Modulation of the in vivo actions of morphine by the mixed CCKA/B receptor antagonist PD 142898.

Abstract

The ability of a mixed CCKA/B receptor antagonist PD 142898 (benzenebutanic acid, beta-[[3-(1 H-indol-3-yl)-2-methyl-2-[[[(2-methyl- cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-[1 S-[1 alpha [S*(R*)]-2 beta]]) to modulate the antinociceptive, positive reinforcing and gastrointestinal actions of morphine was investigated in the rat. PD 142898 antagonised the development and maintenance of morphine (2.0 mg/kg, s.c.) induced conditioned place preference at 0.1 mg/kg, i.p. However, it potentiated the antinociceptive action of a subthreshold dose of morphine in the radiant tail flick model at doses of 0.001 and 0.01 mg/kg, s.c. Furthermore, PD 142898 (0.0001-1.0 mg/kg, s.c.) also potentiated the antinociceptive action of morphine (1.0 mg/kg, s.c.) against the late phase of formalin response associated with inflammation at the dose of 0.001-1.0 mg/kg. PD 142898 (0.001 mg/kg, s.c.) blocked the development of tolerance to morphine in the formalin test. It failed (0.001-1.0 mg/kg, i.p.) to modulate the inhibitory action of morphine (5.0 mg/kg, s.c.) on gastrointestinal transit as measured using the charcoal meal test. It is argued that the effect of PD 142898 in the conditioned place preference test involves antagonism of CCKA receptors, whilst the potentiation of the antinociceptive action of morphine is mediated via blockade of CCKB receptors. These results suggest that the mixed CCKA/B receptor antagonist may potentiate the analgesic action of morphine, block the development of tolerance without a concomitant increase in constipation and may also reduce the abuse potential of the opiate.

• Authors: L Singh, M J Field, J C Hunter, R J Oles, G N Woodruff
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 307 Issue 3 Pg. 283-9 (Jul 04 1996) ISSN: 0014-2999 [Print] Netherlands
• PMID: 8836616 (Publication Type: Journal Article)

Chemical References

• Hormone Antagonists
• Indoles
• PD 142898
• Receptor, Cholecystokinin A
• Receptor, Cholecystokinin B
• Receptors, Cholecystokinin
• Formaldehyde
• Morphine

Topics

• Animals
• Conditioning, Psychological (drug effects)
• Formaldehyde (adverse effects)
• Gastrointestinal Transit (drug effects)
• Hormone Antagonists (pharmacology)
• Indoles (pharmacology)
• Male
• Morphine (antagonists & inhibitors, pharmacology)
• Pain Measurement
• Pain Threshold (drug effects)
• Rats
• Rats, Sprague-Dawley
• Receptor, Cholecystokinin A
• Receptor, Cholecystokinin B
• Receptors, Cholecystokinin (antagonists & inhibitors)