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

The dissociation constant (K_A) of morphine for its receptor 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 effects 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 K_A was (1.1±0.2)×10^-5 mol/kg, a value close to that previously reported (2.9×10^-5 mol/kg) by us with these compounds in the rat tail flick test. The value of [A₅₀] found here was 2.15×10^-6 mol/kg, approximately 1 5 of that of K_A. 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 K_A and [A₅₀], argues against the application of classical drug-receptor theory to this system. The apparent agreement between K_A values for anticiception and inhibition of gastrointestinal transit is interesting, but does not necessarily prove equivalent receptors mediating the two different effects.