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
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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