Analgesic and anti-inflammatory effects of modafinil in a mouse model of neuropathic pain: A role for nitrergic and serotonergic pathways

ABSTRACT

Objectives

To evaluate the effects of modafinil on neuropathic pain induced by sciatic nerve cuffing in mice, and possible contribution of nitrergic/inflammatory and serotonergic systems.

Methods

Neuropathic pain was induced by applying a polyethylene cuff around the left sciatic nerve. Seven days later, mice received modafinil (50, 100, and 200 mg/kg; intraperitoneal [i.p.]) and morphine (10 mg/kg, i.p.) as control. Mice also received pretreatments of the nonselective nitric oxide (NO) synthase (NOS) inhibitor L-NAME, the selective neuronal NOS inhibitor 7-nitroindazole, the selective inducible NOS inhibitor aminoguanidine, and the selective serotonin reuptake inhibitor citalopram before modafinil (100 mg/kg). von Frey test was used to evaluate mechanical allodynia. Additionally, sciatic nerves were collected for histopathological analysis. Tissue levels of NO metabolites, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were assessed.

Results

Animals whose sciatic nerves were cuffed had a significantly (P<0.001) decreased paw withdrawal threshold (PWT) compared with the sham-operated group. Modafinil (100 mg/kg) and morphine significantly reversed PWT (P<0.001). Pretreatments with L-NAME, 7-nitroindazole, aminoguanidine, and citalopram in different groups markedly reversed analgesic effects of modafinil. Tissue homogenates of Cuffed sciatic nerves showed significantly higher levels of NO metabolites, TNF-α and IL-6 (P<0.001). Modafinil lowered NO metabolites, TNF-α, and IL-6 levels (P<0.001). Histopathology illustrated marked axonal degeneration and shrinkage in the cuffed sciatic nerve, which were improved in the modafinil-treated group.

Conclusions

Modafinil exerts analgesic and neuroprotective effects in cuff-induced neuropathic mice via possible involvement of the nitrergic/inflammatory and serotonergic systems.

KEYWORDS:

• Modafinil
• neuropathic pain
• nitric oxide
• interleukin (il)-6
• tumor necrosis factor (TNF)-α
• mice

Author’s contribution

HG and PM conceived of the presented idea. HG, PM, MN, NR, and MR took part in data gathering by performing the surgeries, behavioral assessments and providing post-operative care for the rodents. HG, PM, NR, and MR participated in preparing histopathological tissue samples and their assessment. MG, HG, PM, and NR prepared the primary draft under ARD’s supervision and other authors took part in editing and completing the parts of the manuscript that were mostly related to their prior participation in addition to reviewing and confirming full manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Tehran University of Medical Sciences (TUMS) [grant numbers 99-1-209-39689, 2019]; the Iran National Science Foundation (INSF) [grant number 96002757].

Notes on contributors

Hossein Ghorbanzadeh

Hossein Ghorbanzadeh is a medical intern and researcher at school of medicine, Tehran University of Medical Sciences. He is also taking an MPH course at school of public health, Tehran University of Medical Sciences.

Parastoo Mohebkhodaei

Parastoo Mohebkhodaei recieved her B.S. in microbiology from Tehran Medical sciences Islamic Azad University. She is a lab expert at Imam Khomeini Hospital Complex and researcher at Brain and Spinal Cord Injury Research Center, Tehran University of Medical Sciences.

Mehran Nematizadeh

Mehran Nematizadeh is a medical student and researcher at school of medicine, Tehran University of Medical Sciences. He is also taking an MPH course at school of public health, Tehran University of Medical Sciences.

Nastaran Rahimi

Nastaran Rahimi is a postgraduate researcher and coordinator at the department of pharmacology, Tehran University of Medical Sciences. She received her B.S. in Cellular and Molecular Biology and M.S. in Biochemistry.

Mahsa Rafeiean

Mahsa Rafeiean is a MD-MPH student and researcher at Tehran University of medical sciences. She is now medical intern.

Mehdi Ghasemi

Mehdi Ghasemi , MD, is an Associate Program Director and Assistant Professor of Neurology and clinician-scientist at University of Massachusetts Medical Center, USA, with subspecialty in Neuromuscular Medicine from Harvard University. He has over 15 years of research experience in the fields of neuropharmacology, neurodegenerative diseases, and neuromuscular disorders.

Ahmad R. Dehpour

Ahmad Reza Dehpour , PharmD, PhD, is a distinguished Professor of Pharmacology in the Department of Pharmacology, School of Medicine, at Tehran University of Medical Sciences. He is one of the world’s highly cited researchers announced by Thomson Reuters ISI with main area of research on neuropharmacology.