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: Xiuchao Wang, Shan Wang, Wenting Wang, Jianhong Duan, Ming Zhang, Xiaohua Lv, Chunxiao Niu, Chao Tan, Yuanbin Wu, Jing Yang, Sanjue Hu, Junling Xing
• Journal: Pain (Pain) Vol. 157 Issue 10 Pg. 2235-2247 (10 2016) ISSN: 1872-6623 [Electronic] United States
• PMID: 27583680 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
• Pyrimidines
• ICI D2788
• Freund's Adjuvant
• Calcium

Topics

• Animals
• Biophysics
• Calcium (metabolism)
• Disease Models, Animal
• Female
• Freund's Adjuvant (toxicity)
• Ganglia, Spinal (cytology)
• Hyperalgesia (physiopathology)
• Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels (metabolism)
• Inflammation (chemically induced, complications)
• Membrane Potentials (drug effects, physiology)
• Nerve Fibers, Unmyelinated (drug effects, physiology)
• Neural Conduction (drug effects, physiology)
• Neurons (drug effects, physiology)
• Pain (etiology, pathology)
• Pain Threshold (drug effects)
• Patch-Clamp Techniques
• Pyrimidines (pharmacology)
• Rats
• Rats, Sprague-Dawley