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

Cheng, Yu‐Che; Tsai, Ray Jui-Fang; Sung, Yen‐Tseng; Chen, Ing‐Jung; Tu, Tzu-Yi; Mao, Ya‐Yuan; Wong, Chih‐Shung

doi:10.3892/ijmm.2018.4030

Cited by 12 publications

(9 citation statements)

References 38 publications

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“…Our microarray analysis also showed that a single i.t. injection of melatonin in the morphine-tolerant rat inverts the bulk of genes down/upregulated by the chronic morphine treatment [ 39 ], suggesting a crucial genetic regulation of high-dose melatonin treatment and consequently the morphine tolerance reversal. However, the effect of long-term administration of melatonin directly targeting the spinal cord on a morphine-tolerant rat model has not been fully explored.…”

Section: Introductionmentioning

confidence: 99%

The Circadian Hormone Melatonin Inhibits Morphine-Induced Tolerance and Inflammation via the Activation of Antioxidative Enzymes

et al. 2020

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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 μg/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.

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Section: Introductionmentioning

confidence: 99%

The Circadian Hormone Melatonin Inhibits Morphine-Induced Tolerance and Inflammation via the Activation of Antioxidative Enzymes

et al. 2020

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“…It has been demonstrated that melatonin has excellent anti‐inflammatory and antioxidant effects [133,134]. Melatonin regulates the expression of genes related in morphine tolerance [129,135‐137]; this effect may be a result of its potent anti‐inflammatory and antioxidant properties ( Figure ).…”

Section: Discussionmentioning

confidence: 99%

Melatonin and morphine: potential beneficial effects of co‐use

Karim

Pourhanifeh

Dehdashtian

et al. 2020

Fundamemntal Clinical Pharma

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Morphine is a potent analgesic agent used to control acute or chronic pain. Chronic administration of morphine results in analgesic tolerance, hyperalgesia, and other side effects including dependence, addiction, respiratory depression, and constipation, which limit its clinical usage. Therefore, identifying the new analgesics with fewer side effects which could increase the effect of morphine and reduce its side effects is crucial. Melatonin, a multifunctional molecule produced in the body, is known to play an important role in pain regulation. The strong anti‐inflammatory effect of melatonin is suggested to be involved in the attenuation of the pain associated with inflammation. Melatonin also increases the anti‐nociceptive actions of opioids, such as morphine, and reverses their tolerance through regulating several cellular signaling pathways. In this review, published articles evaluating the effect of the co‐consumption of melatonin and morphine in different conditions were investigated. Our results show that melatonin has pain‐killing properties when administered alone or in combination with other anti‐nociceptive drugs. Melatonin decreases morphine consumption in different pathologies. Furthermore, attenuation of morphine intake can be accompanied by reduction of morphine‐associated side‐effects, including physical dependence, morphine tolerance, and morphine‐related hyperalgesia. Therefore, it is reasonable to believe that the combination of melatonin with morphine could reduce morphine‐induced tolerance and hyperalgesia, which may result from anti‐inflammatory and antioxidant properties of melatonin. Overall, we underscore that, to further ameliorate patients' life quality and control their pain in various pathological conditions, melatonin deserves to be used with morphine by anesthesiologists in clinical practice.

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“…This revealed the characteristics of the transcriptome in the T1-T4 spinal cord following cardiac I/R injury and the specific spinal segment that innervates the heart serves a significant role in cardiac I/R injury. Cheng et al (53) reported that melatonin regulation of the transcriptome was associated with the reversal of morphine tolerance by transcriptomic analysis of the L5-S3 segmental spinal cord. Mohrman et al (54) revealed the spinal cord transcriptomic and metabolic patterns in a excitotoxic injection injury model of syringomyelia.…”

Section: Discussionmentioning

confidence: 99%

Identification of lncRNA and mRNA expression profiles in rat spinal cords at various time‑points following cardiac ischemia/reperfusion

Wang

et al. 2019

Int J Mol Med

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The identification of the expression patterns of long non-coding RNAs (lncRNAs) and mRNAs in the spinal cord under normal and cardiac ischemia/reperfusion (I/R) conditions is essential for understanding the genetic mechanisms underlying the pathogenesis of cardiac I/R injury. The present study used high-throughput RNA sequencing to investigate differential gene and lncRNA expression patterns in the spinal cords of rats during I/R-induced cardiac injury. Male Sprague Dawley rats were assigned to the following groups: i) Control; ii) 2 h (2 h post-reperfusion); and iii) 0.5 h (0.5 h post-reperfusion). Further mRNA/lncRNA microarray analysis revealed that the expression profiles of lncRNA and mRNA in the spinal cords differed markedly between the control and 2 h groups, and in total 7,980 differentially expressed (>2-fold) lncRNAs (234 upregulated, 7,746 downregulated) and 3,428 mRNAs (767 upregulated, 2,661 downregulated) were identified. Reverse transcription-quantitative polymerase chain reaction analysis was performed to determine the expression patterns of several lncRNAs. The results indicated that the expression levels of lncRNA NONRATT025386 were significantly upregulated in the 2 and 0.5 h groups when compared with those in the control group, whereas the expression levels of NONRATT016113, NONRATT018298 and NONRATT018300 were elevated in the 2 h group compared with those in the control group; however, there was no statistically significant difference between the 0.5 h and control groups. Furthermore, the expression of lncRNA NONRATT002188 was significantly downregulated in the 0.5 and 2 h groups when compared with the control group. The present study determined the expression pattern of lncRNAs and mRNAs in rat spinal cords during cardiac I/R. It was suggested that lncRNAs and mRNAs from spinal cords may be novel therapeutic targets for the treatment of I/R-induced cardiac injury.

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

Cited by 12 publications

References 38 publications

The Circadian Hormone Melatonin Inhibits Morphine-Induced Tolerance and Inflammation via the Activation of Antioxidative Enzymes

The Circadian Hormone Melatonin Inhibits Morphine-Induced Tolerance and Inflammation via the Activation of Antioxidative Enzymes

Melatonin and morphine: potential beneficial effects of co‐use

Identification of lncRNA and mRNA expression profiles in rat spinal cords at various time‑points following cardiac ischemia/reperfusion

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