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

Wei Wei, Weili Liu, Shibin Du, Gokulapriya Govindarajalu, Antony Irungu, Alex Bekker, Yuanxiang Tao

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2436-2448
Number of pages13
JournalNeurotherapeutics
Volume18
Issue number4
DOIs
StatePublished - Oct 2021

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)

Keywords

  • Anterior cingulate cortex
  • Chemotherapy-induced neuropathic pain
  • GABA receptor
  • Intravenous injection
  • Metastatic bone cancer pain
  • PSD-95
  • Spinal cord dorsal horn
  • ZL006-05
  • nNOS

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