Background: Ventrolateral orbital cortex (VLO) has been found to play an important role in the regulation of neuropathic pain (NPP). As a traditional mood stabilizer, valproic acid (VPA) is currently employed in the treatment of NPP. However, whether VPA plays an analgesic role in VLO is still unknown.

Objective: To elucidate the underlying analgesic mechanism of microinjection of VPA into the VLO on spared nerve injury (SNI), an animal model of NPP.

Methods: We firstly examined the role of VPA by intraperitoneal and intral-VLO injection. Then, we accessed its role as a histone deacetylase inhibitor by intral-VLO microinjection of sodium butyrate. Finally, the GABAergic mechanism was measured through the intra-VLO microinjection of several agonists and antagonists of various GABAergic receptor subtypes.

Results: Both intraperitoneal and intral-VLO injection of VPA attenuated SNI-induced mechanical allodynia. Microinjection of sodium butyrate, one of the histone deacetylase inhibitors, into the VLO attenuated the mechanical allodynia. Besides, microinjection of valpromide, a derivative of VPA which is a GABAergic agonist, into the VLO also attenuated allodynia. Furthermore, microinjection of picrotoxin, a GABAA receptor antagonist, into the VLO attenuated mechanical allodynia; microinjection of picrotoxin before VPA into the VLO increased VPA-induced anti-allodynia. Besides, microinjection of CGP 35348, a GABAB receptor antagonist, into the VLO attenuated allodynia; microinjection of CGP 35348 before VPA into the VLO also increased VPA-induced anti-allodynia. What is more, microinjection of imidazole-4-acetic acid (I4AA), a GABAC receptor antagonist, into the VLO enhanced allodynia; microinjection of I4AA before VPA into the VLO decreased VPA-induced anti-allodynia.

Conclusions: These results suggest that both the histone acetylation mechanism and GABAergic system are involved in mediating VLO-induced anti-hypersensitivity.