Epigallocatechin-3-Gallate Modulates Postoperative Pain by Regulating Biochemical and Molecular Pathways

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

doi:10.3390/ijms22136879

Abstract

Treating postoperative (PO) pain is a clinical challenge. Inadequate PO pain management can lead to worse outcomes, for example chronic post-surgical pain. Therefore, acquiring new information on the PO pain mechanism would increase the therapeutic options available. In this paper, we evaluated the role of a natural substance, epigallocatechin-3-gallate (EGCG), on pain and neuroinflammation induced by a surgical procedure in an animal model of PO pain. We performed an incision of the hind paw and EGCG was administered for five days. Mechanical allodynia, thermal hyperalgesia, and motor dysfunction were assessed 24 h, and three and five days after surgery. At the same time points, animals were sacrificed, and sera and lumbar spinal cord tissues were harvested for molecular analysis. EGCG administration significantly alleviated hyperalgesia and allodynia, and reduced motor disfunction. From the molecular point of view, EGCG reduced the activation of the WNT pathway, reducing WNT3a, cysteine-rich domain frizzled (FZ)1 and FZ8 expressions, and both cytosolic and nuclear β-catenin expression, and the noncanonical β-catenin–independent signaling pathways, reducing the activation of the NMDA receptor subtype NR2B (pNR2B), pPKC and cAMP response element-binding protein (pCREB) expressions at all time points. Additionally, EGCG reduced spinal astrocytes and microglia activation, cytokines overexpression and nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) pathway, downregulating inducible nitric oxide synthase (iNOS) activation, cyclooxygenase 2 (COX-2) expression, and prostaglandin E2 (PGE2) levels. Thus, EGCG administration managing the WNT/β-catenin signaling pathways modulates PO pain related neurochemical and inflammatory alterations.

Highlights

IntroductionClinical analysis showed that only the 25% of surgical patients had satisfactory relief of acute pain [1]
This study was aimed to evaluate the mechanism of EGCG effect on PO pain in rats at different timepoints
Mechanical hyperalgesia and thermal allodynia induced by the incision lasted for several days, while EGCG administration significantly alleviated hyperalgesia and allodynia

Summary

Introduction

Clinical analysis showed that only the 25% of surgical patients had satisfactory relief of acute pain [1]. The lack of a clinically meaningful progress in the PO pain analgesia is probably due to the limited efficacy and side effects of the available analgesic drugs [4,5]. Treatment of PO pain continues to be an important clinical goal. It is of fundamental importance to discover the mechanisms underlying PO pain, as well as to find medications to treat it. Despite numerous implicated processes and decades of investigation, the molecular and cellular mechanisms underlying PO pain remain uncertain, and therapeutic approaches for managing PO pain are limited. It has been described that central neuronal sensitization is involved in PO pain and hyperalgesia [6,7]. In vivo neurological studies have displayed increased rates and prevalence of spontaneous activity of spinal neurons in the dorsal horn after surgery [8,9]

Objectives

Results

Conclusion