1. Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation
- Author
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Mulpuri, Yatendra, Marty, Vincent N, Munier, Joseph J, Mackie, Ken, Schmidt, Brian L, Seltzman, Herbert H, and Spigelman, Igor
- Subjects
Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Neurodegenerative ,Cancer ,Peripheral Neuropathy ,Chronic Pain ,Pain Research ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Analgesics ,Non-Narcotic ,Animals ,Antineoplastic Agents ,Cannabinoid Receptor Modulators ,Cannabinoids ,Cisplatin ,Cold Temperature ,Dose-Response Relationship ,Drug ,Drug Tolerance ,Female ,Ganglia ,Spinal ,Gene Expression Regulation ,Hyperalgesia ,Male ,Peripheral Nervous System Diseases ,RNA ,Messenger ,Rats ,Sprague-Dawley ,Receptor ,Cannabinoid ,CB1 ,Receptor ,Cannabinoid ,CB2 ,Touch ,Chemotherapy neuropathy ,Allodynia ,CB1 receptor ,CB2 receptor ,Endocannabinoid enzymes ,Operant behavior ,Tolerance ,Psychology ,Neurology & Neurosurgery ,Pharmacology and pharmaceutical sciences ,Biological psychology - Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects. Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects. Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy. Results show that local or systemic administration of 4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI) dose-dependently suppressed CIPN mechanical and cold allodynia. Orally administered PrNMI also dose-dependently suppressed CIPN allodynia symptoms in both male and female rats without any CNS side effects. Co-administration with selective cannabinoid receptor subtype blockers revealed that PrNMI's anti-allodynic effects are mediated by CB1 receptor (CB1R) activation. Expression of CB2Rs was reduced in dorsal root ganglia from CIPN rats, whereas expression of CB1Rs and various endocannabinoid synthesizing and metabolizing enzymes was unaffected. Daily PrNMI treatment of CIPN rats for two weeks showed a lack of appreciable tolerance to PrNMI's anti-allodynic effects. In an operant task which reflects cerebral processing of pain, PrNMI also dose-dependently suppressed CIPN pain behaviors. Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms.
- Published
- 2018