CannabinEYEds: The Endocannabinoid System as a Regulator of the Ocular Surface Nociception, Inflammatory Response, Neovascularization and Wound Healing

Abstract

The endocannabinoid system (ECS) is a complex regulatory system, highly conserved among vertebrates. It has been widely described in nearly all human tissues. In the conjunctiva and cornea, the ECS is believed to play a pivotal role in the modulation of the local inflammatory state as well as in the regulation of tissue repair and fibrosis, neo-angiogenesis and pain perception. This review aims to summarize all the available data on ECS expression and its function in ocular surface structures to provide a specific insight concerning its modulation in dry eye disease, and to propose directions for future research.

Keywords: CB1-receptor; CB2-receptor; ECS; PPAR; TRPV1; conjunctiva; cornea; dry eye; endocannabinoid system; ocular surface.

Figure 1

Agonism on cannabinoid receptor 1 (CB1r) by 2-arachidonoylglycerol (2-AG), N-arachidonoylethanolamine (AEA), docosahexaenoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA) is able to desensitize transient receptor potential cation channel subfamily V member 1 (TRPV1) (yellow arrow) and, via the epidermal growth factor receptor (EGFR)/MAPK, to promote human corneal epithelial cells (HCEC) migration and proliferation (violet pathway). The activation of transient receptor potential vanilloid-1 (TRPV1) elicit TAK1-JNK1 signaling cascade, which in turn is responsible for the promotion of tissue immune infiltration, fibrosis and neovascularization (blue pathway).

Figure 2

Agonism on peroxisome proliferator-activated receptor (PPAR) family members, mediated by a wide array of molecules (i.e., AEA, palmitoylethanolamide (PEA), virodhamine, DHEA and EPEA), negatively interferes with corneal tissue immune infiltration, fibrosis and neovascularization.