Medial prefrontal cortex diclofenac-induced antinociception is mediated through GPR55, cannabinoid CB1, and mu-opioid receptors of this area and periaqueductal gray
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.
KeywordsDiclofenac Cannabinoid receptors Opioid receptors Orofacial pain mPFC vlPAG
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.
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
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.
- Ahmad T, Lauzon NM, de Jaeger X, Laviolette SR (2013) Cannabinoid transmission in the prelimbic cortex bidirectionally controls opiate reward and aversion signaling through dissociable kappa versus μ-opiate receptor dependent mechanisms. J Neurosci 33:15642–15651PubMedPubMedCentralCrossRefGoogle Scholar
- DaSilva AF, Nascimento TD, DosSantos MF, Lucas S, van Holsbeeck H, DeBoer M, Maslowski E, Love T, Martikainen IK, Koeppe RA, Smith YR, Zubieta JK (2014) Association of μ-opioid activation in the prefrontal cortex with spontaneous migraine attacks - brief report I. Ann Clin Transl Neurol 1:439–444PubMedPubMedCentralCrossRefGoogle Scholar
- Der-Ghazarian T, Widarma CB, Gutierrez A, Amodeo LR, Valentine JM, Humphrey DE, Gonzalez AE, Crawford CA, McDougall SA (2014) Behavioral effects of dopamine receptor inactivation in the caudate-putamen of preweanling rats: role of the D2 receptor. Psychopharmacology 231:651–662PubMedCrossRefPubMedCentralGoogle Scholar
- Freitas RL, Salgado-Rohner CJ, Hallak JE, Crippa JA, Coimbra NC (2013) Involvement of prelimbic medial prefrontal cortex in panic-like elaborated defensive behaviour and innate fear-induced antinociception elicited by GABAA receptor blockade in the dorsomedial and ventromedial hypothalamic nuclei: role of the endocannabinoid CB1 receptor. Int J Neuropsychopharmacol 16:1781–1798PubMedCrossRefPubMedCentralGoogle Scholar
- Guerrero-Alba R, Barragán-Iglesias P, González-Hernández A, Valdez-Moráles EE, Granados-Soto V, Condés-Lara M, Rodríguez MG, Marichal-Cancino BA (2018) Some prospective alternatives for treating pain: the endocannabinoid system and its putative receptors GPR18 and GPR55. Front Pharmacol 9:1496PubMedCrossRefPubMedCentralGoogle Scholar
- Naderi N, Majidi M, Mousavi Z, Khoramian Tusi S, Mansouri Z, Khodagholi F (2012) The interaction between intrathecal administration of low doses of palmitoylethanolamide and AM251 in formalin-induced pain related behavior and spinal cord IL1-β expression in rats. Neurochem Res 37:778–785PubMedCrossRefPubMedCentralGoogle Scholar
- Ossipov MH (2012) The perception and endogenous pain modulation. Scientifica (Cairo) 2012:561761Google Scholar
- Patrick GW, Robinson MA (1987) Collateral projection from trigeminal sensory nuclei to ventrobasal thalamus and cerebellar cortex. J Comp Neurol 192:229–236Google Scholar
- Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates, 6th edn. Elsevier, New YorkGoogle Scholar
- Vazquez E, Hernandez N, Escobar W, Vanegas H (2005) Antinociception induced by intravenous dipyrone (metamizol) upon dorsal horn neurons: involvement of endogenous opioids at the periaqueductal gray matter, the nucleus raphe magnus, and the spinal cord in rats. Brain Res 1048:211–217PubMedCrossRefPubMedCentralGoogle Scholar