Inhibition of Spinal Oxidative Stress by Bergamot Polyphenolic Fraction Attenuates the Development of Morphine Induced Tolerance and Hyperalgesia in Mice.

Filomena Lauro,Bianca M Goffredo,Carolina Muscoli,Vincenzo Mollace,Maurizio Muraca,Sara Ilari,Valentina Malafoglia,Micaela Gliozzi,William Raffaeli,Luigino Antonio Giancotti,Chiara Morabito,Concetta Dagostino,Shao-Jun Tang

doi:10.1371/journal.pone.0156039

Abstract

Citrus Bergamia Risso, commonly known as Bergamot, is a fruit whose Essential Oil and Bergamot Polyphenolic Fraction have numerous medicinal properties. It is also an excellent antioxidant and in this study, for the first time, its potential effect on morphine induced tolerance in mice has been investigated. Our studies revealed that development of antinociceptive tolerance to repeated doses of morphine in mice is consistently associated with increased formation of superoxide, malondialdehyde and tyrosine-nitrated proteins in the dorsal horn of the spinal cord such as the enzyme glutamine synthase. Nitration of this protein is intimately linked to inactivation of its biological function and resulting increase of glutamate levels in the spinal cord. Administration of Bergamot Polyphenolic Fraction (5–50 mg/kg) attenuated tolerance development. This effect was accompanied by reduction of superoxide and malondialdehyde production, prevention of GS nitration, re-establishment of its activity and of glutamate levels. Our studies confirmed the main role of free radicals during the cascade of events induced by prolonged morphine treatment and the co-administration of natural derivatives antioxidant such as Bergamot Polyphenolic Fraction can be an important therapeutic approach to restore opioids analgesic efficacy.

Highlights

Opioid drugs have been the mainstay of pain treatment [1], but long-term morphine administration leads to analgesic tolerance [2]
We evaluated the ability of BPF (Bergamot Polyphenolic Fraction) to inhibit tolerance induced by morphinerepeated administration
To investigate whether the increased superoxide synthesis had a functional role in the development of morphine antinociceptive tolerance, morphine was coadministered with antioxidants such as BPF (Table 1) [16]

Summary

Introduction

Opioid drugs have been the mainstay of pain treatment [1], but long-term morphine administration leads to analgesic tolerance [2]. Tolerance to the analgesic effects of opiates results from the complex changes in various molecular and biochemical pathways [3]. Role of Natural Antioxidant on Morphine Tolerance for authors [FL, LAG, SI], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section

Methods

Results

Conclusion