A pain killer without analgesic tolerance designed by co-targeting PSD-95-nNOS interaction and α2-containning GABAARs
Autor: | Lei Chang, Hai-Yin Wu, Dong-Ya Zhu, Yu-Hui Lin, Chu Xu, Rong Chen, Fei Li, Ying-Ying Shen, Lin Zhang, Ying-Dong Zhang, Yu Zhang, Jun Li, Chun-Xia Luo, Zheng-Ping Zhang |
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Rok vydání: | 2021 |
Předmět: |
Male
0301 basic medicine Benzylamines Analgesic Medicine (miscellaneous) excitatory/inhibitory synaptic transmission Nitric Oxide Synthase Type I Neurotransmission Pharmacology Cell Line Rats Sprague-Dawley Mice 03 medical and health sciences 0302 clinical medicine Postsynaptic potential Animals Humans Pain Management Pharmacology Toxicology and Pharmaceutics (miscellaneous) gamma-Aminobutyric Acid neuropathic pain Neurons Analgesics analgesic tolerance GABAA receptor Chemistry GABAA receptors Membrane Proteins central sensitization Receptors GABA-A Rats Mice Inbred C57BL Aminosalicylic Acids HEK293 Cells Neuroprotective Agents 030104 developmental biology Spinal Cord nervous system Neuropathic pain Excitatory postsynaptic potential Neuralgia NMDA receptor GABAergic Disks Large Homolog 4 Protein 030217 neurology & neurosurgery Research Paper Signal Transduction |
Zdroj: | Theranostics |
ISSN: | 1838-7640 |
Popis: | Overactivation of N-methyl-D-aspartate receptor (NMDAR) in the spinal cord dorsal horn (SDH) in the setting of injury represents a key mechanism of neuropathic pain. However, directly blocking NMDAR or its downstream signaling, interaction between postsynaptic density-95 (PSD-95) and neuronal nitric oxide synthase (nNOS), causes analgesic tolerance, mainly due to GABAergic disinhibition. The aim of this study is to explore the possibility of preventing analgesic tolerance through co-targeting NMDAR downstream signaling and γ-aminobutyric acid type A receptors (GABAARs). Methods: Mechanical/thermal hyperalgesia were quantified to assess analgesic effects. Miniature postsynaptic currents were tested by patch-clamp recording to evaluate synaptic transmission in the SDH. GABA-evoked currents were tested on HEK293 cells expressing different subtypes of recombinant GABAARs to assess the selectivity of (+)-borneol and ZL006-05. The expression of α2 and α3 subunits of GABAARs and BDNF, and nNOS-PSD-95 complex levels were analyzed by western blotting and coimmunoprecipitation respectively. Open field test, rotarod test and Morris water maze task were conducted to evaluate the side-effect of ZL006-05. Results: (+)-Borneol selectively potentiated α2- and α3-containing GABAARs and prevented the disinhibition of laminae I excitatory neurons in the SDH and analgesic tolerance caused by chronic use of ZL006, a nNOS-PSD-95 blocker. A dual-target compound ZL006-05 produced by linking ZL006 and (+)-borneol through an ester bond blocked nNOS-PSD-95 interaction and potentiated α2-containing GABAAR selectively. Chronic use of ZL006-05 did not produce analgesic tolerance and unwanted side effects. Conclusion: By targeting nNOS-PSD-95 interaction and α2-containing GABAAR simultaneously, chronic use of ZL006-05 can avoid analgesic tolerance and unwanted side effects. Therefore, we offer a novel candidate drug without analgesic tolerance for treating neuropathic pain. |
Databáze: | OpenAIRE |
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