# Activation of Cannabinoid Receptor 1 Enhances Wound Healing by Promoting the Proliferative Phase

## TL;DR

Activating the cannabinoid receptor 1 (CB1) promotes wound healing by enhancing cell proliferation and collagen production in both human cells and mice.

## Contribution

This study is the first to demonstrate that CB1 activation accelerates wound healing through specific molecular mechanisms in both in vitro and in vivo models.

## Key findings

- CB1 agonists increased fibroblast proliferation, migration, and collagen synthesis in human dermal cells.
- ACEA treatment in mice accelerated wound closure and increased dermal and epidermal thickness.
- CB1 activation upregulated α-SMA, type I collagen, and fibronectin expression in wound healing models.

## Abstract

The mechanisms underlying wound healing mediated by cannabinoid receptor 1 (CB1)—known for its neuromodulatory functions—remain incompletely understood. Therefore, we investigated the impact of activating CB1 using specific agonists, both in vitro and in vivo, with a focus on wound healing. In the in vitro study, fibroblasts were isolated and cultured from the dermis of human skin and treated with a CB1 agonist, 2-arachidonyl glyceryl ether (2-AGE). In the in vivo study, a mouse acute wound model was created using a skin biopsy punch and treated with the CB1 agonist arachidonoyl 2′-chloroethylamide (ACEA). The in vitro study revealed that 2-AGE increased cell proliferation and differentiation, upregulated the expression of alpha-smooth muscle actin (α-SMA), N-cadherin, and vimentin, and enhanced cell migration as well as the synthesis of type I and III collagen and fibronectin in normal human dermal fibroblasts. The CB1 antagonist AM251 abolished 2-AGE-induced expression of α-SMA, type I collagen, and fibronectin. In vivo, ACEA treatment accelerated wound closure, increased expression of α-SMA, type I collagen, and fibronectin, and ultimately increased epidermal and dermal thickness. Overall, these findings suggest that the activation of CB1 promotes wound healing and provides evidence for the therapeutic potential of CB1 agonists in wound treatment.