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

Abstract

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 [A 50] 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 [A 50], 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.