Peripheral gating of pain signals by endogenous lipid mediators

Pain Gating is not only related to nerves, non-neuronal cells play an important role!

Pain Gating is not only related to nerves, non-neuronal cells play an important role!

Peripheral gating of pain signals by endogenous lipid mediators, is the title of a new article from the palmitoylethanolamide experts Daniele Piomelli and Oscar Sasso from the Department of Anatomy and Neurobiology, University of California, Irvine. These key opninion leaders ask more interest in the role of lipid-derived mediators as crucial players in this peripheral gating mechanism in chronic pain.

Thus they stress the importance of non-neuronal cells and mediators in the pathophysiology of pain. This is a much forgotten chapter in pain medicine, and a reason why so many patients unnecessary  suffer from pain. Treatment with compounds influencing these non-neuronal mechanisms in gating of pain are the base of a new chapter in pain medicine.

Gating of pain and the role of endogenous lipid mediators, such as palmitoylethanolamide

In this article they review the properties of endogenous bioactive lipids such as palmitoylethanolamide that modulate pain initiation by interacting with receptor systems on primary sensory afferents and neighboring cells that are not neurons, including macrophages, mast cells and keratinocytes. Especially the focus on non-neuronal cells and the interaction with these lipid mediators is the central topic of their elaborate paper.

In their conclusion the highlight three different mechanisms by which palmitoylethanolamide and related lipids modify pain:

The evidence presented here allows us to conjecture that bioactive lipid mediators regulate the access of nociceptive information to the CNS at three distinct stages.

1. In healthy tissues, the tonic release of endogenous PPAR-alpha agonists, such as PEA and OEA, may help set the threshold for nociception by regulating the baseline transcriptional activity of the NF-kappa-B complex and the opening of membrane ion channels in primary sensory afferents and nearby host-defense cells.

2. After an injury has occurred, the temporary interruption of OEA and PEA biosynthesis caused by cell damage and infection may disable the inhibitory influence exerted by these lipid messengers, allowing inflammation to unfold and nociceptive thresholds to decrease.

At the same time, the localized on-demand formation of endocannabinoids such as anandamide may mitigate the effects of exogenous and endogenous proalgesic agents by attenuating nociceptor excitability and counteracting local proinflammatory signals.

3. Lastly, as the response to tissue damage moves toward its resolution phase, a wave of analgesic products of oxidative PUFA metabolism, including lipoxins and resolvins, may help normalize nociceptive responses in the healing tissue.

So these steps make clear how important exogenous palmitoylethanolamide can be, by restoring the decreased endogenous PEA synthesis during phases related to damage and chronic pain.

Source: VOLUME 17 | NUMBER 2 | FEBRUARY 2014 NATURE NEUROSCIENCE: Peripheral gating of pain signals by endogenous lipid mediators

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