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Papers of the Week

Papers: 24 Apr 2021 - 30 Apr 2021

Animal Studies, Pharmacology/Drug Development





A pain killer without analgesic tolerance designed by co-targeting PSD-95-nNOS interaction and α2-containning GABARs.


Li J, Zhang L, Xu C, Shen Y-Y, Lin Y-H, Zhang Y, Wu H-Y, Chang L, Zhang Y-D, Chen R, Zhang Z-P, Luo C-X, Li F, Zhu D-Y
Theranostics. 2021; 11(12):5970-5985.
PMID: 33897893.


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 (GABARs). 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 GABARs to assess the selectivity of (+)-borneol and ZL006-05. The expression of α2 and α3 subunits of GABARs 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. (+)-Borneol selectively potentiated α2- and α3-containing GABARs 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 GABAR selectively. Chronic use of ZL006-05 did not produce analgesic tolerance and unwanted side effects. By targeting nNOS-PSD-95 interaction and α2-containing GABAR 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.