Journal
THERANOSTICS
Volume 11, Issue 12, Pages 5970-5985Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.58364
Keywords
neuropathic pain; central sensitization; excitatory/inhibitory synaptic transmission; analgesic tolerance; GABA(A) receptors
Categories
Funding
- National Natural Science Foundation of China [82090042, 31530091, 81870912]
- National Key Research and Development Program of China [2016YFC1306703]
- Science and Technology Program of Guangdong [2018B030334001]
- Collaborative Innovation Center for Cardiovascular Disease Translational Medicine
- Science and Technology Development Foundation of Nanjing Medical University
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The study aims to prevent analgesic tolerance by co-targeting NMDAR downstream signaling and GABA(A)Rs. Results show that chronic use of the dual-target compound ZL006-05 can avoid analgesic tolerance and unwanted side effects in treating neuropathic pain.
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 gamma-aminobutyric acid type A receptors (GABA(A)Rs). 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 GABA(A)Rs to assess the selectivity of (+)-borneol and ZL006-05. The expression of alpha 2 and alpha 3 subunits of GABA(A)Rs 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 alpha 2- and alpha 3-containing GABA(A)Rs 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 alpha 2-containing GABA(A)R selectively. Chronic use of ZL006-05 did not produce analgesic tolerance and unwanted side effects. Conclusion: By targeting nNOS-PSD-95 interaction and alpha 2-containing GABA(A)R 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.
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