MORPHINE TISSUE-LEVELS AND REDUCTION OF GASTROINTESTINAL TRANSIT IN RATS - CORRELATION SUPPORTS PRIMARY ACTION SITE IN THE GUT

  • 1 January 1983
    • journal article
    • research article
    • Vol. 85  (4) , 852-858
Abstract
Overnight-fasted male rats given a single dose of 3H-morphine either i.p. or i.v. were fed a charcoal test meal by stomach tube. The drug remaining in tissues was assayed by liquid scintillation counting of TLC from homogenates, and gastrointestinal transit was tested by measuring the portion of the small intestine traversed by charcoal in 5 min. Morphine, 0.15 mg/kg, given i.p. either 10 min or 30 min before testing substantially reduced gastrointestinal transit (to 23% and 55% of drug-free controls, respectively), and produced maximum drug levels 5 min after administration in small intestine longitudinal muscle with attached myenteric plexus (500 .+-. 42 ng/g, mean .+-. SE, n = 4). Intact small intestine, plasma and brain, respectively, contained decreasing drug concentrations that, in the latter, never exceeded 2%-3% of that in longitudinal muscle. Rats receiving 0.15 mg/kg morphine i.v. presented only minor and short-lived inhibition of gastrointestinal transit that was significantly below (.apprx. 35%) that of drug-free controls at 10 min, but not 30 min, after drug administration. Morphine levels in the brain and plasma of these rats were up to 5 times higher, and in the intact small intestine longitudinal muscle were up to 20 times lower than in i.p. treated rats. Morphine concentration in the tissues assayed was plotted against the effect on gastrointestinal transit at the same interval for individual rats regardless of dose, administration route and observation time; data analysis, in small intestine longitudinal muscle, but not in the brain or plasma, indicated a highly significant correlation and fitting of computer-generated curves described by a currently accepted equation according to the receptor occupation theory of drug response. In view of these findings, and of the complete prevention by the peripherally selective narcotic antagonist N-methyl naloxone of gastrointestinal transit inhibition after an i.v. analgesic dose of morphine (1 mg/kg), the investigated animal model is consistent with the primary role of a gut-located action site in opiate-induced constipation.