Spinal astrocyte-neuron lactate shuttle contributes to the PACAP/PAC1 receptor-induced nociceptive behaviors

Previously, we showed that spinal pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC1 receptor signaling triggers long-lasting pain behaviors through astroglial activation. Since astrocyte-neuron lactate shuttle (ANLS) could be essential for long-term synaptic facilitation, we aimed to elucidate a possible involvement of spinal ANLS in the development of the PACAP/PAC1 receptor-induced pain behaviors. A single intrathecal administration of PACAP induced short-term spontaneous aversive behaviors, followed by long-lasting mechanical allodynia. These pain behaviors were inhibited by DAB, an inhibitor of glycogenolysis, and this inhibition was reversed by simultaneous L-lactate application. In the cultured spinal astrocytes, the PACAP-evoked glycogenolysis and lactate secretion were inhibited by a protein kinase C (PKC) inhibitor, and the PKC inhibitor attenuated the PACAP-induced pain behaviors. Finally, an inhibitor for the monocarboxylate transporters blocked the lactate secretion from the spinal astrocytes and inhibited the PACAP-induced pain behaviors. These results suggested that PAC1 receptor-PKC-ANLS signaling is involved in the PACAP-induced pain behaviors.