κ-Opioid Receptor Agonists Modulate Visceral Nociception at a Novel, Peripheral Site of Action

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Abstract
κ-opioid receptor agonists (κ-ORAs) have been shown to modulate visceral nociception through an interaction with a peripheral, possibly novel, κ-opioid-like receptor. We used in the present experiments an antisense strategy to further explore the hypothesis that κ-ORA effects in the colon are produced at a site different from the cloned κ-opioid receptor (KOR). An antisense oligodeoxynucleotide (ODN) to the cloned rat KOR was administered intrathecally (12.5 μg, 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 peripherally administered κ- (EMD 61,753 and U 69,593), μ- (DAMGO) and δ- (deltorphin) ORAs in the formalin test. Intrathecal antisense, but not mismatch 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 κ-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. Additionally, Western blot analysis demonstrated a significant downregulation of KOR protein in the L4-S1 dorsal root ganglia of antisense, but not mismatch ODN-treated rats. The present results support the existence of a non-κ-opioid receptor site of action localized in the colon.