期刊
PLOS ONE
卷 13, 期 7, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0199643
关键词
-
资金
- NIH [DA032464, 1R21DA033831, GM087519]
- Lehigh Accelerator
- PA CURE
- Danish Research Foundation
- XSEDE [MCB-070009]
- HHMI
- Lehigh University Mountaintop Project
- Lehigh Presidential Scholar's program
- CAS
- Department of Biological Sciences
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [U54GM087519] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R41DA032464, R21DA033831, R44DA032464] Funding Source: NIH RePORTER
Neuronal nicotinic acetylcholine receptors (nAChRs) of the cholinergic system have been linked to antinociception, and therefore could be an alternative target for pain alleviation. nAChR activity has been shown to be regulated by the nicotinic modulator, lynxl, which forms stable complexes with nAChRs and has a negative allosteric action on their function. The objective in this study was to investigate the contribution of lynxl to nicotine-mediated antinociception. Lynxl contribution was investigated by mRNA expression analysis and electrophysiological responses to nicotine in the dorsal raphe nucleus (DRN), a part of the pain signaling pathway. In vivo antinociception was investigated in a test of nociception, the hot-plate analgesia assay with behavioral pharmacology. Lynx1/alpha 4 beta 2 nAChR interactions were investigated using molecular dynamics computational modeling. Nicotine evoked responses in serotonergic and GABAergic neurons in the DRN are augmented in slices lacking lynx1(lynx1KO). The antinociceptive effect of nicotine and epibatidine is enhanced in lynx1KO mice and blocked by mecamylamine and DH beta E. Computer simulations predict preferential binding affinity of lynx1 to the alpha:alpha interface that exists in the stoichiometry of the low sensitivity (alpha 4)(3)(beta 2)(2) nAChRs. Taken together, these data point to a role of lynx1 in mediating pain signaling in the DRN through preferential affinity to the low sensitivity alpha 4 beta 2 nAChRs. This study suggests that lynx1 is a possible alternative avenue for nociceptive modulation outside of opioid-based strategies.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据