PEA is considered an endogenous Peroxisome Proliferator Activated Receptors (PPAR) agonist or activator, interacting with this receptor to inhibit inflammatory pathways & oxidative stress.¹⁰

During neuropathic pain, PEA can modulate the PPAR pathway that is able to attenuate Nuclear Factor Kappa B cells (NFKB) induced inflammatory factors or tumor necrosis factor (IL-1 or TNF), inhibit infiltration and activation of mast cells, reduce mesangial matrix proliferation induced by reactive oxidative stress (ROS) which then resulted in albuminuria.¹⁰
PEA’s analgesic actions may be due to its agonism of PPAR-α which has been shown to have a pivotal role in the PEA pharmacodynamics mechanisms for pain relief).⁷

PEA does not bind the classical cannabinoid receptors but may indirectly stimulate the effects of both phyto- or endocannabinoids, either by its role as an agonist of the transient receptor potential vanilloid type 1 (TRPV1), peroxisome proliferator-activated receptor-α (PPAR-α) and and novel orphan cannabinoid receptors GPR55 and GPR119 ^7,15 (figure 1).

PEA plays an important role in suppression of inflammation by reducing the activity of the pro-inflammatory enzymes such as COX, eNOS, and iNOS and by reducing mast cell activation.⁷

PEA reduces mast cell filtration, migration, and degranulation.⁷
PEA stops chemostaxis of monocytes to affected areas.¹⁴