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Medial prefrontal cortex diclofenac-induced antinociception is mediated through GPR55, cannabinoid CB1, and mu-opioid receptors of this area and periaqueductal gray

  • Esmaeal Tamaddonfard
  • Amir ErfanparastEmail author
  • Reza Salighedar
  • Sina Tamaddonfard
Original Article

Abstract

Supraspinal mechanisms of non-steroidal anti-inflammatory drug (NSAID)-induced antinociception are not well understood. In the present study, the possible antinociceptive mechanisms induced by intra-medial prefrontal cortex (intra-mPFC) microinjection of diclofenac were investigated after blockade of GPR55, cannabinoid CB1, and mu-opioid receptors in this area and ventrolateral periaqueductal gray (vlPAG). For drug delivery, unilateral (left side) of mPFC and bilateral (right and left sides) of vlPAG were surgically cannulated. Formalin test was induced by subcutaneous injection of a diluted formalin solution into the right vibrissa pad. A typical biphasic (neurogenic and inflammatory phases) pain behavior was produced following formalin injection. Microinjection of diclofenac (2.5, 5, and 10 μg/0.25 μL) into the mPFC suppressed both phases of pain. Intra-mPFC microinjection of naloxonazine (a mu-opioid receptor antagonist, 1 μg/0.25 μL) and AM251 (a cannabinoid CB1 receptor antagonist, 1 μg/0.25 μL) increased both phases of pain intensity. In addition, intra-mPFC-microinjected diclofenac-induced antinociception was inhibited by prior intra-mPFC and intra-vlPAG administration of naloxonazine and AM251. On the other hand, intra-mPFC and intra-vlPAG microinjection of AM251 (0.25 μg/0.25 μL) decreased pain severity which was inhibited by prior administration of ML193. The above-mentioned drugs did not alter locomotor activity. In conclusion, diclofenac suppressed both the neurogenic and inflammatory phases of formalin-induced orofacial pain at the level of mPFC. GPR55, cannabinoid CB1, and mu-opioid receptors of the mPFC and vlPAG might be involved in the mPFC analgesic effects of diclofenac.

Keywords

Diclofenac Cannabinoid receptors Opioid receptors Orofacial pain mPFC vlPAG 

Notes

Authors’ contributions

ET and AE conceived and designed the research. The experiments were conducted by RS and ST. ET and AE analyzed the data and wrote the manuscript. All of the authors read and approved the manuscript.

Funding information

This study was financially supported by the Faculty of Veterinary Medicine of Urmia University (grant no. 1396-03-22/D10-485).

Compliance with ethical standards

Ethical approval

All experiments were approved by the Veterinary Ethics Committee of the Faculty of Veterinary Medicine of Urmia University.

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Esmaeal Tamaddonfard
    • 1
  • Amir Erfanparast
    • 1
    Email author
  • Reza Salighedar
    • 1
  • Sina Tamaddonfard
    • 1
  1. 1.Division of Physiology, Department of Basic Sciences, Faculty of Veterinary MedicineUrmia UniversityUrmiaIran

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