Opioid Activity Of Hybrid Peptides Based On Endomorphins And Neurotensin Structures

Endomorphins(endomorphns,EMs)are endogenous ?-opioid receptor ligands widely distributed in mammals,which are divided into endomorphin-1(endomorphin-1,EM-1)and endomorphin-2(endomorphin-2,EM-2).Endomorphins are involved in the regulation of various physiological functions such as pain modulation,cardiovascular activity,gastrointestinal activity,endocrine and immunity by binding to opioid receptors.EMs have extremely high affinity and selectivity for ?-opioid receptors,and can exert high-efficiency analgesic activity with lower side effects in the central nervous system and peripheral nervous system.However,endorphins are still limited by side effects such as sedation,constipation,respiratory depression,blood pressure reduction,and analgesic tolerance.In addition,as short peptides,endomorphins have disadvantages such as poor enzymatic stability and difficulty in crossing the blood-brain barrier,which limit its clinical application as an analgesic drug.In recent years,researchers have been working on the modification of the endorphin structure to develop new,high-efficiency,low-side effect analgesic drugs based on endomorphins.Neurotensin(NT),as an endogenous neuropeptide,can regulate pain feeling by activating specific neurotensin receptors in the nervous system,and has an important connection with opioid peptides in regulating pain.This topic mainly studies hybrid peptides based on endomorphins and neurotensin,including opioid activity,central and peripheral analgesic activity,opioid analgesic mechanism,analgesic tolerance and side effects on intestinal specimen contraction,and use the SNI model to further study the anti-neuropathic effects of endorphins and hybrid peptides,and provide basic research for the development of new clinical analgesics.Based on the structural design of EMs and neurotensin,the subject obtained the hybrid peptides EMNT-1 and EMNT-2,and mainly study EMs,hybrid peptides EMNT-1 and EMNT-2 in vitro opioid agonist activity,colon contractile activity,acute analgesia and analgesic tolerance,and anti-neuralgia activity against the SNI model,which provide basic research for the development of new and effective analgesic drugs.Detection of in vitro specimen activity found that the hybrid peptides EMNT-1 and EMNT-2 have higher guinea-pig ileum and mouse vas deferens agonistic activities,and the effect on mouse colon contraction is lower than that of the parent peptide EMs.Detection of in vitro specimen activity found that the hybrid peptides EMNT-1 and EMNT-2 have higher opioid agonistic activity,and the effect on mouse colon contraction is lower than that of the parent peptide EMs.These indicate that the hybrid peptides EMNT-1 and EMNT-2 have higher opioid receptor agonistic activity on opioid receptors and have lower side effects on colon contraction.In the heat radiation paw contraction experiment in mice,the hybrid peptides EMNT-1 and EMNT-2 showed highly effective central and peripheral analgesic activity,and the analgesic effect lasted longer.After using a variety of opioid antagonists to study the opioid mechanism,it was found that the analgesic effect of the hybrid peptide EMNT-1 is mainly regulated by the ?2-opioid receptor,and the analgesic effect of the hybrid peptide EMNT-2 is mainly regulated by ?1-opioid receptor,?2-opioid receptor and ?-opioid receptor.In addition,the analgesic tolerance test results show that the hybrid peptide EMNT-1 has high-efficiency analgesic activity without side effects of analgesic tolerance.In the end,the subject successfully established a neuropathic pain model using the SNI method to study the anti-neuralgia activity of EMs,hybrid peptides EMNT-1 and EMNT-2 in SNI model mice,and the results show that the hybrid peptides EMNT-1 and EMNT-2 can produce more effective anti-neuralgia effects than the parent peptide EMs.This subject confirmed that the hybrid peptides based on the structural design of EMs and neurotensin have high opioid agonistic activity and can exert high-efficiency central and peripheral analgesic activity.The tolerance of hybrid peptides has been reduced,and the adverse effects on the gastrointestinal tract have been improved to a certain extent.Among them,EMNT-1 has the best pharmacological activity,which can exert intolerant and highly effective central and peripheral analgesic effects,and has low side effects on the gastrointestinal tract.This subject provides an important scientific basis for the development and research of opioid analgesics with high efficiency and low side effects.