Quaternary narcotic antagonists' relative ability to prevent antinociception and gastrointestinal transit inhibition in morphine-treated rats as an index of peripheral selectivity

Giancarlo Bianchi, Roberto Fiocchi, Alessandra Tavani, Luciano Manara

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Abstract

Single doses of naloxone (0.025 to 0.5 mg/kg) or of one of four quaternary narcotic antagonists (i.e. nalorphine allobromide, nalorphine methobromide, naloxone methobromide or naltrexone methobromide, 1 to 60 mg/kg) were given s.c. to rats before morphine, 5 mg/kg i.v. In the absence of antagonists morphine reduced G.I. transit of a charcoal meal to about 15% of drug-free controls and consistently delayed nociceptive reactions (55°C hot plate) in all animals. Doses of antagonists slightly reducing morphine antinociception (centrally effective = A) and restoring G.I. transit to about 50% of drug-free rats (peripherally effective = B) were estimated. The A:B ratio, indicating peripheral selectivity, was at least 8 for any of the quaternary antagonists given 10 min before morphine, but prolonging this interval may have resulted in a lower figure (i.e. less peripheral selectivity) because of reduced A and increased B. This was definitely so for naltrexone methobromide (A:B, > 60 at 10 min, about 1 at 80 min) and was not apparent for nalorphine methobromide according to available data, which for nalorphine allobromide and to a lesser extent for naloxone methobromide showed only an increase in B at intervals longer than 10 min. Both morphine-induced antinociception and inhibition of G.I. transit were reduced by naloxone at the lower doses tested and were fully prevented at the higher. These findings indicate that, unlike naloxone, the investigated quaternary narcotic antagonists are interesting prototype drugs for selective blockade of opiate receptors outside the CNS, although certain critical aspects, possibly biological N-dealkylation to the corresponding tertiary antagonists, condition peripheral selectivity.

Original languageEnglish
Pages (from-to)1875-1883
Number of pages9
JournalLife Sciences
Volume30
Issue number22
DOIs
Publication statusPublished - May 31 1982

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Gastrointestinal Transit
Nalorphine
Narcotic Antagonists
Morphine
Rats
Naloxone
Pharmaceutical Preparations
Dealkylation
Drug and Narcotic Control
Charcoal
Opioid Receptors
Meals
Animals

ASJC Scopus subject areas

  • Pharmacology

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Quaternary narcotic antagonists' relative ability to prevent antinociception and gastrointestinal transit inhibition in morphine-treated rats as an index of peripheral selectivity. / Bianchi, Giancarlo; Fiocchi, Roberto; Tavani, Alessandra; Manara, Luciano.

In: Life Sciences, Vol. 30, No. 22, 31.05.1982, p. 1875-1883.

Research output: Contribution to journalArticle

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