Design, Synthesis And Pharmacological Studies Of Chimeric Peptides Of Mu-opioid And NPFF Systems

Opioid analgesics such as morphine are extremely effective treatments for pain, however, their long-term utility is limited by the development of tolerance. Endomorphin-2 (EM-2), which is as one ofμ-opioid receptor selective endogenous agonists, has been widely studied. In 1985, neuropeptide FF was first found by use of an antiserum to FMRF-amide in bovine brain, and was found can modulate the action of morphine in pain. Subsequently, two G protein-coupled receptors, defined as NPFF1 and NPFF2, were cloned. So far, NPFF is involved in mediating a variety of biological activities, including nociceptive modulation, opioid tolerance and dependence modulation, cardiovascular modulation, thermoregulatory, gastrointestinal modulation, food intake, learning and memorying, endocrine modulation, and so on. One of these actions is that NPFF is involved in the development of tolerance of opioid analgesic morphine.Based on the above findings, we design and synthesiz a series of new chimeric peptides of mu-opioid and NPFF systems:YPFFLFQPQRFa (EN-11), YPFFQPQRFa (EN-9), YPFFMRFa (EFM-7) and YPFFRFa (EFF-6). These chimeric peptides were synthesized by solid phase peptide synthesis method, and then analgesic effects and tolerance to antinociceptive effects of these peptides after i.c.v. injection were investigated in mice.Our results show that:1) i.c.v. injection of EN-9 (5-30nmol) produced a dose-dependent and longer lasting analgesic effect compared with EM-2 with no development of tolerance during 6 days of high-dose (60nmol) treatment.2) i.c.v. injection of EFM-7 and EFF-6 (5-30nmol) also produced the dose-dependent and longer lasting antinociception compared with EM-2, but it induced significant tolerance during 6 days of high-dose (60nmol) treatment.3) EN-11 exhibited NPFF-like anti-opioid action in pain modulation. In conclusion, our results suggest that the new design chimeric peptide EN-9, which induce antinociception with no tolerance, can be as a useful analgesic drug with low side effects.