kappa-ORAs) have been shown to modulate vis ceral nociception through an interaction with a peripheral, possibly novel, kappa-opioid-like receptor. We used in the present experiments an antisens e strategy to further explore the hypothesis that kappa-ORA effects in the colon are produced at a site different from the cloned kappa-opioid recepto r (KOR). An antisense oligodeoxynucleotide (ODN) to the cloned rat KOR was administered intrathecally (12.5 mu g, twice daily for 4 d) to specifically knock-down the cloned KOR. Efficacy of the KOR antisense ODN treatment was behaviorally evaluated by assessing the antinociceptive effects of periphe rally administered kappa- (EMD 61,753 and U 69,593), mu- (DAMGO) and delta- (deltorphin) ORAs in the formalin test. Intrathecal antisense, but not mis match ODN blocked the actions of EMD 61,753 and U 69,593 without affecting the actions of DAMGO or deltorphin; a complete recovery of antinociceptive actions of the kappa-ORA EMD 61,753 was observed 10 d after the termination of antisense ODN treatment. In contrast, the ability of EMD 61,753 to dose -dependently attenuate responses of pelvic nerve afferent fibers to noxious colonic distension was unaffected in the same rats in which the antisense ODN effectively knocked-down the KOR as assessed in the formalin test. Addi tionally, Western blot analysis demonstrated a significant downregulation o f KOR protein in the L4-S1 dorsal root ganglia of antisense, but not mismat ch ODN-treated rats. The present results support the existence of a non-kap pa-opioid receptor site of action localized in the colon.