Inhibition of gastro intestinal transit and anti nociceptive effects of morphine and fk 33 824 in rats are differently prevented by naloxone and its n methyl quaternary analog

Ferretti, P.; Bianchi, G.; Tavani, A.; Manara, L.

Research Communications in Substances of Abuse 2(1): 1-12


ISSN/ISBN: 0193-0818
Accession: 005703254

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After s.c. administration to rats (30 min) of 0.15-10 mg/kg morphine or 0.005-5 mg/kg of the enkephalin-like peptide FK 33-824 [(D-Ala2, MePhe4, Met(O)5-ol) enkephalin], gastrointestinal transit of a forced charcoal meal was inhibited with closely comparable potency at the higher doses producing major effects; considerably less (about 100 times) FK 33-824 than morphine was sufficient to elicit threshold and even substantial (> 50%) inhibition. The marked transit inhibition (to < 40% of control) caused by a small i.p. dose (0.04 mg/kg) of either drug was prevented almost completely in rats pretreated with the N-methyl quaternary analog of naloxone (1 mg/kg i.p.). Gastrointestinal transit and nociceptive reaction (jumping) to the hot-plate ( C) were blocked in rats given i.v. 2.5 mg/kg FK 33-824 or double this dose of morphine; pretreatment with 1 mg/kg naloxone i.p. fully prevented both effects of morphine and antinociception by FK 33-824 whose intestinal action was only partially antagonized. Morphine-induced inhibition of gastrointestinal transit was substantially reversed but there was no impairment of the drug's antinociceptive action when naloxone was replaced with its N-methyl quaternary analog (4 mg/kg) which under the same conditions did not affect FK 33-824's efficacy on these 2 endpoints. FK 33-824 has potent opiate-like action on gastrointestinal transit in rats and, unlike naloxone, its N-methyl quaternary analog can selectively prevent morphine's effect on the gut without affecting antinociception.