Oral Ultramicronized Palmitoylethanolamide: Plasma and Tissue Levels and Spinal Anti-hyperalgesic Effect

Abstract

Palmitoylethanolamide (PEA) is a pleiotropic lipid mediator with established anti-inflammatory and anti-hyperalgesic activity. Ultramicronized PEA (PEA-um) has superior oral efficacy compared to naïve (non-micronized) PEA. The aim of the present study was two-fold: (1) to evaluate whether oral PEA-um has greater absorbability compared to naïve PEA, and its ability to reach peripheral and central tissues under healthy and local inflammatory conditions (carrageenan paw edema); (2) to better characterize the molecular pathways involved in PEA-um action, particularly at the spinal level. Rats were dosed with 30 mg/kg of [13C]4-PEA-um or naïve [13C]4-PEA by oral gavage, and [13C]4-PEA levels quantified, as a function of time, by liquid chromatography/atmospheric pressure chemical ionization/mass spectrometry. Overall plasma levels were higher in both healthy and carrageenan-injected rats administered [13C]4-PEA-um as compared to those receiving naïve [13C]4-PEA, indicating the greater absorbability of PEA-um. Furthermore, carrageenan injection markedly favored an increase in levels of [13C]4-PEA in plasma, paw and spinal cord. Oral treatment of carrageenan-injected rats with PEA-um (10 mg/kg) confirmed beneficial peripheral effects on paw inflammation, thermal hyperalgesia and tissue damage. Notably, PEA-um down-regulated distinct spinal inflammatory and oxidative pathways. These last findings instruct on spinal mechanisms involved in the anti-hyperalgesic effect of PEA-um in inflammatory pain.

Palmitoylethanolamide counteracts hepatic metabolic inflexibility modulating mitochondrial function and efficiency in diet‐induced obese mice

“…60 Even if this exogenous administration increases PEA levels in liver of HFD mice, we did not detect any change either of palmitic or palmitoleic or oleic acid content. 60 Even if this exogenous administration increases PEA levels in liver of HFD mice, we did not detect any change either of palmitic or palmitoleic or oleic acid content.…”

“…It has been demonstrated that ultramicronized PEA formulation is promptly absorbed. 60 Even if this exogenous administration increases PEA levels in liver of HFD mice, we did not detect any change either of palmitic or palmitoleic or oleic acid content. In addition, it should be considered that the amount of palmitic acid derived by PEA degradation is negligible respect to whole tissue concentration, which is tightly controlled around a well-defined concentration and depends on exogenous source and endogenous biosynthesis.…”

The neuroprotective effects of micronized PEA (PEA‐m) formulation on diabetic peripheral neuropathy in mice

“…Moreover, in a previous study, we displayed superior efficacy of micronized and ultramicronized PEA formulations matched to PEA that was not micronized (15). The process of micronization is useful to reduce the size of a particle and to improve the bioavailability and effectiveness of particular low-watersoluble molecules increasing the dissolution rate (42)(43)(44).…”

Combination of Rehabilitative Therapy with Ultramicronized Palmitoylethanolamide for Chronic Low Back Pain: An Observational Study

“…This smaller size (implying a higher surface-to-volume ratio) along with increased potential energy of the particles leads to better solute solubility. These characteristics result in better diffusion and distribution of micronized and ultramicronized PEA compared to the naïve form, and thus superior biological efficacy [10,12]. The properties of umPEA prompted us to investigate the effect of umPEA ?…”