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Exploring the Role of Bergamot Polyphenols in Alleviating Morphine-Induced Hyperalgesia and Tolerance through Modulation of Mitochondrial SIRT3.

ABSTRACT: Morphine is an important pain reliever employed in pain management, its extended utilize is hindered by the onset of analgesic tolerance and oxidative stress. Long-term morphine administration causes elevated production of reactive oxygen species (ROS), disrupting mitochondrial function and inducing oxidation. Sirtuin 3 (SIRT3), a mitochondrial protein, is essential in modulating ROS levels by regulating mitochondrial antioxidant enzymes as manganese superoxide dismutase (MnSOD). Our investigation focused on the impact of SIRT3 on hyperalgesia and morphine tolerance in mice, as evaluating the antioxidant effect of the polyphenolic fraction of bergamot (BPF). Mice were administered morphine twice daily for four consecutive days (20 mg/kg). On the fifth day, mice received an acute dose of morphine (3 mg/kg), either alone or in conjunction with BPF or Mn (III)tetrakis (4-benzoic acid) porphyrin (MnTBAP). We evaluated levels of malondialdehyde (MDA), nitration, and the activity of SIRT3, MnSOD, glutamine synthetase (GS), and glutamate 1 transporter (GLT1) in the spinal cord. Our findings demonstrate that administering repeated doses of morphine led to the development of antinociceptive tolerance in mice, accompanied by increased superoxide production, nitration, and inactivation of mitochondrial SIRT3, MnSOD, GS, and GLT1. The combined administration of morphine with either BPF or MnTBAP prevented these effects.

SUBMITTER: Ilari S

PROVIDER: S-EPMC11357234 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Exploring the Role of Bergamot Polyphenols in Alleviating Morphine-Induced Hyperalgesia and Tolerance through Modulation of Mitochondrial SIRT3.

Ilari Sara S Nucera Saverio S Passacatini Lucia Carmela LC Scarano Federica F Macrì Roberta R Caminiti Rosamaria R Ruga Stefano S Serra Maria M Giancotti Luigino Antonio LA Lauro Filomena F Dagostino Concetta C Mazza Valeria V Ritorto Giovanna G Oppedisano Francesca F Maiuolo Jessica J Palma Ernesto E Malafoglia Valentina V Tomino Carlo C Mollace Vincenzo V Muscoli Carolina C

Nutrients 20240809 16

Morphine is an important pain reliever employed in pain management, its extended utilize is hindered by the onset of analgesic tolerance and oxidative stress. Long-term morphine administration causes elevated production of reactive oxygen species (ROS), disrupting mitochondrial function and inducing oxidation. Sirtuin 3 (SIRT3), a mitochondrial protein, is essential in modulating ROS levels by regulating mitochondrial antioxidant enzymes as manganese superoxide dismutase (MnSOD). Our investigati ...[more]

PMID: 39203757

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Project description:ObjectiveTo evaluate the effect of berberine on morphine analgesia, tolerance, and hyperalgesia.MethodsMorphine-induced acute tolerance model: mice received intraperitoneal berberine at doses of 2.5, 5.0, and 10 mg/kg; 30 min later, subcutaneous morphine 10 mg/kg was injected every hour for nine continuous h. Morphine 10 mg/kg alone was administered at 24 and 48 h. Morphine-induced chronic tolerance model: mice received intraperitoneal berberine 2.5, 5.0, and 10 mg/kg; 30 min later, 10 mg/kg morphine was injected subcutaneously for eight consecutive days. On the ninth day, morphine 10 mg/kg was given alone. Morphine-induced established tolerance model: mice were injected subcutaneously with morphine 10 mg/kg once a day for eight consecutive days. Berberine 2.5 mg/kg was administered on day one, four, and seven and morphine 10 mg/kg alone on day nine. The baseline latency (T0) and post-treatment latency (T1) were determined by the hot plate test, and the maximum possible analgesic effect (MPAE) was calculated. Nitric oxide synthase (NOS) activity and nitric oxide (NO) content in the spinal cord were measured by spectrophotometer. Verification of berberine analgesic effect by blocking N-methyl-D-aspartate (NMDA) receptor: HT-22 and HEK-293 cells transfected with NMDA plasmid were randomly divided into five groups: control group, NMDA group, berberine low-dose, medium-dose, and high-dose groups (5, 10, 20 μmol/L, respectively). Except for the control group, cells were treated with NMDA (HT-22 cells: 20 mmol/L; HEK-293 cells: 50 μmol/L). After 24 h, cell viability was detected by cell counting kit-8. The molecular mechanism between berberine and the NMDA receptor was studied by molecular docking.ResultsBerberine 2.5 and 5.0 mg/kg could prolong the analgesic time of morphine. In acute and chronic morphine tolerance models, berberine could inhibit the decrease of MPAE and baseline latency (0.05). In the established tolerance model, berberine could rapidly reverse the decreased MPAE (0.05). The combination of berberine and morphine on day one could effectively inhibit the morphine-induced increase of NOS activity and NO content in the spinal cord (0.05). Berberine significantly increased the cell viability of NMDA-induced nerve injury in HT-22 and HEK-293 cells (0.05). Molecular docking showed that berberine binds to the receptor pocket of NMDA.ConclusionsBerberine could effectively enhance and prolong the duration of morphine analgesia and inhibit the development of morphine-induced tolerance and hyperalgesia. Furthermore, berberine has a certain neuroprotective effect, which may be related to the inhibition of NMDA activity.

Project description:Morphine and related compounds are the first line of therapy in the treatment of moderate to severe pain. Over time, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even evolving into a painful response to previously non-noxious stimuli (opioid-induced hyperalgesia; OIH). The mechanism underlying OIH is not well understood although complex intracellular neural mechanisms, including opioid receptor desensitization and down-regulation, are believed to be major mechanisms underlying OIH. However, OIH may also be associated with changes in gene expression. A growing body of evidence suggests that cellular exposure to mu agonists upregulate chemokines/receptors and recent work from our laboratory implicates chemokine upregulation in a variety of neuropathic pain behaviors. Here we characterized the degree to which chemokines/receptors signaling is increased in primary afferent neurons of the dorsal root ganglion (DRG) following chronic morphine sulfate treatment and correlated these changes with tactile hyperalgesic behavior in rodents. We demonstrate that mRNA expression of the chemokine, stromal-derived factor-1 (SDF1/CXCL12) is upregulated following morphine treatment in sensory neurons of the rat. The release of SDF1 was found to be constitutive when compared with the activity dependent release of the C-C chemokine, monocyte chemoattractant protein-1 (MCP1/CCL2) in a line of F11 neuroblastoma-sensory neuron hybrid cells. We further determined that there is pronounced CXCR4 expression in satellite glial cells and following morphine treatment, increased functional CXCR4 expression in sensory neurons of the DRG. Moreover, intraperitoneal administration of the specific CXCR4 antagonist, AMD3100, completely reversed OIH in the rat. Taken together; the data suggest that opioid-induced SDF1/CXCR4 signaling is central to the development of long lasting OIH and that receptor antagonists represent a promising novel approach to the management of the side effects associated with the use of opioids for chronic pain management.

Dataset Information

Exploring the Role of Bergamot Polyphenols in Alleviating Morphine-Induced Hyperalgesia and Tolerance through Modulation of Mitochondrial SIRT3.

Publications

Exploring the Role of Bergamot Polyphenols in Alleviating Morphine-Induced Hyperalgesia and Tolerance through Modulation of Mitochondrial SIRT3.

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