Evolution in pharmacologic thinking around the natural analgesic palmitoylethanolamide: from nonspecific resistance to PPAR-α agonist and effective nutraceutical

Journal of Pain Research Dovepress open access to scientific and medical research Review Journal of Pain Research downloaded from https://www.dovepress.com/ by 37.59.46.207 on 13-Jul-2018 For personal use only. Open Access Full Text Article Evolution in pharmacologic thinking around the natural analgesic palmitoylethanolamide: from nonspecific resistance to PPAR-α agonist and effective nutraceutical This article was published in the following Dove Press journal: Journal of Pain Research 1 August 2013 Number of times this article has been viewed Jan M Keppel Hesselink Department of Pharmacology, University of Witten/Herdecke, Witten, Germany Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: http://dvpr.es/133WKTE Correspondence: Jan M Keppel Hesselink Department of Pharmacology, University of Witten/Herdecke, Alfred-Herrhausen Straße 50, 58448 Witten, Germany Tel +31 65 170 0527 Email PEA and the sociology of science The history of palmitoylethanolamide (PEA) started in 1954 with a publication addressing the anti-inflammatory properties of egg yolk.1 The finding that egg yolk appeared to be some sort of “protomedical diet food” and the fact that extracts from egg yolk and peanut oil had anti-inflammatory activity were discussed in that paper. That anti-inflammatory compound would later be known as PEA. The history of the development of insights into the biological role of PEA after its identification in 1957 is worth telling because it demonstrates the close interrelationship between the scientific context and the development of scientific facts. The importance of such studies has already been pointed out by the science sociologists, Ludwig Fleck and Thomas Kuhn. This analysis serves to add a new chapter to the sociology of medical and scientific knowledge. The paper demonstrates that 625 submit your manuscript | www.dovepress.com Journal of Pain Research 2013:6 625–634 Dovepress © 2013 Hesselink. This work is published by Dove Medical Press Ltd, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Ltd, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Ltd. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php http://dx.doi.org/10.2147/JPR.S48653 Powered by TCPDF (www.tcpdf.org) Abstract: The history of development of new concepts in pharmacology is a highly interesting topic. This review discusses scientific insights related to palmitoylethanolamide (PEA) and its progression over a period of six decades, especially in light of the work of the science sociologists, Ludwig Fleck and Thomas Kuhn. The discovery of the cannabis receptors and the nuclear peroxisome proliferator-activated receptors was the beginning of a completely new understanding of many important homeostatic physiologic mechanisms in the human body. These discoveries were necessary for us to understand the analgesic and anti-inflammatory activity of PEA, a bodyown fatty amide. PEA is a nutrient known already for more than 50 years. PEA is synthesized and metabolized in animal cells via a number of enzymes and has a multitude of physiologic functions related to metabolic homeostasis. PEA was identified in the 1950s as a therapeutic principle with potent anti-inflammatory properties. Since 1975, its analgesic properties have been noted and explored in a variety of chronic pain states. Since 2008, PEA has been available as a nutraceutical under the brand names Normast® and PeaPure®. A literature search on PEA meanwhile has yielded over 350 papers, all referenced in PubMed, describing the physiologic properties of this endogenous modulator and its pharmacologic and therapeutic profile. This review describes the emergence of concepts related to the pharmacologic profile of PEA, with an emphasis on the search into its mechanism of action and the impact of failing to identify such mechanism in the period 1957–1993, on the acceptance of PEA as an anti-inflammatory and analgesic compound. Keywords: palmitoylethanolamide, sociology, science, paradigm, peroxisome proliferatoractivated receptor-alpha, nutraceutical Dovepress Journal of Pain Research downloaded from https://www.dovepress.com/ by 37.59.46.207 on 13-Jul-2018 For personal use only. Hesselink plausible explanations for the mechanism of action of drugs are required before a treatment concept can be explored in more detail in science and in the clinic, and before it can be accepted. Efficacy of a compound alone will not be enough to convince the scientific community. The case of PEA supports the validity of this scientific sociologic observation. Starting with the work of Rita Levi-Montalcini, a Nobel laureate, in the 1990s, more attention is being paid by the scientific community to the clinical relevance and usefulness of PEA in chronic pain and chronic inflammation. Step by step emergence of insight When studying the published papers relevant to PEA one can define four different periods leading to a step by step increase in insight into the pharmacology of this endogenous modulating fatty compound. These four periods are: • 1954–1979, when PEA was found to be an nonspecific immunologic resistance enhancer, with anti-inflammatory properties and anti-influenza and anti-common cold indications • 1980–1992, “a silent gap”, with unanswered questions related to the mechanism of action of PEA • 1992–1998, due to the work of Levi-Montalcini, PEA was recognized as a mast cell modulator, and then (wrongly as it appeared later) as a CB2 cannabinoid agonist • 1998 onwards, when PEA was identified as having high affinity for peroxisome proliferator-activated receptor alpha (PPAR-α), transient receptor potential vanilloid type 1, and the GRP 55 receptor. First insights The birth date of PEA can be identified as October 20, 1957, when Kuehl et al published a seminal paper clarifying its structure.2 In that paper, they reported having isolated an anti-inflammatory factor in crystalline form from soybean lecithin as well as from a phospholipid fraction of egg yolk and hexane-extracted peanut meal. That product was tested using a local passive joint anaphylaxis assay in the guinea pig and identified as N-palmitoylethanolamine, ie, N-(2-hydroxyethyl)-palmitamide. They also synthesized the compound as well as various analogs, and attributed the anti-inflammatory activity to the ethanolamine moiety of the series of molecules they had synthesized. This was the first description of PEA and its biological activity as an anti-inflammatory agent. Identification was clear after hydrolysis of the compound yielded palmitic acid and etha (...truncated)