Phyto-cannabinoids, natural compounds from Cannabis sativa, have attracted growing interest for their therapeutic potential across various conditions, including chronic pain, inflammation, epilepsy, sleep disorders, psychiatric illnesses, and metabolic dysfunctions. Historically used for pain relief, medical cannabis is now primarily prescribed for severe, neuropathic, cancer-related, and migraine pain. Despite extensive use, the molecular mechanisms by which cannabinoids exert their effects remain incompletely understood. The peripheral cannabinoid hypothesis suggests that cannabinoid receptors outside the central nervous system, particularly on sensory neurons, play a significant role in mediating analgesic and anti-inflammatory effects. This peripheral targeting may allow effective pain relief without central side effects like sedation or cognitive impairment. A key focus of current research is the interaction between phyto-cannabinoids and voltage-gated sodium (NaV) channels, which are essential for neuronal excitability and pain signaling. Recent studies show that cannabinoids modulate NaV channel activity, reducing nociceptor excitability and contributing to analgesia. However, the molecular mechanisms and the diversity of cannabinoid effects on various NaV subtypes remain poorly defined. Our preliminary results demonstrate that selected phyto-cannabinoids significantly inhibit NaV channel activity in key pain-related subtypes, supporting their role in peripheral analgesia. Additionally, our targeted mutations in NaV channels have begun to reveal potential cannabinoid binding sites. The current research aims to characterize the effects of cannabinoids on NaV channels, identify key binding sites, and evaluate their therapeutic potential in relevant pain models. This work will advance the understanding of cannabinoid-mediated analgesia and support the development of safer, non-opioid pain therapeutics.

Supervisor: Prof. Avi Priel