Sexually dimorphic effects of Amylin 1 receptor activation in trigeminovascular neurons

Background: Migraine is more prevalent in women, and although the mechanisms involved in this disparity remain poorly understood, an interaction between the trigeminovascular system and cycling estrogen levels in biologically-predisposed women has been suggested. We investigated the role of amylin 1 (AMY1) receptor activation in the modulation of the trigeminal nociceptive system in female rats across the estrous cycle in cycle stages with falling and rising estrogen levels and compared these to the responses in males. Methods: We recorded neuronal activity in vivo within the trigeminocervical complex (TCC) and examined the effects of targeting AMY1 receptors on ongoing spontaneous and dural stimulus evoked firing rates of trigeminovascular neurons. The selective AMY1 receptor agonist pramlintide and AMY1 receptor antagonist AC 187 were used. Estrous cycle stages were identified via cytology from vaginal smears. Results: Administration of pramlintide increased the spontaneous activity and dural stimulus-evoked neuronal responses in the TCC, only during falling estrogen phases of the female estrous cycle. Moreover, the administration per se of AC 187 decreased spontaneous evoked firing rates of central trigeminovascular neurons in females and males, whereas pretreatment with AC 187 prevented pramlintide-induced increases in spontaneous activity and dural stimulus-evoked responses in females with falling estrogen levels. Conclusion: AMY1 receptors modulate the trigeminal nociceptive system. The facilitating effect is most pronounced in female rats during falling estrogen phases of the estrous cycle. Our data also supports selective AMY1 receptor antagonists as potentially effective targets for the treatment of migraine. ### Competing Interest Statement The authors have declared no competing interest.