Effect of suvorexant on morphine tolerance and dependence in mice: Role of NMDA, AMPA, ERK and CREB proteins

• Published in: Neurotoxicology (Park Forest South) 2021-05, Vol.84, p.64-72
• Main Authors: Esmaili-Shahzade-Ali-Akbari, Peyman, Hosseinzadeh, Hossein, Mehri, Soghra
• Format: Article
• Language: English
• Subjects: Brain; Clonidine; CREB; Cyclic AMP response element-binding protein; Dependence; Drug tolerance; ERK; Evaluation; Extracellular signal-regulated kinase; Field tests; Injection; Locomotor activity; Morphine; N-Methyl-D-aspartic acid; Naloxone; Opioids; Orexin receptors; Orexins; Proteins; Receptors; Suvorexant; Tolerance; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2021.02.005

[Display omitted] •Administration of suvorexant reduced morphine-induced tolerance and dependence in mice.•Suvorexant decreased morphine-enhanced levels of CREB and p-ERK proteins in brain.•Suvorexant did not reduce morphine-enhanced levels of NMDA protein in brain. The major problems of morphine use in the clinic are its tolerance and dependence. This study aimed to investigate the effect of suvorexant, a dual orexin receptor antagonist, on morphine-induced dependence and tolerance in mice and evaluate the level of NMDA, AMPA, ERK, p-ERK, CREB and p-CREB proteins in the brain. Tolerance and dependence were induced by repeated injection of morphine in mice (three times a day for 3 days, 50, 50, and 75 mg/kg /day). To evaluate the effects of the drugs on morphine-induced tolerance and dependence, suvorexant (30, 60 and 90 mg/kg), clonidine (positive control, 0.1 mg/kg) and saline were injected intraperitoneally 30 min before each injection of morphine. Tolerance and locomotor activity were assessed by tail-flick and open-field tests, respectively. The effect of suvorexant on the naloxone (5 mg/kg, ip)-induced morphine withdrawal, was also evaluated. Finally, the expression of proteins in the brain of mice was measured by western blot. Administration of suvorexant with morphine significantly reduced morphine-induced tolerance. Also, suvorexant attenuated the naloxone-precipitated opioid withdrawal. Suvorexant decreased morphine-enhanced levels of CREB and p-ERK proteins but did not affect the expression of NMDA and AMPA proteins compared to the morphine group. Suvorexant reduced morphine-induced tolerance and dependence through the inhibition of orexin receptors as well as changes in CREB and p-ERK protein levels in the brain.