The Bioactivity Study Of Endogenous Opioid Peptides On The Antinociceptive Tolerance And Angiogenesis

Endogenous peptides are a kind of neurotransmitter and neuroregulator existing in animal and human widely.They have various physiological and pharmacological actions,involving such as analgesia,development and endocrinology,cardiovascular response,immunological response,angiogenesis and so on Opioid drugs are used clinically as unsurpassed analgesic agents for pain treatment,whereas,the usage of opioid is limited because of their tendency to produce tolerance,respiratory depression and constipation.They are often used combined with other pharmacological agents to reduce the side effects.Besides the central nervous system, the mu and delta opioid receptors exist on endothelium and the endothelial cells are the most important component involving in angiogenesis.In the present work,we investigated the effect of melatonin on the development of antinociceptive tolerance to opioid receptor agonists and the adjusting effect of endogenous opioid peptides on angiogenesis in vivo and in vitro.1.The effects of melatonin(Mel)on the development of tolerance to antinociceptive actions induced by mu and delta-opioid receptor agonists were determined in male Kunming mice.In the mouse tail-flick tests,selective mu and delta receptor agonists were repeatedly administered to mice supraspinally (intracerebroventricularly,i.c.v)in the absence or presence of melatonin. Administration of endomorphin-1(EM-1,a mu opioid receptor agonist)or deltorphinâ… (delâ… ,a delta opioid receptor agonist)twice daily for 4 days produced antinociceptive tolerance compared with vehicle controls.Co-administration with melatonin prevented the development of tolerance to deltorphinâ… analgesia,and this effect was dose-dependent.However,melatonin did not affect the development of antinociceptive tolerance to endomorphin-1.Additionally,the attenuation of deltorphinâ… tolerance by melatonin was reduced by chronic treatment with luzindole (luz),a selective antagonist on the MT2 receptor subtype.These data suggest that melatonin interferes with the neural mechanisms involved in the development of tolerance to delta opioid agonist analgesia via its receptor. 2.The effects of endogenous opioid peptides on angiogenesis were evaluated in the chick embryo chorioallantoic membrane(CAM)assay.Endomorphin-1, endomorphin-2 and deltorphinâ… at the dosage of 1,10,100 nmol/embryo could stimulate angiogenesis dose-dependently,respectively.Naloxone,the nonselective opioid receptor antagonist,did not influence angiogenesis alone;but it could antagonize the stimulative effects of the opioid peptides on angiogenesis when it was administrated in combination with the opioid peptides.The results suggested that endogenous opioid peptides(endomorphin-1 and -2 and deltorphinâ… )stimulated angiogenesis in the CAM assay,and these effects were modulated with the opioid receptors.3.Furthermore,the adjusting effects of endogenous opioid peptides on angiogenesis were evaluated in the proliferation,migration,adhesion and tube formation assays of the human umbilical vein endothelial cell(HUVEC). Endomorphin-1,endomorphin-2 and deltorphinâ… at the lower dosage could stimulate HUVECs proliferation,migration,adhesion and tube formation in a dose dependent manner,respectively;whereas,they exhibited the inhibitory effects on those assays of HUVECs at the higher dose.Naloxone did not influence angiogenesis alone;but it could antagonize the regulative effects of the opioid peptides on angiogenesis when it was administrated in combination with the opioid peptides.The data suggested that endogenous opioid peptides(endomorphin-1 and -2 and deltorphinâ… )affected angiogenesis bidirectionally at the cellular level,and these effects were modulated with the opioid receptors.