title: Melittin activates TRPV1 receptors in primary nociceptive sensory neurons via the phospholipase A2 cascade pathways.
abstract: Previous studies demonstrated that melittin, the main peptide in bee venom, could cause persistent spontaneous pain, primary heat and mechanical hyperalgesia, and enhance the excitability of spinal nociceptive neurons. However, the underlying mechanism of melittin-induced cutaneous hypersensitivity is unknown. Effects of melittin applied topically to acutely dissociated rat dorsal root ganglion neurons were studied using whole-cell patch clamp and calcium imaging techniques. Melittin induced intracellular calcium increases in 60% of small (<25 μm) and medium (<40 μm) diameter sensory neurons. In current clamp, topical application of melittin evoked long-lasting firing in 55% of small and medium-sized neurons tested. In voltage clamp, melittin evoked inward currents in sensory neurons in a concentration-dependent manner. Repeated application of melittin caused increased amplitude of the inward currents. Most melittin-sensitive neurons were capsaicin-sensitive, and 65% were isolectin B4 positive. Capsazepine, the TRPV1 receptor inhibitor, completely abolished the melittin-induced inward currents and intracellular calcium transients. Inhibitions of signaling pathways showed that phospholipase A(2), but not phospholipase C, was involved in producing the melittin-induced inward currents. Inhibitors of cyclooxygenases (COX) and lipoxygenases (LOX), two key components of the arachidonic acid metabolism pathway, each partially suppressed the inward current evoked by melittin. Inhibitors of protein kinase A (PKA), but not of PKC, also abolished the melittin-induced inward currents. These results indicate that melittin can directly excite small and medium-sized sensory neurons at least in part by activating TRPV1 receptors via PLA2-COXs/LOXs cascade pathways.
authors: Institute for Biomedical Sciences of Pain, Capital Medical University, Beijing 100069, PR China.
authors: Yi-Ru
authors: YR
authors: Du
authors: Yong
authors: Y
authors: Xiao
authors: Zhuo-Min
authors: ZM
authors: Lu
authors: Jing
authors: J
authors: Ding
authors: Fang
authors: F
authors: Xie
authors: Han
authors: H
authors: Fu
authors: Yan
authors: Y
authors: Wang
authors: Judith A
authors: JA
authors: Strong
authors: Jun-Ming
authors: JM
authors: Zhang
authors: Jun
authors: J
authors: Chen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D008297:Male; D008555:Melitten / Q000494:pharmacology*; D054467:Phospholipases A2 / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D050916:TRPV Cation Channels / Q000819:agonists* / Q000037:antagonists & inhibitors
chemical_list: D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D008555:Melitten; D011451:Prostaglandin-Endoperoxide Synthases; D054467:Phospholipases A2