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A Compound Mitigates Cancer Pain and Chemotherapy-Induced Neuropathic Pain by Dually Targeting nNOS-PSD-95 Interaction and GABA_A Receptor.

ABSTRACT: Metastatic bone pain and chemotherapy-induced peripheral neuropathic pain are the most common clinical symptoms in cancer patients. The current clinical management of these two disorders is ineffective and/or produces severe side effects. The present study employed a dual-target compound named as ZL006-05 and examined the effect of systemic administration of ZL006-05 on RM-1-induced bone cancer pain and paclitaxel-induced neuropathic pain. Intravenous injection of ZL006-05 dose-dependently alleviated RM-1-induced mechanical allodynia, heat hyperalgesia, cold hyperalgesia, and spontaneously ongoing nociceptive responses during both induction and maintenance periods, without analgesic tolerance, affecting basal/acute pain and locomotor function. Similar behavioral results were observed in paclitaxel-induced neuropathic pain. This injection also decreased neuronal and astrocyte hyperactivities in the lumbar dorsal horn after RM-1 tibial inoculation or paclitaxel intraperitoneal injection. Mechanistically, intravenous injection of ZL006-05 potentiated the GABA_A receptor agonist-evoked currents in the neurons of the dorsal horn and anterior cingulate cortex and also blocked the paclitaxel-induced increase in postsynaptic density-95-neuronal nitric oxide synthase interaction in dorsal horn. Our findings strongly suggest that ZL006-05 may be a new candidate for the management of cancer pain and chemotherapy-induced peripheral neuropathic pain.

SUBMITTER: Wei W

PROVIDER: S-EPMC8804143 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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A Compound Mitigates Cancer Pain and Chemotherapy-Induced Neuropathic Pain by Dually Targeting nNOS-PSD-95 Interaction and GABA<sub>A</sub> Receptor.

Wei Wei W Liu Weili W Du Shibin S Govindarajalu Gokulapriya G Irungu Antony A Bekker Alex A Tao Yuan-Xiang YX

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20211001 4

Metastatic bone pain and chemotherapy-induced peripheral neuropathic pain are the most common clinical symptoms in cancer patients. The current clinical management of these two disorders is ineffective and/or produces severe side effects. The present study employed a dual-target compound named as ZL006-05 and examined the effect of systemic administration of ZL006-05 on RM-1-induced bone cancer pain and paclitaxel-induced neuropathic pain. Intravenous injection of ZL006-05 dose-dependently allev ...[more]

PMID: 34796458

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Project description: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.

Dataset Information

A Compound Mitigates Cancer Pain and Chemotherapy-Induced Neuropathic Pain by Dually Targeting nNOS-PSD-95 Interaction and GABA_A Receptor.

Publications

A Compound Mitigates Cancer Pain and Chemotherapy-Induced Neuropathic Pain by Dually Targeting nNOS-PSD-95 Interaction and GABA<sub>A</sub> Receptor.

Similar Datasets

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Dataset Information

A Compound Mitigates Cancer Pain and Chemotherapy-Induced Neuropathic Pain by Dually Targeting nNOS-PSD-95 Interaction and GABAA Receptor.

Publications

A Compound Mitigates Cancer Pain and Chemotherapy-Induced Neuropathic Pain by Dually Targeting nNOS-PSD-95 Interaction and GABA<sub>A</sub> Receptor.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

A Compound Mitigates Cancer Pain and Chemotherapy-Induced Neuropathic Pain by Dually Targeting nNOS-PSD-95 Interaction and GABA_A Receptor.