MEL Endomorphins Act As Potent Inflammatory Analgesics In The CFA-induced Chronic Pain Model

Effective treatment of inflammatory pain is a major clinical concern for both patients and physicians.Traditional analgesics such as morphine and coxibs are not obviously effective in patients and have various unwanted side effects.Accumulating evidence suggested that endomorphins(EMs),particularly EM-1,possess potent anti-inflammatory effects.However,poor bioavailability and low resistance to enzymatic degradation impede their direct application in the treatment of inflammation.A series of novel peptides based on the structure of EM-1,with lower undesired effects than their parent compounds,called MEL-EMs were discovered and synthetized in our preceding studies.Here,we selected two(MEL-0614 and MEL-N1606)to further investigate their antiinflammatory effects.Firstly,the Von Frey,Hargreaves and tail-flick tests were used to evaluate the analgesic effects of MEL analogs.Behavior tests indicated that MEL-EMs can relieve chronic pain in CFA inflammatory model following peripheral administration.The antinociceptive effect of MEL analogs were as potent as morphine.Meanwhile,parecoxib also produced antinociception whereas was significantly weaker than morphine and MEL analogs.Next,western blot and real-time PCR were employed to further evaluate the analgesic mechanism.Western blot showed that MEL analogs could significantly reduce the over-activation of spinal glial cells and peripheral macrophages in CFA induced inflammation,in contrast to morphine.Meanwhile,real-time PCR suggested that the two MEL analogs could markedly down-regulate the over-expression of proinflammatory molecules.Repetitive administrations of morphine have pro-inflammatory effects.Therefore,inflammatory prolongation experiments were finally carried out to further investigate whether MEL analogs would prolong CFA-induced persistent hypersensitivity.The results strongly suggested that repetitive doses of MEL analogs do not prolong CFA-induced chronic inflammatory pain,but morphine exacerbates the persistent pain.Besides,MEL analogs may not participate in the spinal microglia-activation and NLRP3 signal pathway in which morphine is involved.Additionally,the prolongation and amplification of inflammatory pain induced by morphine can be reversed by MEL analogs.When these data are considered together with our previous results showing that MEL analogs are less likely than morphine to result in constipation,motor impairment,and drug-seeking,we come to the conclusion that MEL-EMs may serve as valuable candidates in pharmacological research for novel,effective anti-inflammatory drugs and pain treatment.