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.
Highlights
Palmitoylethanolamide (PEA) is an endogenous fatty acid amide signaling molecule synthesized “on demand” in response to tissue injury/stress, as part of a mechanism to restore/maintain homeostasis with anti-inflammatory, pain-relieving and neuroprotective actions (Solorzano et al, 2009; Skaper and Facci, 2012; Piomelli and Sasso, 2014; Petrosino and Di Marzo, 2017)
[13C]4-PEA-um treatment resulted in higher levels of [13C]4-PEA across all time points in CAR-injected compared to healthy rats (p = 0.0046)
Marked increases in the absorption of orally administered [13C]4-PEA-um were observed at 30, 60, and 180 min compared to baseline (p < 0.0001 for each time, Figure 1B)
Summary
Palmitoylethanolamide (PEA) is an endogenous fatty acid amide signaling molecule synthesized “on demand” in response to tissue injury/stress, as part of a mechanism to restore/maintain homeostasis with anti-inflammatory, pain-relieving and neuroprotective actions (Solorzano et al, 2009; Skaper and Facci, 2012; Piomelli and Sasso, 2014; Petrosino and Di Marzo, 2017). This view is supported by studies showing that PEA levels change in settings of tissue injury, especially in situations associated with inflammatory and neurodegenerative processes. PEA-m/PEA-um has a favorable safety profile in genetox assays as well as in acute and repeat dose oral toxicity studies (Nestmann, 2016)
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