Related Experiment Videos
Met-enkephalin alteration in the rat during chronic injection of morphine and/or midazolam
1Department of Pharmacology, Ohio State University, College of Medicine and Public Health, Columbus 43210-1239, USA. tejwani.1@osu.edu
Abstract:
We have recently reported that the short-acting anesthetic and analgesic drug midazolam can produce analgesia and decrease morphine tolerance and dependence in the rat by interacting with the opioid system. This study was designed to investigate the effect of midazolam, morphine, and both together on met-enkephalin levels in the rat. Male Sprague-Dawley rats were divided into four groups: (1) saline-saline; (2) saline-morphine; (3) midazolam-saline, and (4) midazolam-morphine groups. First, a saline or midazolam injection was given intraperitoneally and after 30 min a second injection of saline or morphine was given subcutaneously once daily for 11 days. Animals were sacrificed on the 11th day 60 min after the last injection to measure met-enkephalin by radioimmunoassay. Morphine tolerant animals showed a significant increase in met-enkephalin levels in the cortex (137%) and midbrain (89%), and a significant decrease in met-enkephalin levels in the pituitary (74%), cerebellum (34%) and medulla (72%). Midazolam treated animals showed a significant decrease in met-enkephalin levels in the pituitary (63%), cortex (39%), medulla (58%), kidneys (36%), heart (36%) and adrenals (43%), and a significant increase in met-enkephalin levels in the striatum (54%) and pons (51%). When morphine and midazolam were injected together, midazolam antagonized the increase in met-enkephalin levels in cortex and midbrain region and the decrease in met-enkephalin level in the medulla region observed in morphine tolerant animals. These results indicate that morphine tolerance and dependence is associated with changes in the concentration of met-enkephalin in the brain. Midazolam may inhibit morphine tolerance and dependence by reversing some of the changes induced in met-enkephalin levels in brain by morphine in morphine tolerant and dependent animals.
Insights
Midazolam may reduce morphine tolerance and dependence by altering met-enkephalin levels in the brain. This study investigated how midazolam and morphine affect these opioid system peptides in rats.
Area of Science:
- Neuroscience
- Pharmacology
- Endocrinology
Background:
- Opioid tolerance and dependence are significant clinical challenges.
- Midazolam, a short-acting anesthetic, has shown potential in modulating opioid effects.
- Met-enkephalin is a key endogenous opioid peptide involved in pain and reward pathways.
Purpose of the Study:
- To investigate the effects of midazolam, morphine, and their combination on met-enkephalin levels in rat brain and peripheral tissues.
- To explore the potential role of met-enkephalin in midazolam's observed modulation of morphine tolerance and dependence.
Main Methods:
- Male Sprague-Dawley rats were administered saline, midazolam, morphine, or a combination daily for 11 days.
- Met-enkephalin levels were quantified using radioimmunoassay in brain regions (cortex, midbrain, pituitary, cerebellum, medulla, striatum, pons) and peripheral organs (kidneys, heart, adrenals).
- Animals were sacrificed 60 minutes after the final injection on day 11.
Main Results:
- Morphine treatment led to increased met-enkephalin in the cortex and midbrain, but decreased levels in the pituitary, cerebellum, and medulla.
- Midazolam alone decreased met-enkephalin in the pituitary, cortex, medulla, kidneys, heart, and adrenals, while increasing it in the striatum and pons.
- Co-administration of midazolam antagonized morphine-induced increases in cortical and midbrain met-enkephalin and the decrease in the medulla.
Conclusions:
- Morphine tolerance and dependence are associated with significant alterations in central and peripheral met-enkephalin concentrations.
- Midazolam appears to mitigate morphine tolerance and dependence by reversing specific met-enkephalin level changes induced by morphine.
- These findings highlight a potential mechanism for midazolam in managing opioid tolerance and dependence through interaction with the endogenous opioid system.