PEA Palmitoylethanolamide – “Glia & Mast Cells as Target, An Anti-Inflammatory & Neuroprotective Lipid Mediator”


Another oustanding article on palmitoylethanolamide “PEA.” I have seen profound results with it relieving intractable neuropathic pain in a woman with CRPS for years, and I suspect it may help Major Depressive Disorder but that remains to be tested.


I need to add that opioids create pain. One mechanism by which that occurs is that opioids create pro-inflammatory cytokines, which creates more pain. Patients may see no response to essential pain relieving medications untill they taper off all opioids and allow the system to stabilize. Otherwise, they will have pain forever and it may increase.


Glia and mast cells as targets for palmitoylethanolamide,

an anti-inflammatory and neuroprotective lipid mediator



Authors  Skaper SD, Facci L, Giusti P.

Mol Neurobiol. 2013 Oct;48(2):340-52.  Epub 2013 Jun 28.


Glia are key players in a number of nervous system disorders. Besides releasing glial and neuronal signaling molecules directed to cellular homeostasis, glia respond also to pro-inflammatory signals released from immune-related cells, with the mast cell being of particular interest. A proposed mast cell-glia communication may open new perspectives for designing therapies to target neuroinflammation by differentially modulating activation of non-neuronal cells normally controlling neuronal sensitization-both peripherally and centrally. Mast cells and glia possess endogenous homeostatic mechanisms/molecules that can be upregulated as a result of tissue damage or stimulation of inflammatory responses. Such molecules include the N-acylethanolamines, whose principal family members are the endocannabinoid N-arachidonoylethanolamine (anandamide), and its congeners N-stearoylethanolamine, N-oleoylethanolamine, and N-palmitoylethanolamine (PEA). A key role of PEA may be to maintain cellular homeostasis when faced with external stressors provoking, for example, inflammation: PEA is produced and hydrolyzed by microglia, it downmodulates mast cell activation, it increases in glutamate-treated neocortical neurons ex vivo and in injured cortex, and PEA levels increase in the spinal cord of mice with chronic relapsing experimental allergic encephalomyelitis. Applied exogenously, PEA has proven efficacious in mast cell-mediated experimental models of acute and neurogenic inflammation. This fatty acid amide possesses also neuroprotective effects, for example, in a model of spinal cord trauma, in a delayed post-glutamate paradigm of excitotoxic death, and against amyloid β-peptide-induced learning and memory impairment in mice. These actions may be mediated by PEA acting through “receptor pleiotropism,” i.e., both direct and indirect interactions of PEA with different receptor targets, e.g., cannabinoid CB2 and peroxisome proliferator-activated receptor-alpha.




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It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.


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2 Responses to “PEA Palmitoylethanolamide – “Glia & Mast Cells as Target, An Anti-Inflammatory & Neuroprotective Lipid Mediator””

  1. Rich Askew Says:

    I can only speak for myself, but, opiates are the ONLY source of relief offered to me as treatment for cold hand, 4 limb, advanced stage CRPS RSD. I also have a number of significant stenosis and past fractures which have been overcome with causalgia ( which I believe is central nerve pain ). The pain levels are so severe that it changed me. It is so overwhelming that ANY relief is appreciated. I have noticed however, that laws of diminishing returns and drug does lose its effectiveness. That being said, opiates have been the only treatment other than a tenacious PT regiment, which help me function. I cannot emphasize enough just how flipping ‘out of the ordinary’ overwhelming, CRPS pain is! Lord help us.

    • Nancy Sajben MD Says:

      Yes, opioids are viewed by all as one of the ten essential medications. Sadly they work for acute pain far better. What we urgently need is funding research for better medications to treat **chronic** pain. There is little to no funding to understand the innate immune system just discovered this century, and its profound role in chronic pain. Instead billions have gone in to one “new” opioid after another and another and another, charging $100 or more for each dose 6 times a day. And the US is alone is prescribing opioids so frequently and in such high doses. We need better. People with prostate cancer or breast cancer or heart disease organize for research funding. No one seems to care about chronic pain except opioid manufacturers.

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