Implication of Allopregnanolone in the Antinociceptive Effect of N-Palmitoylethanolamide in Acute or Persistent Pain

The study explored the role of allopregnanolone in the antinociceptive effects of N-palmitoylethanolamide (PEA) in mice experiencing acute and persistent pain. It was found that PEA's analgesic effects were linked to the activation of peroxisome proliferator-activated receptor (PPAR)-α, as these effects were absent in PPAR-α-null mice. The study also indicated that de novo neurosteroid synthesis contributed to PEA's effects, as evidenced by reduced antinociceptive activity when mice were treated with aminoglutethimide or finasteride. PEA treatment increased allopregnanolone levels in the spinal cord and restored the expression of proteins involved in neurosteroidogenesis, specifically in the affected areas of the spinal cord. These findings suggested that neurosteroid synthesis played a significant role in PEA's modulation of pain behavior.