Role of 5-HT2A Receptor in Modulating Glutamatergic Activity in the Ventrolateral Orbital Cortex: Implication in Trigeminal Neuralgia.

• Knockdown of 5-HT 2A R in the ventrolateral orbital cortex (VLO) aggravated pain in a mouse model of trigeminal neuralgia (TN). • Knockdown or inhibition of 5-HT 2A R decreased neuronal glutamatergic activity in the VLO. • Activation of 5-HT 2A R increased neuronal glutamatergic activity in the VLO. 5-HT 2A receptors (5-HT 2A Rs) are widely expressed in the central nervous system, including in the ventrolateral orbital cortex (VLO). The VLO is an important cortical component for pain processing. Brain 5-HT 2A Rs are implicated in both pro- and anti- nociceptive functions. However, the roles of 5-HT 2A Rs in the VLO in trigeminal neuralgia and neuronal synaptic function remain to be understood. We used chronic constriction injury of infraorbital nerve (IoN-CCI) model and shRNA mediated gene knockdown in mice to investigate the role of 5-HT 2A Rs in the VLO in trigeminal neuralgia. We found that knockdown of 5-HT 2A Rs in the VLO aggravated spontaneous pain and mechanical allodynia in mice after IoN-CCI. At the synaptic level, decreasing 5-HT 2A R expression by shRNA or inhibition of 5-HT 2A R activity by its antagonist ketanserin decreased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) of the neurons in the VLO, whereas 5-HT 2A R partial agonist 2,5-Dimethoxy-4-iodoamphetamine (DOI) enhanced sEPSCs of the neurons in the VLO. In summary, 5-HT 2A Rs in the VLO modulate the trigeminal pain by regulating neuronal glutamatergic activity. [ABSTRACT FROM AUTHOR]