title: kappa -opioid receptor agonists modulate visceral nociception at a novel, peripheral site of action.
abstract: 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 microg, 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), mu- (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.
authors.affiliation: Department of Pharmacology, College of Medicine, The University of Iowa, Iowa City 52242, USA. shailen-joshi@uiowa.edu
authors.forename: S K
authors.initials: SK
authors.lastname: Joshi
authors.forename: X
authors.initials: X
authors.lastname: Su
authors.forename: F
authors.initials: F
authors.lastname: Porreca
authors.forename: G F
authors.initials: GF
authors.lastname: Gebhart
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D003106:Colon / Q000294:innervation*; D004202:Disinfectants; D004594:Electrophysiology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005557:Formaldehyde; D005727:Ganglia, Spinal / Q000737:chemistry / Q000502:physiology; D008297:Male; D009619:Nociceptors / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology*; D010812:Physical Stimulation; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000032:analysis / Q000235:genetics; D012007:Rectum / Q000294:innervation; D017833:Visceral Afferents / Q000502:physiology*
chemical_list: D000081:Acetamides; D000701:Analgesics, Opioid; D004202:Disinfectants; D016376:Oligonucleotides, Antisense; D009842:Oligopeptides; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C059567:deltorphin; D005557:Formaldehyde; C092095:asimadoline