A. Both WT and ECE-2 KO animals developed tolerance to daily morphine administration on the hot-plate; however, tolerance appeared more rapidly in KO mice. By day 6, no genotype differences were evident. B. Development of tolerance to daily injections of morphine on tail-flick was again significantly slower in WT than KO animals. By day 6, no genotype differences were apparent. MPE, maximum possible effect. N=9 mice/genotype. *p<0.05, WT versus KO mice; #p<0.05, WT response to morphine compared to WT baseline; &p<0.05, KO response to morphine compared to KO baseline.