The Endocannabinoid System (ECS) represents a promising therapeutic target for pain management, with cannabinoid type 1 (CB1) receptors playing a prominent role in pain modulation. However, the widespread distribution of CB1 receptors throughout the central nervous system poses a major therapeutic challenge, as their activation is also associated with unwanted psychoactive, cognitive, and motor effects.

This seminar will explore two complementary strategies to harness the analgesic potential of ECS modulation while minimizing adverse effects. First, indirect modulation of the ECS will be explored through the exogenous administration of palmitoylethanolamide (PEA), an N-acylethanolamine belonging to the broader endocannabinoid-related lipid signaling network, in experimental models of central post-stroke pain, with particular emphasis on the role of neuroinflammatory mechanisms. Second, the potential to dissociate CB1-mediated antinociception from unwanted effects will be explored, with particular emphasis on the functional dichotomy between plasma membrane-localized CB1 receptors, associated with antinociception, and mitochondrial CB1 receptors, implicated in unwanted effects such as catalepsy and memory impairment. This will be discussed through the pharmacological characterization of the novel phytocannabinoid Δ⁹-tetrahydrocannabiphorol (Δ⁹-THCP) across different experimental pain models and using genetic mouse models, including CB1-KO and DN22-CB1-KI mice, the latter expressing CB1 receptors at the plasma membrane but not in mitochondria.

Together, these findings highlight novel strategies to improve the therapeutic selectivity of ECS-targeted pain treatments.

More information:

• https://research.universityofgalway.ie/en/persons/rosmara-infantino/