Morphine-receptor dissociation constant and the stimulus-effect relation for inhibition of gastrointestinal transit in the rat.

The dissociation constant (KA) of morphine for its receptors was determined by the method of partial irreversible blockade of the receptor population using inhibition of gastrointestinal transit of a forced charcoal meal as the pharmacological endpoint. The anti-motility effect of morphine was antagonized when rats were pretreated with buprenorphine (0.3 mg/kg s.c.), a narcotic antagonist analgesic, 30 min before morphine and the extent of gastrointestinal transit was estimated a further 45 min later. With this schedule of drug administration, the agonist action of buprenorphine is minimal and its antagonist action predominates. The value of KA was (1.1 +/- 0.2) x 10(-5) mol/kg, a value close to that previously reported (2.9 x 10(-5) mol/kg) by us with these compounds in the rat tail flick test. The value of [A50], found here was 2.15 x 10(-6) mol/kg, approximately 1/5 of that of KA. Also, the stimulus-effect relation of the tissue, defined in Stephenson's theory, was plotted and found to be nonlinear. This result, when coupled with the inequality of KA and [A50], argues against the application of classical drug-receptor theory to this system. The apparent agreement between KA values for antinociception and inhibition of gastrointestinal transit is interesting, but does not necessarily prove equivalent receptors mediating the two different effects.