title: A novel intrinsic analgesic mechanism: the enhancement of the conduction failure along polymodal nociceptive C-fibers.
abstract: Although conduction failure has been observed in nociceptive C-fibers, little is known regarding its significance or therapeutic potential. In a previous study, we demonstrated that C-fiber conduction failure, which is regarded as an intrinsic self-inhibition mechanism, was reduced in circumstances of painful diabetic neuropathy. In this study, we extend this finding in the complete Freund's adjuvant model of inflammatory pain and validate that the degree of conduction failure decreased and led to a greater amount of pain signals conveyed to the central nervous system. In complete Freund's adjuvant-injected animals, conduction failure occurred in a C-fiber-selective, activity-dependent manner and was associated with an increase in the rising slope of the C-fiber after-hyperpolarization potential. To target conduction failure in a therapeutic modality, we used ZD7288, an antagonist of hyperpolarization-activated, cyclic nucleotide-modulated channels which are activated by hyperpolarization and play a pivotal role in both inflammatory and neuropathic pain. ZD7288 promoted conduction failure by suppressing Ih as a mechanism to reduce the rising slope of the after-hyperpolarization potential. Moreover, perineuronal injection of ZD7288 inhibited abnormal mechanical allodynia and thermal hyperalgesia without affecting motor function or heart rate. Our data highlight the analgesic potential of local ZD7288 application and identify conduction failure as a novel target for analgesic therapeutic development.
authors: Department of Neurobiology and Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.|Department of Psychology, Fourth Military Medical University, Xi'an, China.
authors: Xiuchao
authors: X
authors: Wang
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Shan
authors: S
authors: Wang
authors: Department of Neurobiology and Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
authors: Wenting
authors: W
authors: Wang
authors: Department of Neurobiology and Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
authors: Jianhong
authors: J
authors: Duan
authors: Department of Neurobiology and Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
authors: Ming
authors: M
authors: Zhang
authors: Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan, China.
authors: Xiaohua
authors: X
authors: Lv
authors: Department of Neurobiology and Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
authors: Chunxiao
authors: C
authors: Niu
authors: Department of Neurobiology and Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
authors: Chao
authors: C
authors: Tan
authors: Department of Neurobiology and Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
authors: Yuanbin
authors: Y
authors: Wu
authors: The 323 Military Hospital, Xi'an, China.
authors: Jing
authors: J
authors: Yang
authors: Department of Neurobiology and Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
authors: Sanjue
authors: S
authors: Hu
authors: Department of Neurobiology and Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.|Department of Radiation Biology, Faculty of Preventive Medicine, Fourth Military Medical University, Xi'an, China.
authors: Junling
authors: J
authors: Xing
mesh_terms: D000818:Animals; D001703:Biophysics; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005620:Freund's Adjuvant / Q000633:toxicity; D005727:Ganglia, Spinal / Q000166:cytology; D006930:Hyperalgesia / Q000503:physiopathology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology*; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000209:etiology / Q000473:pathology*; D017288:Pain Threshold / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D011743:Pyrimidines; C082246:ICI D2788; D005620:Freund's Adjuvant; D002118:Calcium