Lack of tolerance and morphine-induced cross-tolerance to the analgesia of chimeric peptide of Met-enkephalin and FMRFa

Chimeric peptide of Met-enkephalin and FMRFa (YGGFMKKKFMRFa-YFa), a κ-opioid receptor specific peptide, did not induce tolerance and cross-tolerance effects to its analgesic action on day 5 after pretreatment with either YFa or morphine for 4 days. However, pretreatment with YFa for 4 days led to the development of cross-tolerance to the analgesic effects of morphine and also 4 days of pretreatment of morphine resulted in the expression of tolerance to its own analgesic effects. Similar expression of tolerance and cross-tolerance were also observed when YFa was compared with the κ receptor agonist peptide dynorphin A(1–13) [DynA(1–13)]. Cross-tolerance effects between YFa and DynA(1–13) analgesia were also not observed on day 5. Interestingly, when YFa and DynA(1–13) were tested for their analgesic effects for 5 days, reduction in analgesia on day 3 was observed in case of DynA(1–13) whereas YFa maintained its analgesia for 5 days. Thus, chimeric peptide YFa may serve as a useful probe to understand pain modulation and expression of tolerance and cross-tolerance behavior with other opioids.