Involvement of a central amygdaloid nucleus-lateral habenular nucleus pathway in the processing of formalin-induced pain.

The central amygdaloid nucleus (CeA) and the lateral habenular nucleus (LHb) are essential nuclei playing modulatory roles in encoding noxious stimuli. Their interaction has recently been demonstrated in chronic pain-induced depression. However, little is known about the CeA-LHb pathway in a formalin-induced pain model. In the present study, we aimed to clarify whether the CeA-LHb pathway modulates the formalin-induced pain model using a neuroanatomical tracing method combined with a designer receptor exclusively activated by a designer drugs strategy (DREADD). The results revealed that the CeA predominantly sends projections to vesicular glutamate transporter-2 (VGluT2)-expressing neurons of the LHb, and inhibition of LHb function exhibits an analgesic effect in the formalin-induced pain model. Furthermore, activating the CeA-LHb pathway significantly attenuates pain sensation only in phase 2 of formalin-induced pain in mice. The present results indicate the participation of the LHb in inflammatory pain sensation and reveal a CeA-LHbVGluT2 pathway that displays analgesic effects in a formalin pain model.