The endomorphins are peptides isolated from the brain with high affinity and selectivity for the mu opioid receptor (MOR) (Nature 386:499, 1997). At least two paradigms illustrate differences in the effects of endomorphin-1 (Tyr-Pro-Trp-Phe) (EM1) and morphine. In contrast to morphine, the respiratory and cardiovascular effects of EM1 are not reached at doses capable of inducing antinociception (Czapla et al., 2001). In addition, at antinociceptive doses, morphine was shown to produce conditioned place preference (CPP), while EM1 did not (Wilson et al., 2000). These findings indicate that compounds similar to EM1 may (1) produce a different profile of effects at the MOR and (2) provide a favorable 'therapeutic ratio' of analgesic action relative to unwanted side effects such as respiratory depression and reward Because native peptides are rapidly degraded, a series of endomorphin analogs were synthesized in this lab. One of these compounds, a cyclized (c) D-lysine (k)-containing analog of EM1 (Tyr-c[DLys-Trp-Phe]) (ck1/CYT-1010), showed higher affinity than the parent EM1 and morphine for the MOR. In addition, it showed greater selectivity for the MOR, relative to delta and kappa receptors, than morphine. ck1/CYT-1010 is being used in our laboratory as a tool to investigate differential actions of MOR agonists in paradigms where a peptide-based MOR agonist can show a profile of effects distinct from that of morphine This dissertation characterizes the dose-dependent antinociception induced by the analog after intracerebroventricular (ICV) injections, and its effects on reward. The metabolic stability of the analog enabled us to carefully match the antinociceptive effects of morphine and the analog across the time period of exposure to the CPP apparatus. This provides a conceptually valid comparison of the compounds for their antinociceptive properties relative to their rewarding potential. At doses of the analog and morphine that produced antinociception of virtually identical maximal effect and duration, morphine induced a significant place preference while the analog did not. Given that CPP has been correlated with abuse potential, our results show promise for the development of novel opioids with less abuse potential relative to morphine at equally effective analgesic doses