Ultramicronized Palmitoylethanolamide and Paracetamol, a New Association to Relieve Hyperalgesia and Pain in a Sciatic Nerve Injury Model in Rat.

Alessio Filippo Peritore,Marika Cordaro,Ramona D’Amico,Salvatore Cuzzocrea,Rosanna Di Paola,Roberta Fusco,Enrico Gugliandolo,Rosalba Siracusa,Rosalia Crupi,Tiziana Genovese,Daniela Impellizzeri

doi:10.3390/ijms21103509

Alessio Filippo Peritore, Marika Cordaro + Show 9 more

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https://doi.org/10.3390/ijms21103509

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Abstract

Inflammation is known to be an essential trigger of the pathological changes that have a critical impact on nerve repair and regeneration; moreover, damage to peripheral nerves can cause a loss of sensory function and produces persistent neuropathic pain. To date, various potential approaches for neuropathic pain have focused on controlling neuroinflammation. The aim of this study was to investigate the neuroprotective effects of a new association of ultramicronized Palmitoylethanolamide (PEAum), an Autacoid Local Injury Antagonist Amide (ALIAmide) with analgesic and anti-inflammatory properties, with Paracetamol, a common analgesic, in a rat model of sciatic nerve injury (SNI). The association of PEAum–Paracetamol, in a low dose (5 mg/kg + 30 mg/kg), was given by oral gavage daily for 14 days after SNI. PEAum–Paracetamol association was able to reduce hyperalgesia, mast cell activation, c-Fos and nerve growth factor (NGF) expression, neural histological damage, cytokine release, and apoptosis. Furthermore, the analgesic action of PEAum–Paracetamol could act in a synergistic manner through the inhibition of the NF-κB pathway, which leads to a decrease of cyclooxygenase 2-dependent prostaglandin E2 (COX-2/PGE2) release. In conclusion, we demonstrated that PEAum associated with Paracetamol was able to relieve pain and neuroinflammation after SNI in a synergistic manner, and this therapeutic approach could be relevant to decrease the demand of analgesic drugs.

Highlights

Injury to peripheral nerve tissue is often due to compression, various forms of trauma, or ischemic and metabolic disorders
A previous clinical study showed no effect of PEAum as an add-on therapy for neuropathic pain following Spinal Cord Injury (SCI), with the exception of rescue drug use, which was decreased in the PEAum-treated patient group [15]
Histological analysis by staining with hematoxylin and eosin staining (H&E) showed different areas of edema with abundant presence of infiltrated and degraded myelin layers at 14 days after the lesion in the sciatic nerve of sciatic nerve injury (SNI) + vehicle rats compared to sham groups (Figure 1a,b)

Summary

Introduction

Injury to peripheral nerve tissue is often due to compression, various forms of trauma, or ischemic and metabolic disorders. Loss of sensory function following persistent neuropathic pain are two causes of peripheral nerve damage: the injury to nerves can lead to a cascade of events, including increased infiltration of inflammatory cells (for example, macrophages), degeneration of the distal part of the nerve, and other events that are part of a complex mechanism known as Wallerian degeneration [1]. Among the various pharmacological treatments for chronic neuropathic pain, paracetamol is often used for its anti-inflammatory and antinociceptive effect, both individually and in association with other molecules [3]. A previous clinical study showed no effect of PEAum as an add-on therapy for neuropathic pain following Spinal Cord Injury (SCI), with the exception of rescue drug use (such as paracetamol), which was decreased in the PEAum-treated patient group [15]. The decreased demand of analgesic drugs reported in this trial [15] is very relevant to the scope of our study

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