TY - JOUR
T1 - Histone deacetylase inhibitors prevented the development of morphine tolerance by decreasing IL6 production and upregulating μ-opioid receptors
AU - Jindal, Sahil
AU - Kumar, Nitesh
AU - Shah, Aarti Abhishek
AU - Shah, Abhishek
AU - Gourishetti, Karthik
AU - Chamallamudi, Mallikarjuna R.
N1 - Funding Information:
All acknowledge the infrastructural support provided by Manipal Academy of Higher Education, Manipal, India, for the execution of this study. We are grateful to the Excise Department, Karnataka State Government and Sri K.V. Nagaraj (Assistant Drug Controller, Public Information Office, Udupi Office, Karnataka State Govt.) for permitting and providing Morphine vials for the study. We thank Dr. Sree Lalitha Bojja, Post Doctoral Research Fellow, Department of Pharmacology, Manipal College of Pharmaceutical Sciences, for language and grammar editing of this manuscript.
Publisher Copyright:
© 2021 Bentham Science Publishers.
PY - 2021
Y1 - 2021
N2 - Background: Morphine tolerance on long-term usage leads to chronic pain conditions. Preclinical studies demonstrated that the upregulation of HDACs is associated with a decrease in the sensitivity of μ-opioid receptors, which results in morphine tolerance. Objective: The present study was designed to assess the influence of the selected known HDAC inhibitors (NMJ2 and NMJ3) on the pain tolerance induced by chronic administration of morphine in Balb/c mice. Methods: In the present study, morphine was administered in incremental doses 1, 2, 3.6, 6.5, 11.2, 21, and 21 mg/kg daily for seven days to develop morphine tolerance. The nociceptive thresholds, analgesia, and tolerance were assessed 30 min after morphine administration alternatively from 1st day to 7th day using the hot plate and mechanical allodynia methods. Results: The morphine control group showed a reduction in the Paw Withdrawal Threshold (PWT) and the percentage Maximum Possible Effects (MPEs). In contrast, the combination of SAHA and test drugs with morphine increased the PWT and MPEs as compared to the morphine alone group. Administration of morphine alone also showed an increase in the production of the pro-inflammatory mediator, IL-6, and down-regulation of the μ-opioid receptor in the brain tissues. Treatment with HDAC inhibitors, SAHA, and test drugs showed a reversal in these changes. Conclusion: Results indicated that HDAC inhibitors were involved in the prevention of morphine tolerance in normal mice by inhibiting pro-inflammatory marker production and by increasing the sensitivity of neurons towards morphine in producing an analgesic effect in morphine tolerated mice.
AB - Background: Morphine tolerance on long-term usage leads to chronic pain conditions. Preclinical studies demonstrated that the upregulation of HDACs is associated with a decrease in the sensitivity of μ-opioid receptors, which results in morphine tolerance. Objective: The present study was designed to assess the influence of the selected known HDAC inhibitors (NMJ2 and NMJ3) on the pain tolerance induced by chronic administration of morphine in Balb/c mice. Methods: In the present study, morphine was administered in incremental doses 1, 2, 3.6, 6.5, 11.2, 21, and 21 mg/kg daily for seven days to develop morphine tolerance. The nociceptive thresholds, analgesia, and tolerance were assessed 30 min after morphine administration alternatively from 1st day to 7th day using the hot plate and mechanical allodynia methods. Results: The morphine control group showed a reduction in the Paw Withdrawal Threshold (PWT) and the percentage Maximum Possible Effects (MPEs). In contrast, the combination of SAHA and test drugs with morphine increased the PWT and MPEs as compared to the morphine alone group. Administration of morphine alone also showed an increase in the production of the pro-inflammatory mediator, IL-6, and down-regulation of the μ-opioid receptor in the brain tissues. Treatment with HDAC inhibitors, SAHA, and test drugs showed a reversal in these changes. Conclusion: Results indicated that HDAC inhibitors were involved in the prevention of morphine tolerance in normal mice by inhibiting pro-inflammatory marker production and by increasing the sensitivity of neurons towards morphine in producing an analgesic effect in morphine tolerated mice.
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U2 - 10.2174/1871527319999201113102852
DO - 10.2174/1871527319999201113102852
M3 - Article
C2 - 33191889
AN - SCOPUS:85107749128
SN - 1871-5273
VL - 20
SP - 190
EP - 198
JO - CNS and Neurological Disorders - Drug Targets
JF - CNS and Neurological Disorders - Drug Targets
IS - 2
ER -