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Venlafaxine inhibits naloxone-precipitated morphine withdrawal symptoms: Role of inflammatory cytokines and nitric oxide

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Abstract

Opioid-induced neuroinflammation plays a role in the development of opioid physical dependence. Moreover, nitric oxide (NO) has been implicated in several oxidative and inflammatory pathologies. Here, we sought to determine whether treatment with venlafaxine during the development of morphine dependence could inhibit naloxone-precipitated withdrawal symptoms. The involvement of neuro-inflammation related cytokines, oxidative stress, and L-arginine (L-arg)-NO pathway in these effects were also investigated. Mice received morphine (50 mg/kg/daily; s.c.), plus venlafaxine (5 and 40 mg/kg, i.p.) once a day for 3 consecutive days. In order to evaluate the possible role of L-arg-NO on the effects caused by venlafaxine, animals received L-arg, L-NAME or aminoguanidine with venlafaxine (40 mg/kg, i.p.) 30 min before each morphine injection for 3 consecutive days. On 4th day of experiment, behavioral signs of morphine-induced physical dependence were evaluated after i.p. naloxone injection. Then, brain levels of tissue necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10), brain-derived neurotrophic factor (BDNF), NO and oxidative stress factors including; total thiol, malondialdehyde (MDA) contents and glutathione peroxidase (GPx) activity were determined. Co-administration of venlafaxine (40 mg/kg) with morphine not only inhibited the naloxone-precipitated withdrawal signs including jumping and weight loss, but also reduced the up-regulation of TNF-α, IL-1β, IL-6, NO and MDA contents in mice brain tissue. However, repeated administration of venlafaxine inhibited the decrease in the brain levels of BDNF, total thiol and GPx. Pre-administration of L-NAME and aminoguanidine improved, while L-arg antagonized the venlafaxine-induced effects. These results provide evidences that venlafaxine could be used as a candidate drug to inhibit morphine withdrawal through the involvement of inflammatory cytokines and l-arginine-NO in mice.

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Acknowledgements

This work was financially supported by the Vice Chancellor of Research, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran (APRC-9810).

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Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Mohammad Taghi Mansouri

  2. Department of Anesthesiology, College of Physicians & Surgeons, Columbia University, New York, NY, 10032, USA

    Mohammad Taghi Mansouri

  3. Department of Pharmacology, School of Pharmacy, Toxicology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Bahareh Naghizadeh, Neda Amirgholami & Soheila Alboghobeish

  4. Department of Pharmacology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran

    Behnam Ghorbanzadeh

  5. Department of Pharmacology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

    Gholamreza Houshmand

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  1. Mohammad Taghi Mansouri
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  2. Bahareh Naghizadeh
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Correspondence to Mohammad Taghi Mansouri or Bahareh Naghizadeh.

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Mansouri, M., Naghizadeh, B., Ghorbanzadeh, B. et al. Venlafaxine inhibits naloxone-precipitated morphine withdrawal symptoms: Role of inflammatory cytokines and nitric oxide. Metab Brain Dis 35, 305–313 (2020). https://doi.org/10.1007/s11011-019-00491-4

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