Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation

Yatendra Mulpuri, Vincent N. Marty, Joseph J. Munier, Ken Mackie, Brian Schmidt, Herbert H. Seltzman, Igor Spigelman

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)85-97
Number of pages13
JournalNeuropharmacology
Volume139
DOIs
StatePublished - Sep 1 2018

Fingerprint

Cannabinoid Receptor CB1
Cannabinoids
Peripheral Nervous System Diseases
Drug Therapy
Pain
Hyperalgesia
Central Nervous System
Cannabinoid Receptor Antagonists
Endocannabinoids
Spinal Ganglia
Therapeutics
Cisplatin
Neoplasms

Keywords

  • Allodynia
  • CB1 receptor
  • CB2 receptor
  • Chemotherapy neuropathy
  • Endocannabinoid enzymes
  • Operant behavior
  • Tolerance

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation. / Mulpuri, Yatendra; Marty, Vincent N.; Munier, Joseph J.; Mackie, Ken; Schmidt, Brian; Seltzman, Herbert H.; Spigelman, Igor.

In: Neuropharmacology, Vol. 139, 01.09.2018, p. 85-97.

Research output: Contribution to journalArticle

Mulpuri, Yatendra ; Marty, Vincent N. ; Munier, Joseph J. ; Mackie, Ken ; Schmidt, Brian ; Seltzman, Herbert H. ; Spigelman, Igor. / Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation. In: Neuropharmacology. 2018 ; Vol. 139. pp. 85-97.
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