Meclizine and Metabotropic Glutamate Receptor Agonists Attenuate Severe Pain and Ca2+Activity of Primary Sensory Neurons in Chemotherapy-Induced Peripheral Neuropathy

John Shannonhouse, Matteo Bernabucci, Ruben Gomez, Hyeonwi Son, Yan Zhang, Chih Hsuan Ai, Hirotake Ishida, Yu Shin Kim

Research output: Contribution to journalArticlepeer-review

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) affects ;68% of patients undergoing chemotherapy, causing debilitating neuropathic pain and reducing quality of life. Cisplatin is a commonly used platinum-based chemotherapeutic drug known to cause CIPN, possibly by causing oxidative stress damage to primary sensory neurons. Metabotropic glutamate receptors (mGluRs) are widely hypothesized to be involved in pain processing and pain mitigation. Meclizine is an H1 histamine receptor antagonist known to have neuroprotective effects, including an anti-oxidative effect. Here, we used a mouse model of cisplatin-induced CIPN using male and female mice to test agonists of mGluR8 and Group II mGluR as well as meclizine as interventions to reduce cisplatin-induced pain. We performed behavioral pain tests, and we imaged Ca2+activity of the large population of dorsal root ganglia (DRG) neurons in vivo. For the latter, we used a genetically-encoded Ca2+indicator, Pirt-GCaMP3, which enabled us to monitor different drug interventions at the level of the intact DRG neuronal ensemble. We found that CIPN increased spontaneous Ca2+activity in DRG neurons, increased number of Ca2+transients, and increased hyper-responses to mechanical, thermal, and chemical stimuli. We found that mechanical and thermal pain caused by CIPN was significantly attenuated by the mGluR8 agonist, (S)23,4-DCPG, the Group II mGluR agonist, LY379268, and the H1 histamine receptor antagonist, meclizine. DRG neuronal Ca2+activity elevated by CIPN was attenuated by LY379268 and meclizine, but not by (S)23,4-DCPG. Furthermore, meclizine and LY379268 attenuated cisplatin-induced weight loss. These results suggest that Group II mGluR agonist, mGluR8 agonist, and meclizine are promising candidates as new treatment options for CIPN, and studies of their mechanisms are warranted.

Original languageEnglish (US)
Pages (from-to)6020-6037
Number of pages18
JournalJournal of Neuroscience
Volume42
Issue number31
DOIs
StatePublished - Aug 3 2022

Keywords

  • chemotherapy-induced neuropathy
  • chronic pain
  • GCaMP calcium imaging
  • in vivo imaging
  • meclizine
  • primary sensory neuron

ASJC Scopus subject areas

  • Medicine(all)

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