Abstract
Purpose: To determine the influence of miR-140-5p on morphine tolerance in rats.Methods: Sprague-Dawley (SD) rats were randomly divided into morphine tolerance (MT) and saline control (NS) groups, respectively. Rats in MT group were injected with 10 μL (10 μg) morphine twice daily for seven consecutive days while those in NS group were administered the equivalent volume of normal saline. The maximum effect of morphine (MPE) was computed from tail-flick test results. MiR-140-5p mimics and toll-like receptor 4 (TLR4) lentivirus were transfected separately or co-transfected into model rats. MiR-140-5p and TLR4 expression were determined by quantitative real-time polymerase chain reaction (RT-qPCR) or western blotting. Dual-luciferase reporter assay was used to verify the target relationship between miR-140-5p and TLR4.Results: The expression of miR-140-5p was decreased, while the expression of TLR4 increased in morphine-tolerant rats (p < 0.05). TLR4 was a target of miR-140-5p. At 24 and 48 h after injection, MPE clearly increased and TLR4 expression was reduced under miR-140-5p overexpression or TLR4 knockdown (p < 0.05). Moreover, there were no significant changes in MPE or levels of TLR4 when miR-140-5p and TLR4 were co-transfected into morphine-tolerant rats.Conclusion: MiR-140-5p inhibits morphine resistance in rats via targeted regulation of TLR4 expression. These provide a theoretical basis for the clinical management of morphine tolerance.
Highlights
Numerous malignant tumors can cause patients unbearable pain when tumors develop to a certain stage
The %MPE in the morphine tolerance (MT) group gradually weakened from the 1st to the 7th days (p < 0.05), and on the 7th day, the rats in the MT group showed little difference in %MPE compared with the NS group
The expression level of miR-140-5p was highly negatively correlated with toll-like receptor 4 (TLR4) (r = -0.762, p < 0.05)
Summary
Numerous malignant tumors can cause patients unbearable pain when tumors develop to a certain stage. In addition to the pain caused by the tumor itself, the local compression of intravascular nerves, viscera, or bones by the tumor, the elevation of intracranial pressure caused by tumor metastasis to the brain, and the pathological fracture, obstruction, and pressure sores caused by metastasis to bone can result in pain [1]. Morphine is the primary effective analgesic for patients with advanced cancer, but long-term morphine use can lead to drug tolerance. There is increasing evidence that morphine tolerance is a complex process. Studies on the mechanisms of morphine tolerance are not limited to neurons; intraperitoneal injection of morphine can lead to significant morphine tolerance, while causing significant hypertrophy of astrocytes in the spinal cord as well as in the hippocampus [2]. The specific mechanisms of morphine resistance remain to be further investigated [3]
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