Melittin, the Major Pain-Producing Substance of Bee Venom  

作　　者：Jun Chen Su-Min Guan Wei Sun Han Fu 

机构地区：[1]Institute for Biomedical Sciences of Pain, Tangdu Hospital,The Fourth Military Medical University, Xi'an 710038,China [2]Key Laboratory of Brain Stress and Behavior, PLA,Xi'an 710038, China [3]Beijing Institute for Brain Disorders, Beijing 100069, China [4]School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China

出　　处：《Neuroscience Bulletin》2016年第3期265-272,共8页神经科学通报（英文版）

基　　金：supported by grants from the National Basic Research Development Program of China (2013CB 835100);the National Natural Science Foundation of China (81171049,31300919,and 31400948);the National Key Technology R&D Program,China (2013BAI04B04);the Twelfth Five-Year Project of China (AWS12J004)

摘　　要：Melittin is a basic 26-amino-acid polypeptide that constitutes 40-60% of dry honeybee（Apis mellifera）venom.Although much is known about its strong surface activity on lipid membranes,less is known about its painproducing effects in the nervous system.In this review,we provide lines of accumulating evidence to support the hypothesis that melittin is the major pain-producing substance of bee venom.At the psychophysical and behavioral levels,subcutaneous injection of melittin causes tonic pain sensation and pain-related behaviors in both humans and animals.At the cellular level,melittin activates primary nociceptor cells through direct and indirect effects.On one hand,melittin can selectively open thermal nociceptor transient receptor potential vanilloid receptor channels via phospholipase A2-lipoxygenase/cyclooxygenase metabolites,leading to depolarization of primary nociceptor cells.On the other hand,algogens and inflammatory/proinflammatory mediators released from the tissue matrix by melittin＇s pore-forming effects can activate primary nociceptor cells through both ligand-gated receptor channels and the G-protein-coupled receptor-mediated opening of transient receptor potential canonical channels.Moreover,subcutaneous melittin up-regulates Nav1.8 and Nav1.9subunits,resulting in the enhancement of tetrodotoxinresistant Na~＋currents and the generation of long-term action potential firing.These nociceptive responses in the periphery finally activate and sensitize the spinal dorsal horn pain-signaling neurons,resulting in spontaneous nociceptive paw flinches and pain hypersensitivity to thermal and mechanical stimuli.Taken together,it is concluded that melittin is the major pain-producing substance of bee venom,by which peripheral persistent pain and hyperalgesia（or allodynia）,primary nociceptive neuronal sensitization,and CNS synaptic plasticity（or metaplasticity） can be readily induced and the molecular and cellular mechanisms underlying naturally-occurring venomous biotoxins can be experimentally Melittin is a basic 26-amino-acid polypeptide that constitutes 40-60% of dry honeybee（Apis mellifera）venom.Although much is known about its strong surface activity on lipid membranes,less is known about its painproducing effects in the nervous system.In this review,we provide lines of accumulating evidence to support the hypothesis that melittin is the major pain-producing substance of bee venom.At the psychophysical and behavioral levels,subcutaneous injection of melittin causes tonic pain sensation and pain-related behaviors in both humans and animals.At the cellular level,melittin activates primary nociceptor cells through direct and indirect effects.On one hand,melittin can selectively open thermal nociceptor transient receptor potential vanilloid receptor channels via phospholipase A2-lipoxygenase/cyclooxygenase metabolites,leading to depolarization of primary nociceptor cells.On the other hand,algogens and inflammatory/proinflammatory mediators released from the tissue matrix by melittin＇s pore-forming effects can activate primary nociceptor cells through both ligand-gated receptor channels and the G-protein-coupled receptor-mediated opening of transient receptor potential canonical channels.Moreover,subcutaneous melittin up-regulates Nav1.8 and Nav1.9subunits,resulting in the enhancement of tetrodotoxinresistant Na~＋currents and the generation of long-term action potential firing.These nociceptive responses in the periphery finally activate and sensitize the spinal dorsal horn pain-signaling neurons,resulting in spontaneous nociceptive paw flinches and pain hypersensitivity to thermal and mechanical stimuli.Taken together,it is concluded that melittin is the major pain-producing substance of bee venom,by which peripheral persistent pain and hyperalgesia（or allodynia）,primary nociceptive neuronal sensitization,and CNS synaptic plasticity（or metaplasticity） can be readily induced and the molecular and cellular mechanisms underlying naturally-occurring venomous biotoxins can be experimentally

关 键 词：MELITTIN Algogen - Nociceptor Spinaldorsal horn PAIN 

分 类 号：R996.3[医药卫生—毒理学] R402[医药卫生—药学]