Role of N-Acylethanolamines in the Neuroinflammation: Ultramicronized Palmitoylethanolamide in the Relief of Chronic Pain and Neurodegenerative DiseasesRole of N-Acylethanolamines in the Neuroinflammation: Ultramicronized Palmitoylethanolamide in the Relief of Chronic Pain and Neurodegenerative Dise

Pain and neuroinflammation are protective responses aimed at preventing and removing injurious stimuli. However, when prolonged, they can override the bounds of physiological control and become destructive. Chronic pain and neuroinflammation are critical components in the pathophysiology of neurodegenerative diseases, stroke, spinal cord injury, diabetes, and neuropsychiatric disorders. Natural mechanisms, including the production of lipid mediators, represent an endogenous protective process and a program of resolution stimulated and triggered by tissue injury or inflammation. Lipid mediators include N-acylethanolamines (NAEs) such as palmitoylethanolamide (PEA), an endocannabinoid anandamide congener which has shown to be endowed of neuroprotective and antinflammatory properties activated under several pathological states. PEA does not bind the classical cannabinoid receptors but indirectly stimulates the effects of cannabinoids. Its antinflammatory, analgesic and neuroprotective actions have been however associated with peroxisome proliferator-activated receptor-α (PPAR-α) activation. The administration of exogenous PEA requires parenteral routes owing to its lipid structure. The micronized and ultramicronized (m- and um-) formulation permits oral administration increasing the versatility, easiness and compliance of administrations in clinical studies. This review is intended to deal with the effects of m- and um-PEA on chronic pain and neuroinflammation in several animal models of chronic pain and neudegenerative disorders and in clinical studies.