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Melatonin regulation of transcription in the reversal of morphine tolerance: Microarray analysis of differential gene expression.

ABSTRACT: Tolerance and associated hyperalgesia induced by long?term morphine administration substantially restrict the clinical use of morphine in pain treatment. Melatonin, a neurohormone released by the pineal gland, has been demonstrated to attenuate anti?nociceptive morphine tolerance. The present study investigates differentially expressed genes in the process of morphine tolerance and altered gene expression subsequent to melatonin treatment in chronic morphine?infused ratspinal cords. Morphine tolerance was induced in male Wistar rats by intrathecal morphine infusion (the MO group). Melatonin (the MOMa group) was administered to overcome the effects derived by morphine. The mRNA collected from L5?S3 of the spinal cord was extracted and analysed by rat expression microarray. Principal component analysis and clustering analysis revealed that the overall gene profiles were different in morphine and melatonin treatments. Subsequent to Gene Ontology analysis, the biological processes of differentially expressed genes of MO and MOMa compared with the control group were constructed. Furthermore, a panel of genes exclusively expressed following melatonin treatment and another panel of genes with inverse expression between the MO and MOMa group were also established. Subsequent to PANTHER pathway analysis, a group of genes with inverse expression following melatonin administrated compared with morphine alone were identified. The expression levels of genes of interest were also confirmed using a reverse transcription?quantitative polymerase chain reaction. The gene panel that was constructed suggests a potential signaling pathway in morphine tolerance development and is valuable for investigating the mechanism of morphine tolerance and the regulatory gene profiles of melatonin treatment. These results may contribute to the discovery of potential drug targets in morphine tolerance treatments in the future.

SUBMITTER: Cheng YC

PROVIDER: S-EPMC6317689 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Melatonin regulation of transcription in the reversal of morphine tolerance: Microarray analysis of differential gene expression.

Cheng Yu-Che YC Tsai Ru-Yin RY Sung Yen-Tseng YT Chen Ing-Jung IJ Tu Tzu-Yi TY Mao Ya-Yuan YY Wong Chih-Shung CS

International journal of molecular medicine 20181218 2

Tolerance and associated hyperalgesia induced by long‑term morphine administration substantially restrict the clinical use of morphine in pain treatment. Melatonin, a neurohormone released by the pineal gland, has been demonstrated to attenuate anti‑nociceptive morphine tolerance. The present study investigates differentially expressed genes in the process of morphine tolerance and altered gene expression subsequent to melatonin treatment in chronic morphine‑infused ratspinal cords. Morphine tol ...[more]

PMID: 30569162

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Project description:Opioids are commonly prescribed for clinical pain management; however, dose-escalation, tolerance, dependence, and addiction limit their usability for long-term chronic pain. The associated poor sleep pattern alters the circadian neurobiology, and further compromises the pain management. Here, we aim to determine the correlation between constant light exposure and morphine tolerance and explore the potential of melatonin as an adjuvant of morphine for neuropathic pain treatment. METHODS:Wistar rats were preconditioned under constant light (LL) or a regular light/dark (LD) cycle before neuropathic pain induction by chronic constriction injury. An intrathecal (i.t.) osmotic pump was used for continued drug delivery to induce morphine tolerance. Pain assessments, including the plantar test, static weight-bearing symmetry, and tail-flick latency, were used to determine the impact of the light disruption or exogenous melatonin on the morphine tolerance progression. RESULTS:constant light exposure significantly aggravates morphine tolerance in neuropathic rats. Continued infusion of low-dose melatonin (3 ?g/h) attenuated morphine tolerance in both neuropathic and naïve rats. This protective effect was independent of melatonin receptors, as shown by the neutral effect of melatonin receptors inhibitors. The transcriptional profiling demonstrated a significant enhancement of proinflammatory and pain-related receptor genes in morphine-tolerant rats. In contrast, this transcriptional pattern was abolished by melatonin coinfusion along with the upregulation of the Kcnip3 gene. Moreover, melatonin increased the antioxidative enzymes SOD2, HO-1, and GPx1 in the spinal cord of morphine-tolerant rats. CONCLUSION:Dysregulated circadian light exposure significantly compromises the efficacy of morphine's antinociceptive effect, while the cotreatment with melatonin attenuates morphine tolerance/hyperalgesia development. Our results suggest the potential of melatonin as an adjuvant of morphine in clinical pain management, particularly in patients who need long-term opioid treatment.

Dataset Information

Melatonin regulation of transcription in the reversal of morphine tolerance: Microarray analysis of differential gene expression.

Publications

Melatonin regulation of transcription in the reversal of morphine tolerance: Microarray analysis of differential gene expression.

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