Kappa agonists inhibit gastric emptying but not acid secretion in rhesus monkeys.
Gastric function was evaluated in rhesus monkeys during a continuous, s.c. infusion of three kappa agonists; dynorphin-(1-13), (trans-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide methanesulfonate hydrate) (U50,488H) and ketocyclazocine (KETO). A dye dilution technique was used to determine gastric fractional emptying rate, hydrogen ion, sodium ion and fluid secretion after the intragastric administration of a water meal. All agonists significantly inhibited fractional emptying rate after the water meal. The kappa receptor antagonist, (-)-(1R,5R,9R)-5,9-dimethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomor pha n methanesulfonate, prevented the inhibitory response to dynorphin-(1-13) and partially blocked the effect of KETO, but, at the dose used in the present study, was completely ineffective against the specific kappa agonist, U50,488H. This suggests that dynorphin-(1-13) and U50,488H may not bind to the same kappa receptor isotype. The partial antagonism of KETO by both naloxone and (-)-(1R,5R,9R)-5,9-dimethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomor pha n methanesulfonate is consistent with a kappa/mu effect of this compound. Naloxone, at the dose used in these studies, did not modify the response to U50,488H. In contrast to their inhibitory action on gastric emptying, the kappa agonists, dynorphin-(1-13) and U50,488H, did not alter acid secretion. The suppressive action of KETO on acid secretion may be due to activation of mu receptors. The inhibitory effect of dynorphin-(1-13) on sodium output was blocked by (-)-(1R,5R,9R)-5,9-dimethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomor pha n methanesulfonate, suggesting a role for kappa agonists in the control of nonparietal secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Touzeau
P L
PL
Department of Physiology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Shea-Donohue
T
T
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D003496:Cyclazocine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004399:Dynorphins / Q000494:pharmacology*; D016314:Ethylketocyclazocine / Q000031:analogs & derivatives*; D005744:Gastric Acid / Q000378:metabolism*; D005746:Gastric Emptying / Q000187:drug effects*; D008253:Macaca mulatta; D008297:Male; D009294:Narcotics / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000187:drug effects* / Q000502:physiology; D017473:Receptors, Opioid, kappa; D012964:Sodium / Q000378:metabolism
D000959:Antihypertensive Agents; D009294:Narcotics; D010446:Peptide Fragments; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D016314:Ethylketocyclazocine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C012395:ketazocine; C026843:dynorphin (1-13); D004399:Dynorphins; D012964:Sodium; D003496:Cyclazocine