Role of ventrolateral orbital cortex 5-HT_2A receptors in formalin-induced secondary mechanical allodynia and hyperalgesia

BackgroundFormalin injection in hindpaw of rat produced acute nociceptive behaviors (flinching and licking/lifting) followed by secondary mechanical allodynia and hyperalgesia. Our previous study suggests that 5-HT_2A receptors in the ventrolateral orbital cortex (VLO) are involved in Formalin produced acute nociceptive behaviors, but it is not clear whether 5-HT_2A receptors are involved in secondary mechanical allodynia and hyperalgesia. The purpose of this present study is to unveil the role of 5-HT_2A receptors in the VLO and the underlying mechanisms in formalin-induced secondary mechanical allodynia and hyperalgesia.ResultsThe expression level of 5-HT_2A receptors were significantly increased in the VLO tissues at 6 days after formalin injection. Microinjection of the 5-HT_2A receptors agonist DOI into the VLO decreases formalin-induced secondary mechanical allodynia and hyperalgesia in the ipsilateral paw, but not contralateral paw, which was antagonized by pre-treatment with 5-HT_2A receptors antagonist Ketanserin. Furthermore, the antinociceptive effect of DOI was blocked by the phospholipase C (PLC) inhibitor U73122 and the protein kinase C (PKC) inhibitor Chelerythrine, or the non-selective glutamate receptor antagonist Kynurenic acid. respectively. And the antinociceptive effect of DOI was blocked by pre-treatment with GABA in the ventrolateral periaqueductal grey (PAG).ConclusionsThese data suggest that 5-HT_2A receptors in the VLO are involved in mediating the antinociceptive effect of formalin-induced long-lasting hypersensitivity. The possible mechanism underlying this effect is that 5-HT_2A receptors activation regulate glutamatergic neuron transmission via the Gq-PLC-PKC pathway, leading to activation of VLO neurons projecting to the PAG. This could activate the PAG brainstem descending inhibitory system and depression of nociceptive information transmission at the spinal cord level.