CB2 receptors are mainly expressed by immune cells, where they modulate cytokine release and immune cell migration. Palmitoylethanolamide (PEA) exerts anti-inflammatory and analgesic actions via several molecular mechanisms, and probably most important is the direct activation of peroxisome proliferator-activated receptor-α (PPAR-α). In addition to this mechanism of action indirect activation of cannabinoid receptors and of transient receptor potential vanilloid type-1 (TRPV1) channels have been described. Recently the analgesic activity of PEA in animal model of neuropathic pain have been explained not only via indirect activation of the CB1 and TRPV1 receptors but also via the PPAR-γ pathway.

Synthetic cannabinoid agonists as well as the PEA analogue, adelmidrol, could prevent granulomatous tissue formation, which represents a chronic inflammation, via different mechanisms, the inhibition of NF-κB activation, as well as via the control of mast cell degranulation.

Impairment of endocannabinoid and PEA levels might contribute to the development of chronic inflammatory processes, which can also be found in neuropathic pain.

PEA as an inhibitor of chronic inflammation 

Italian researchers of the Endocannabinoid Research Group from the university of Napels used a model of chronic inflammation to study the effects of PEA and related compounds and concluded ^[1]:

Pharmacological elevation of endocannabinoids and palmitoylethanolamide, obtained separately by arachidonoylserotonin and exogenous palmitoylethanolamide treatment, dose-dependently reduced inflammatory hallmarks including tumor necrosis factor-α as well as granuloma-dependent angiogenesis.

The effect of arachidonoylserotonin was accompanied by near-normalization of 2-arachidonoylglycerol and palmitoylethanolamide levels in the tissue.

These findings suggest that chronic inflammation might develop also because of endocannabinoid and palmitoylethanolamide tissue concentration impairment, the correction of which might be exploited to develop new anti-inflammatory drugs. 

PEA seems increasingly to be an interesting molecule, with many properties especially interesting for those working within the field of neuropathic pain. The use of anti-inflammatory drugs in the treatment of neuropathic pain is a new exiting chapter in the development of new therapeutic inroads within this field. And even indications as stroke are starting to being explored via treatment following these mechanisms of action. ^[2] This chapter in neurobiology is only starting to be written! ^[3]

September 2010, prof. dr. Jan M. Keppel Hesselink 

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