In the Journal ‘Pain” Daniele Piomelli, the Americal professor widely known for his work on lipid signaling drugs discusses the growing insight in the important biological roles of lipids like PEA. He uses a scedule to explain the biological action of PEA via the nucleas, see artist impression of his scedule:
He discusses the role of lipid mediators, which are synthesized from membrane components:
Among these membrane-derived analgesics is a small family of lipid molecules in which a saturated or monounsaturated fatty acid – such as palmitic or oleic acid – is chemically linked to ethanolamine through an amide bond. In neurons and innate immune cells, these endogenous lipid amides are formed by cleavage of the phospholipid precursor, N-acylphosphatidylethanolamine, a process that is carried out by a specialized phospholipase D enzyme. One of the best-known members of this family, palmitoylethanolamide (PEA), produces profound analgesic and anti-inﬂammatory effects in animals by recruiting a nuclear receptor called peroxisome proliferator-activated receptor-a (PPAR-a).
He discussed new findings were data point into the direction that that PPAR-a stimulates the transcription of genes encoding for steroidogenic enzymes, resulting in an up-regulation of neurosteroids that contribute to the analgesic effects of PEA.
Commentary of Danielle Piomelli:
A thickening network of lipids in: PAIN 153 (2012) 3–4