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

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.

Efficacy of bergamot: From anti‐inflammatory and anti‐oxidative mechanisms to clinical applications as preventive agent for cardiovascular morbidity, skin diseases, and mood alterations

“…BEO 0.5 ml/kg did not affect basal amino acid levels but significantly reduced excitatory amino acid efflux in frontoparietal cortex (p < 0.05). Injections of different doses of BPF (5, 25, and 50 mg/kg) also inhibited the development of morphine tolerance in a dose-dependent manner (p < 0.01 for 5 mg/kg and p < 0.001 for other doses, compared to morphine alone)(Lauro et al, 2016).…”

“…Amantea et al (2009) tested BEO (0.1 and 0.5 ml/kg) to prevent glutamate accumulation and neuroprotection in microdialysis experiments. Injections of different doses of BPF (5, 25, and 50 mg/kg) also inhibited the development of morphine tolerance in a dose-dependent manner (p < 0.01 for 5 mg/kg and p < 0.001 for other doses, compared to morphine alone)(Lauro et al, 2016). Injections of different doses of BPF (5, 25, and 50 mg/kg) also inhibited the development of morphine tolerance in a dose-dependent manner (p < 0.01 for 5 mg/kg and p < 0.001 for other doses, compared to morphine alone)(Lauro et al, 2016).…”

Combining pain therapy with lifestyle: the role of personalized nutrition and nutritional supplements according to the SIMPAR Feed Your Destiny approach

“…The identification of natural radical scavengers as novel non-narcotic agents is a viable therapeutic target for the development of non-narcotic analgesics in pain of various etiologies. Recent studies reinforce the importance of natural antioxidant products as a source of drugs to alleviate chronic pain 142,143,145. Chronic injection of morphine in mice led to the development of tolerance associated with increased nitrotyrosine and the marker of lipid peroxidation malondialdehyde formation together with nitration and deactivation of manganese SO dismutase (MnSOD) in the spinal cord.…”

Second edition of SIMPAR&rsquo;s &ldquo;Feed Your Destiny&rdquo; workshop: the role of lifestyle in improving pain management

“…The (poly)phenolic profile of bergamot juice is due primarily to flavanones, in particular neoeriocitrin, naringin, and neohesperidin,68 which are antioxidant compounds endowed with biological activity 69. Free radicals play a crucial role in enhanced pain sensitivity experienced during inflammatory diseases, with Lauro et al recently demonstrating that thermal hyperalgesia induced by intraplantar injection of carrageenan is reversed by employment of bergamot juice in a dose-dependent manner 70. The development of thermal hyperalgesia causes carbonylation of mitochondrial proteins, included sirtuin 3 (SIRT3), an important epigenetic factor linked to inflammation, human metabolism, aging, and cancer.…”