New insights in the anti-inflammatory action of palmitoylethanolamide (PEA): Toll-4 receptor

Toll-4 Receptors: natural receptors for PeaPure

Toll-4 Receptors: natural receptors for palmitoylethanolamide

At the EFIC (a Congress for European Pain Specialists) 2013 Dr Svik Assaw and colleagues from the School of Life Sciences, Medical School, University of Nottingham,  United Kingdom presented new exciting data on the mechanism of action of the fatty acid amide N-Palmitoyethanoalamide (PEA) and presented the effects of PEA after activation of toll-like receptors (TLRs) by the inflammatory substance carrageenan.

Toll-4 Receptors

Toll-like receptors (TLRs) are known as transmembrane pattern-recognition receptors that initiate signals in response to diverse pathogen-associated molecular patterns (PAMPs). After tissue injury or cellular stress, TLRs detect endogenous ligands known as danger-associated molecular patterns (DAMPs) [7]. It is well known that TLRs in primary sensory neurons, such as dorsal root ganglion (DRG) and trigeminal ganglion (TG) neurons, are involved in the modulation of neuronal excitation, in particular, primary sensory neurons expressing TLR4 and TLR7 to sense exogenous PAMPs and endogenous DAMPs released after tissue injury or cellular stress [8]. These neuronal TLRs are thought to be involved in the development of pathological pain following peripheral inflammation.

Inflammation model: PEA inhibits TLR4

This inflammatory compound the inflammatory substance carrageenan drives various intracellular signalling pathways which up-regulate the expression of pro inflammatory genes, including cytokines and chemokines which subsequently leads to the recruitment of neutrophils and monocytic cells, among other the mast cells to the site of injury.

These data add new evidence to the already well established mechanisms of action of PEA as an anti-inflammatory compound. The data also show how specific PEA inhibits factors related to chronic inflammation. Activation of the Toll-like receptor 4 (TLR4) complex,which is a receptor of the innate immune system, most probably is related to the pathophysiology of many human diseases, including asthma, cardiovascular disorder, diabetes, obesity, metabolic syndrome, autoimmune disorders, neuroinflammatory disorders, schizophrenia, bipolar disorder, autism, clinical depression, chronic fatigue syndrome and alcohol abuse. Palmitoylethanolamide therefore deserves much attention!

Palmitoylethanolamide against chronic inflammation

The activated immune cells release further cytokines and chemokines which initiate and maintain pain and hyperalgesia by inducing a cascade of inflammatory events. The authors analysed the effects of Effects of PEA in the doserange of 10 nM-10 µM on pro inflammatory gene expression in peripheral blood mononuclear  cells (PBMCs).

PEA downregulates inflammation genes

PEA downregulates inflammation genes

His findings were impressive:

1. PEA inhibits chemotaxis of monocytes, but not neutrophils (clearly a sign that PEA downregulates chronic inflammation  but not acute inflammation)
2. PEA decrease in the carrageenan induced induction of the pro-inflammatory genes IL-1b, CCL4 and NOS2 in the inflamed skin.
3. PEA also blocks CCL4 induced monocyte migration in a chemotaxis assay.
4. PEA clearly modulates the TLR4 mediated inflammatory responses and dose-related inhibits inflammatory evoked TNFa and IL-1b gene expression.

The authors concluded:

The differential effect of PEA on immune cell recruitment and gene expression indicates an effect on specific pathways rather than a general anti-inflammatory action of PEA

.
PEA might thus downregulate many inflammatory pathways, and one less observed pathway, the activation of the TLR4 pathways needs to be further explored, as activation may further enhance chronic inflammation and increased production of reactive oxygen and nitrogen species (ROS/RNS) and oxidative and nitrosative stress.

New data suggest PEA inhibits TLR4 and can be of use in a wide variety of neuropathic pains

In a recent article the influence of TPR-4 in inflammation induced tongue pain was specified, a model for trigeminal pain:

This study has provided novel evidence suggesting a role of TLR4 mediating hyperexcitability of TG neurons innervating the non-inflamed tongue resulting in ectopic tongue pain associated with TP inflammation. To evaluate the mechanisms underlying
ectopic tongue pain following experimental inflammation, measurement of nocifensive reflex and immunohistochemical studies were conducted. The authors demonstrated that mechanical and heat sensitivity were significantly reduced,and TLR4 expression in the Trigeminal Gannglion and the excitability of TG nociceptive neurons innervating the tongue were strongly enhanced.

PEA could therefore play a useful therapeutic role in trigeminal pains and pains comparable to the above described paradigm.

Sources:
1. THE ROLE OF N-PALMITOYLETHANOLAMIDE IN INHIBITION OF THE CARRAGEENAN INDUCED INFLAMMATORY PAIN RESPONSE by Suvik Assaw, Andrew Bennett, Victoria Chapman, James Burston & Gareth Hathway; poster presented at EFIC, 2013, Florence, It.

2. Kinuyo Ohara, Kohei Shimizu, Shingo Matsuura, Bunnai Ogiso, Daisuke Omagari, Masatake Asano, Yoshiyuki Tsuboi, Masamichi Shinoda and Koichi Iwata. Toll-like receptor 4 signaling in trigeminal ganglion neurons contributes tongue-referred pain associated with tooth pulp inflammation. Journal of Neuroinflammation 2013, 10:139 doi:10.1186/1742-2094-10-139

2 responses

  1. […] insight into the mechanism of action of palmitoylethanolamide was presented in 2013 at EFIC, a Congress for European Pain […]

  2. Reblogged this on Chronic Pain as a Patient & Professional and commented:
    Add to knowledge. And relief.

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