title: Contribution of large-sized primary sensory neuronal sensitization to mechanical allodynia by upregulation of hyperpolarization-activated cyclic nucleotide gated channels via cyclooxygenase 1 cascade.
abstract: Under physiological state, small- and medium-sized dorsal root ganglia (DRG) neurons are believed to mediate nociceptive behavioral responses to painful stimuli. However, recently it has been found that a number of large-sized neurons are also involved in nociceptive transmission under neuropathic conditions. Nonetheless, the underlying mechanisms that large-sized DRG neurons mediate nociception are poorly understood. In the present study, the role of large-sized neurons in bee venom (BV)-induced mechanical allodynia and the underlying mechanisms were investigated. Behaviorally, it was found that mechanical allodynia was still evoked by BV injection in rats in which the transient receptor potential vanilloid 1-positive DRG neurons were chemically deleted. Electrophysiologically, in vitro patch clamp recordings of large-sized neurons showed hyperexcitability in these neurons. Interestingly, the firing pattern of these neurons was changed from phasic to tonic under BV-inflamed state. It has been suggested that hyperpolarization-activated cyclic nucleotide gated channels (HCN) expressed in large-sized DRG neurons contribute importantly to repeatedly firing. So we examined the roles of HCNs in BV-induced mechanical allodynia. Consistent with the overexpression of HCN1/2 detected by immunofluorescence, HCNs-mediated hyperpolarization activated cation current (Ih) was significantly increased in the BV treated samples. Pharmacological experiments demonstrated that the hyperexcitability and upregulation of Ihin large-sized neurons were mediated by cyclooxygenase-1 (COX-1)-prostaglandin E2 pathway. This is evident by the fact that the COX-1 inhibitor significantly attenuated the BV-induced mechanical allodynia. These results suggest that BV can excite the large-sized DRG neurons at least in part by increasing Ihthrough activation of COX-1.
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, PR China; Key Laboratory of Brain Stress and Behavior, PLA, Xi'an 710038, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, PR China; Key Laboratory of Brain Stress and Behavior, PLA, Xi'an 710038, PR China.
authors.forename: Fei
authors.initials: F
authors.lastname: Yang
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, PR China; Key Laboratory of Brain Stress and Behavior, PLA, Xi'an 710038, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, PR China; Key Laboratory of Brain Stress and Behavior, PLA, Xi'an 710038, PR China.
authors.forename: Han
authors.initials: H
authors.lastname: Fu
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, PR China; Key Laboratory of Brain Stress and Behavior, PLA, Xi'an 710038, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, PR China; Key Laboratory of Brain Stress and Behavior, PLA, Xi'an 710038, PR China.
authors.forename: Chun-Li
authors.initials: CL
authors.lastname: Li
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, PR China; Key Laboratory of Brain Stress and Behavior, PLA, Xi'an 710038, PR China.
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Department of Psychology, College of Science, The University of Texas at Arlington, Arlington, TX 76019, USA. Electronic address: qilin@uta.edu.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, PR China; Key Laboratory of Brain Stress and Behavior, PLA, Xi'an 710038, PR China; Beijing Institute for Brain Disorders, Beijing 100069, PR China. Electronic address: junchen@fmmu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D001514:Bee Venoms / Q000633:toxicity; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D001514:Bee Venoms; D016861:Cyclooxygenase Inhibitors; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D051545:Cyclooxygenase 1
keywords: Bee venom; Cyclooxygenases 1; Hyperexcitability; Hyperpolarization-activated cation channel; Large-sized DRG neurons; Prostaglandin E2