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The Journal of Neuroscience, August 1, 2000, 20(15):5874-5879

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

S. K. Joshi1, Xin Su1, Frank Porreca2, and G. F. Gebhart1

1 Department of Pharmacology, College of Medicine, The University of Iowa, Iowa City, Iowa 52242, and 2 Department of Pharmacology, University of Arizona, Tucson, Arizona 85721

kappa -opioid receptor agonists (kappa -ORAs) have been shown to modulate visceral nociception through an interaction with a peripheral, possibly novel, kappa -opioid-like receptor. We used in the present experiments an antisense strategy to further explore the hypothesis that kappa -ORA effects in the colon are produced at a site different from the cloned kappa -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 kappa - (EMD 61,753 and U 69,593), µ- (DAMGO) and delta - (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 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. 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-kappa -opioid receptor site of action localized in the colon.

Key words: peripheral opioids; nociception; colorectal distension; formalin test; antisense; visceral pain

Copyright © 2000 Society for Neuroscience  0270-6474/00/20155874-06$05.00/0


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