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Research Articles, Cellular/Molecular

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 and Yu Shin Kim
Journal of Neuroscience 3 August 2022, 42 (31) 6020-6037; DOI: https://doi.org/10.1523/JNEUROSCI.1064-21.2022
John Shannonhouse
1Department of Oral & Maxillofacial Surgery, School of Dentistry
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Matteo Bernabucci
3Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854
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Ruben Gomez
1Department of Oral & Maxillofacial Surgery, School of Dentistry
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Hyeonwi Son
1Department of Oral & Maxillofacial Surgery, School of Dentistry
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Yan Zhang
1Department of Oral & Maxillofacial Surgery, School of Dentistry
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Chih-Hsuan Ai
1Department of Oral & Maxillofacial Surgery, School of Dentistry
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Hirotake Ishida
1Department of Oral & Maxillofacial Surgery, School of Dentistry
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Yu Shin Kim
1Department of Oral & Maxillofacial Surgery, School of Dentistry
2Programs in Integrated Biomedical Sciences, Translational Sciences, Biomedical Engineering, Radiological Sciences, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229
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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)−3,4-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)−3,4-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.

SIGNIFICANCE STATEMENT Chemotherapy-induced peripheral neuropathy (CIPN) is a painful condition that affects most chemotherapy patients and persists several months or longer after treatment ends. Research on CIPN mechanism is extensive but has produced only few clinically useful treatments. Using in vivo GCaMP Ca2+ imaging in live animals over 1800 neurons/dorsal root ganglia (DRG) at once, we have characterized the effects of the chemotherapeutic drug, cisplatin and three treatments that decrease CIPN pain. Cisplatin increases sensory neuronal Ca2+ activity and develops various sensitization. Metabotropic glutamate receptor (mGluR) agonist, LY379268 or the H1 histamine receptor antagonist, meclizine decreases cisplatin's effects on neuronal Ca2+ activity and reduces pain hypersensitivity. Our results and experiments provide insights into cellular effects of cisplatin and drugs preventing CIPN pain.

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

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The Journal of Neuroscience: 42 (31)
Journal of Neuroscience
Vol. 42, Issue 31
3 Aug 2022
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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
Journal of Neuroscience 3 August 2022, 42 (31) 6020-6037; DOI: 10.1523/JNEUROSCI.1064-21.2022

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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
Journal of Neuroscience 3 August 2022, 42 (31) 6020-6037; DOI: 10.1523/JNEUROSCI.1064-21.2022
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Keywords

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

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