PHARMACOLOGICAL EFFECTS OF PALMITOYLETHANOLAMIDE (PEA) IN DIFFERENT ANIMAL MODELS OF NEUROPATHIC PAIN

Neuropathic pain is defined by the International Association for the Study of Pain (IASP) as pain that arises as a direct consequence of a lesion or disease affecting the somatosensory system. Neuropathic pain is often poorly alleviated by first-, and second-line medications recommended by IASP due to lack of efficacy and/or dose-limiting side-effects. Hence, there is an urgent need to develop novel mechanism-based therapeutic agents that are highly efficacious and well tolerated to improve relief of neuropathic pain. Palmitoylethanolamide (PEA) is the parent molecule of ALIAmides (Autacoid Local Injury Antagonism Amides), a group of endogenous fatty acid derivatives sharing anti-inflammatory and antinociceptive effects with the endocannabinoid family mainly through the down-modulation of local mast cell degranulation. Several evidences in literature show the antinociceptive effect of PEA in different animal models of pain, such as spinal cord injury, chronic constriction injury of the sciatic nerve, carrageenan-induced acute inflammation, and complete Freund’s adjuvant-induced chronic inflammation. Based on these fundings, the aim of this study is to further explore the therapeutic potentiality of PEA in resolving painful states in three very common forms of neuropathic pain in human associated to osteoarthritis, diabetes, and chemotherapy. Osteoarthritis (OA) is the most common chronic joint disease characterized by a progressive destruction of cartilage, resulting in pain, and loss of articular function. The monosodium iodoacetate (MIA) rat model of OA was used to investigate the effects of PEA. Under a chronic treatment regiment, PEA was able to completely abolish knee swelling and thermal hyperalgesia, as index of inflammation. Moreover, treatment with PEA resulted in a significant relief of mechanical allodynia, as index of neuropathic pain. Futhermore, PEA treatment completely restored locomotor functionality, and is also able to preserve cartilage from damage. Diabetes mellitus is a metabolic syndrome today affecting 382 million people. One of the most disabling long-term complications of diabetes is diabetic neuropathy. The well established streptozotocin (STZ)-induced mice model of type 1 diabetes was emploied to explore the antinociceptive effect of PEA in diabetic neurophaty. PEA relieved mechanical allodynia, counteracted nerve growth factor deficit, improved insulin level, preserved Langherans islet morphology reducing the development of insulitis in diabetic mice. Chemotherapy-induced neuropathic pain (CINP) is another common form of neurophatic pain, affecting up to 90% of patients. The effect of PEA in paclitaxel model of CINP, one of the most common used antineoplastic drugs in clinic, was investigated. Preliminary results show that PEA is able to evoke a total antiallodynic effect in CINP model, after acute administration. The results of this thesis show the pharmacological effect of PEA to relieve neuropathic pain associated to osteoarthritis, diabetes, and chemotherapy, three very common diseases in human, that lack a resolutive, and effective treatment. These findings allow us to suggest a therapeutic use of PEA in clinic.