PACAP38 SIGNALING IN THE TRIGEMINAL GANGLION UNDERLIES MIGRAINE-LIKE HEADACHE

Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) is a is a well-established mediator of migraine, but its precise cellular targets within the trigeminal ganglion (TG) remain poorly defined. This study aimed to delineate the relative contributions of trigeminal neurons and satellite glial cells (SGCs) to PACAP-induced mechanical hypersensitivity. We combined behavioral assessments in female rats with in vitro functional imaging approaches. Mechanical sensitivity was assessed following either systemic or local intraganglionic administration of PACAP38. Ratiometric calcium imaging and cAMP measurements were used to characterize cell-specific signaling responses in neurons and SGCs. Systemic administration of PACAP38 induced a reversible cephalic mechanical hypersensitivity, without altering extracephalic mechanical sensitivity. Direct intraganglionic injection of PACAP38 similarly induced cephalic, but not extracephalic, mechanical hypersensitivity, with a time course similar to systemic injection. Calcium imaging revealed that PACAP38 activates both TG neurons and SGCs, albeit with distinct kinetic profiles. In SGCs, PACAP38 induced a dose-dependent increase in intracellular cAMP levels. This cAMP response was inhibited by the PAC1 antagonist M65 and the PAC1/VPAC2 antagonist PACAP6-38, whereas the VPAC1-selective antagonist PG97-269 had no effect. These findings suggest that PACAP38 exerts predominantly peripheral effect within the TG through activation of both trigeminal neurons and SGCs. In SGCs specifically, this response is mediated by PAC1 and VPAC2 receptors.