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

• Authors: Wei Wei, Weili Liu, Shibin Du, Gokulapriya Govindarajalu, Antony Irungu, Alex Bekker, Yuan-Xiang Tao
• Journal: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics (Neurotherapeutics) Vol. 18 Issue 4 Pg. 2436-2448 (10 2021) ISSN: 1878-7479 [Electronic] United States
• PMID: 34796458 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The American Society for Experimental NeuroTherapeutics, Inc.

Chemical References

• Antineoplastic Agents
• Receptors, GABA-A
• Nitric Oxide Synthase Type I

Topics

• Animals
• Antineoplastic Agents (adverse effects)
• Cancer Pain (drug therapy)
• Humans
• Neoplasms (drug therapy)
• Neuralgia (chemically induced, drug therapy)
• Nitric Oxide Synthase Type I
• Rats
• Rats, Sprague-Dawley
• Receptors, GABA-A