Experimental Research Article

Korean J Pain 2022; 35(4): 413-422

Published online October 1, 2022 https://doi.org/10.3344/kjp.2022.35.4.413

Copyright © The Korean Pain Society.

Medial prefrontal cortex nitric oxide modulates neuropathic pain behavior through mu opioid receptors in rats

Dorsa Raisian1 , Amir Erfanparast2 , Esmaeal Tamaddonfard2 , Farhad Soltanalinejad-Taghiabad3

1DVM Graduate, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
2Division of Physiology, Department of Basic Sciences, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
3Division of Anatomy, Department of Basic Sciences, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran

Correspondence to:Amir Erfanparast
Division of Physiology, Department of Basic Sciences, Faculty of Veterinary Medicine, Urmia University, Serow highway, Urmia 5756151818, I.R. Iran
Tel: +98 44 32770508
Fax: +98 44 32771926
E-mail: a.erfanparast@urmia.ac.ir

Handling Editor: Sang Hun Kim

Author contributions: Dorsa Raisian: Investigation; Amir Erfanparast: Study conception; Esmaeal Tamaddonfard: Supervision; Farhad Soltanalinejad-Taghiabad: Methodology.

Received: May 8, 2022; Revised: June 14, 2022; Accepted: July 15, 2022

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Background: The neocortex, including the medial prefrontal cortex (mPFC), contains many neurons expressing nitric oxide synthase (NOS). In addition, increasing evidence shows that the nitric oxide (NO) and opioid systems interact in the brain. However, there have been no studies on the interaction of the opioid and NO systems in the mPFC. The objective of this study was to investigate the effects of administrating L-arginine (L-Arg, a precursor of NO) and N(gamma)-nitro-L-arginine methyl ester (L-NAME, an inhibitor of NOS) into the mPFC for neuropathic pain in rats. Also, we used selective opioid receptor antagonists to clarify the possible participation of the opioid mechanism.
Methods: Complete transection of the peroneal and tibial branches of the sciatic nerve was applied to induce neuropathic pain, and seven days later, the mPFC was cannulated bilaterally. The paw withdrawal threshold fifty percent (50% PWT) was recorded on the 14th day.
Results: Microinjection of L-Arg (2.87, 11.5 and 45.92 nmol per 0.25 µL) increased 50% PWT. L-NAME (17.15 nmol per 0.25 µL) and naloxonazine (an antagonist of mu opioid receptors, 1.54 nmol per 0.25 µL) inhibited anti-allodynia induced by L-Arg (45.92 nmol per 0.25 µL). Naltrindole (a delta opioid receptor antagonist, 2.45 nmol per 0.25 µL) and nor-binaltorphimine (a kappa opioid receptor antagonist, 1.36 nmol per 0.25 µL) were unable to prevent L-Arg (45.92 nmol per 0.25 µL)-induced antiallodynia.
Conclusions: Our results indicate that the NO system in the mPFC regulates neuropathic pain. Mu opioid receptors of this area might participate in pain relief caused by L-Arg.

Keywords: Arginine, Hyperalgesia, Pain, Prefrontal Cortex, Narcotic Antagonists, Nitric Oxide, Sciatic Nerve, Rats.