Inhibition of exocrine pancreatic secretion by opiates is mediated by suppression of cholinergic transmission: characterization of receptor subtypes.
This study evaluates the hypothesis that opiates suppress pancreatic enzyme secretion by inhibiting cholinergic transmission in the pancreas. Rat pancreatic lobules were incubated in 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid-Ringer's buffer and amylase release in response to KCl depolarization of the intrapancreatic nerve in the absence or presence of specific opiate subtype receptor agonists was studied. Depolarization by 75 mM KCl resulted in a 5-fold increase in amylase output. Pretreatment with 1 microM atropine inhibited completely the KCl-stimulated amylase release, suggesting stimulation via a cholinergic pathway. Addition of methionine enkephalin or 2-D-penicillamine-5-D-penicillamine-enkephalin [( D-Pen2, D-Pen5]enkephalin, a specific delta receptor agonist) inhibited KCl-stimulated amylase release in a dose-dependent fashion. Methionine enkephalin (1 microM) or [D-Pen2, D-Pen5]enkephalin inhibited KCl-stimulated amylase release by 32 +/- 4 and 45 +/- 4%, respectively. Addition of 1 microM ICI 174,864 (a delta opiate receptor antagonist) blocked the inhibitory effect of [D-Pen2, D-Pen5]enkephalin. Upjohn 50,488H (1 microM, a specific kappa agonist) and 1 microM Tyr-D-Ala-Gly-MePhe-Gly-ol (a specific mu agonist) had no effect. Methionine enkephalin had no effect on carbachol (1 microM)-stimulated amylase release. These data suggest that methionine enkephalin acts on a delta opiate receptor located on postganglionic cholinergic neurons. To examine the ability of methionine enkephalin to alter acetylcholine release from pancreatic tissue, pancreatic lobules were incubated with [3H]choline and the release of synthesized [3H]acetylcholine was stimulated by KCl. Depolarization of the nerves with 75 mM KCl increased [3H]acetylcholine release by 35 +/- 5% over basal.(ABSTRACT TRUNCATED AT 250 WORDS)
Louie
D S
DS
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.
Chen
H T
HT
Owyang
C
C
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000109:Acetylcholine / Q000378:metabolism; D000681:Amylases / Q000378:metabolism; D000818:Animals; D002799:Cholinergic Fibers / Q000187:drug effects*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D004744:Enkephalin, Methionine / Q000494:pharmacology; D004745:Enkephalins / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects*
D004745:Enkephalins; D009294:Narcotics; D011759:Pyrrolidines; D011957:Receptors, Opioid; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004744:Enkephalin, Methionine; D004743:Enkephalin, Leucine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D020881:Enkephalin, D-Penicillamine (2,5)-; C040643:N,N-diallyl-tyrosyl-alpha-aminoisobutyric acid-phenylalanyl-leucine; D000681:Amylases; D000109:Acetylcholine