Antibodies and antisense oligodeoxynucleotides to mu-opioid receptors, selectively block the effects of mu-opioid agonists on intestinal transit and permeability in mice.
1. We have studied the effects of mu and delta opioids on intestinal function (permeability, PER; gastrointestinal transit, GIT), and their antagonism after the intracerebroventricular (i.c.v.) administration of specific antibodies (ABs) or antisense oligodeoxynucleotides (ODN) to mu-receptors (OR). Central versus peripheral site/s of action of subcutaneous (s.c.) mu-opioids, were also assessed. 2. Male Swiss CD-1 mice were used. GIT was measured with charcoal and PER by the passage of 51Cr-EDTA from blood to lumen. 3. Morphine and fentanyl (i.c.v. and s.c.) inhibited GIT and PER in a dose-related manner; they were more potent by i.c.v. route, both on GIT and PER (70 and 17 times for morphine and fentanyl). They also had a greater effect on GIT than PER (4.3 and 1.6 times). DPDPE had a lower potency than mu-agonists in all experiments, and no dose-response could be obtained after s.c. administration on GIT. 4. Pretreatment with i.c.v. ABs (24 h) or antisense ODN (5 days), decreased the effects (GIT and PER) of i.c.v. morphine and fentanyl, while those of DPDPE remained unchanged. The ABs did not alter the peripheral effects of mu-opioids. 5. The results show that (i.c.v. or s.c.) mu opioids produce dose-related inhibitions of PER and GIT, being more potent by the i.c.v. route. Delta-opioids had a greater effect on PER than GIT, while the opposite occurred for mu-agonists. Pretreatment with ABs or ODN to mu-OR, blocked the central effects of mu (but not delta) agonists on GIT and PER.
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Department of Anesthesiology, Hospital Universitario del Mar, IMIM, Barcelona, Spain.
Valle
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Sánchez-Blázquez
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P
Garzón
J
J
Puig
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MM
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004723:Endorphins / Q000494:pharmacology; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000494:pharmacology; D005283:Fentanyl / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005772:Gastrointestinal Transit / Q000187:drug effects*; D007276:Injections, Intraventricular; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D051379:Mice; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000276:immunology
D019138:Antibodies, Blocking; D004723:Endorphins; D004745:Enkephalins; D009292:Narcotic Antagonists; D020319:Oligodeoxyribonucleotides, Antisense; D017450:Receptors, Opioid, mu; D009020:Morphine; C044708:morphiceptin, N-Me-Phe(3)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D005283:Fentanyl