Meclizine and metabotropic glutamate receptor agonists attenuate severe pain and Ca 2+ activity of primary sensory neurons in chemotherapy-induced peripheral neuropathy.
John ShannonhouseMatteo BernabucciRuben GomezHyeonwi SonYan ZhangChih-Hsuan AiHirotake IshidaYu Shin KimPublished in: The Journal of neuroscience : the official journal of the Society for Neuroscience (2022)
Chemotherapy-induced peripheral neuropathy (CIPN) affects about 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 Ca 2+ activity of the large population of DRG neurons in vivo For the latter, we used a genetically-encoded Ca 2+ 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 Ca 2+ activity in DRG neurons, increased number of Ca 2+ 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 Ca 2+ 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 persist several months or longer after treatment ends. Research on CIPN mechanism is extensive but has produced only few clinically useful treatments. Utilizing in vivo GCaMP Ca 2+ imaging in live animals over 1800 neurons/DRG at once, we have characterized the effects of the chemotherapeutic drug, cisplatin and three treatments that decrease CIPN pain. Cisplatin increases sensory neuronal Ca 2+ activity and develops various sensitization. Metabotropic glutamate receptor agonist, LY379268 or the H1 histamine receptor antagonist, meclizine decreases cisplatin's effects on neuronal Ca 2+ activity and reduces pain hypersensitivity. Our results and experiments provide insights into cellular effects of cisplatin and drugs preventing CIPN pain.
Keyphrases
- chemotherapy induced
- neuropathic pain
- chronic pain
- spinal cord
- pain management
- spinal cord injury
- oxidative stress
- mouse model
- end stage renal disease
- weight loss
- emergency department
- chronic kidney disease
- physical activity
- adipose tissue
- type diabetes
- drug induced
- climate change
- body mass index
- newly diagnosed
- radiation therapy
- postoperative pain
- insulin resistance
- metabolic syndrome
- electronic health record
- peritoneal dialysis
- brain injury
- prognostic factors
- deep learning
- high fat diet induced
- adverse drug