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Application of inhibitor in relieving morphine tolerance

A technology for morphine tolerance and inhibitors, which can be applied in compound screening, microbial determination/testing, and medical preparations containing active ingredients. Effect

Active Publication Date: 2022-06-21
NANJING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the role of EZH2 in morphine tolerance has not been reported so far

Method used

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  • Application of inhibitor in relieving morphine tolerance
  • Application of inhibitor in relieving morphine tolerance
  • Application of inhibitor in relieving morphine tolerance

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1: EPZ6438 was purchased from selleck company as 10mg powder, chemical name is [1,1'-biphenyl]-3-carboxamide, N-[(1,2-dihydro-4,6-dimethyl -2-oxo-3-pyridyl)methyl]-5-[ethyl(tetrahydro-2H-pyran)-4-yl)amino]-4-methyl-4'-(4-morpholine methyl)-, which was dissolved in 1.11 ml of DMSO to give a 10 mM stock solution. The groups were set as control group (normal saline, saline), morphine group, morphine and EPZ6438 (EZH2 inhibitor) co-administration group, and EPZ6438 (EZH2 inhibitor) group. The 10 mg / ml morphine stock solution was diluted 10 times with physiological saline to obtain 10 mg / 10 ml morphine (solution 1). A 10 mM solution of EPZ6438 was dissolved in 10 mg / 10 ml morphine to give a solution containing 2 μg / 10 μl EPZ6438 (EZH2 inhibitor) in 10 μg / 10 μl morphine (Solution 2).

[0036] ICR mice were divided into groups of 10. Each group was intrathecally injected with 10 μl of normal saline, 10 μl of solution 1, 10 μl of solution 2, and 10 μl of EPZ6438 (EZH2...

Embodiment 2

[0037] Example 2: CPI-1205 (EZH2 inhibitor) was purchased from selleck company as 5mg powder, its chemical name was 1H-indole-3-carboxamide, N-[(1,2-dihydro-4-methoxyl -6-Methyl-2-oxo-3-pyridyl)methyl]-2-methyl-1-[(1R)-1-[1-(2,2,2-trifluoroethyl)- 4-Piperidinyl]ethyl]-, which was dissolved in 385.6 μl of DMSO to give a stock solution of 10 mM. UNC1999 (EZH2 inhibitor) was purchased from selleck company as 5mg powder, chemical name is 1H-indazole-4-carboxamide, N-[(1,2-dihydro-6-methyl-2-oxo-4 -propyl-3-pyridyl)methyl]-1-(1-methylethyl)-6-[6-[4-(1-methylethyl)-1-piperazinyl]-3- pyridyl]-, which was dissolved in 351 μL DMSO to give a stock solution of 10 mM. The groups were set as control group (normal saline, saline), morphine group, morphine and CPI-1205 (EZH2 inhibitor) co-administration group, morphine and UNC1999 (EZH2 inhibitor EPZ6438 (EZH2 inhibitor) group. ml of morphine stock solution was diluted 10 times with normal saline to obtain 10mg / 10ml morphine (solution 1)....

Embodiment 3

[0039] Example 3: The groups were set as control group (normal saline, saline), morphine group, morphine and lentivirus overexpressing miR30 shRNA (EZH2) group, and the miR30 shRNA sequence was 5'-ACTTGCCCACCTCGGAAATTT-3'.

[0040] ICR mice were grouped into groups of 10. On days -7 and 0, miR30 shRNA (EZH2) was overexpressed with lentivirus to inhibit EZH2. The pSLenti-GAD67-EGFP-3xFLAG-WPRE empty vector was used to construct miR30 shRNA. (Ezh2) plasmid, namely pSLenti-GAD67-EGFP-3xFLAG-miR30shRNA(Ezh2)-WPRE, was injected intrathecally with 10 μl per mouse, followed by intrathecal injection of 10 μg (administration amount) / 10 μl per day for 7 consecutive days in each group. (Administration volume) After 30 min of morphine, the pain sensitivity of mice was detected by tail-flick trail. Behavioral data suggest that inhibition of EZH2 significantly alleviates tolerance induced by chronic morphine administration. ***p### p image 3 shown).

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PUM

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Abstract

The invention discloses an application of an inhibitor in relieving morphine tolerance, an EZH2 inhibitor for cancer treatment is transformed to relieve morphine tolerance, and the treatment target of morphine tolerance is expanded. According to the application disclosed by the invention, the strong relevance between the EZH2 target and morphine tolerance is effectively confirmed, the morphine tolerance can be effectively relieved through the EZH2 inhibitor, a brand new target EZH2 for improving the morphine tolerance is obtained, and a foundation is laid for subsequent screening of medicines for relieving the morphine tolerance. According to the correlation between an EZH2 target and morphine tolerance, an EZH2 inhibitor is successfully applied to relieving morphine tolerance.

Description

technical field [0001] The invention relates to the field of research and development of analgesic drugs, in particular to the application of an inhibitor in relieving morphine tolerance. Background technique [0002] Neuropathic pain results from lesions or diseases affecting the peripheral or central somatosensory nervous system. Examples of neuropathic pain include painful polyneuropathy, postherpetic neuralgia, trigeminal neuralgia, and poststroke pain. Clinically, neuropathic pain is characterized by spontaneous persistent or shooting pain and induction of an amplified pain response following noxious or non-noxious stimuli. Peripheral nerve injury can lead to chronic pain and ultimately neuropathic pain, which remains one of the most common pain disorders worldwide. The chronic compression injury (CCI) model provides a model for a deeper understanding of neuropathic pain. [0003] Morphine, the representative of opioids, has powerful analgesic effects and is the main...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K45/06A61K31/7105A61P25/04C12Q1/02
CPCA61K45/00A61K45/06A61K31/7105A61P25/04G01N33/5008C12N2503/02G01N2500/10Y02A50/30
Inventor 姜春懿刘文涛万莉
Owner NANJING MEDICAL UNIV
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