Abstract
The opioid receptor reserve was measured in the guinea pig ileum myenteric plexus by the site-directed alkylating agent, .beta.-chlornaltrexamine. Treatment of the tissue with low (< 10 nM) concentrations of .beta.-chlornaltrexamine caused a parallel shift of the log concentration-response curves for both normorphine and dynorphin A-(1-13). Analysis of the resulting curves indicated that the Kd values were 1.5 .+-. 0.5 .times. 10-6 and 10 .+-. 4 .times. 10-9, respectively. Using the naloxone Ke to distinguish between the .mu. and .kappa. receptors in this tissue, it was found that the receptor selectivities of normorphine and dynorphin A-(1-13) were unchanged after a maximum parallel shift, thus demonstrating that there are both spare .mu. and spare .kappa. receptors present. The spare-receptor fraction for both receptor types was about 90%. In morphine-tolerant preparations (chronic pellet implantation), there was an apparent reduction in the fraction of spare .mu. receptors without any change in the apparent affinity of normorphine. Reduction in the spare receptor fraction does not necessarily imply reduction in the number of binding sites. This reduction in receptor reserve is probably the basis of opioid tolerance, since the agonist concentration needed to produce a given effect is expected to increase as the receptor reserve decreases.