Amylin 1 receptors produce delayed activation and sensitization of trigeminovascular neurons

Abstract text (incl. figure legends and references)

Objective: Investigate in an in vivo model the role of amylin 1 (AMY₁) receptor activation in the modulation of the trigeminal nociceptive system in rats during the different phases of the estrous cycle, and compare it to the responses observed in males.

Methods: We recorded neuronal activity in male and female rats with extracellular electrodes placed within the trigeminocervical complex and examined the effects of targeting the AMY₁ receptor on ongoing spontaneous and dural-evoked firing rates of central trigeminovascular neurons. The selective AMY₁ receptor agonist pramlintide and AMY₁ receptor antagonist AC187, were used for the present study. The different stages of the estrous cycle were identified and assigned by a blinded experimenter through Cresyl violet-stained vaginal smears.

Results: Compared to males (n=6), intravenous administration of pramlintide (6 µg/kg) significantly augmented the ongoing spontaneous activity and dural-evoked neuronal responses in the trigeminocervical complex, only during the estrus and early diestrus phases of the female estrous cycle, whereas this effect was not observed in the metestrus, proestrus and late diestrus phases (n=4-6 per group). Moreover, compared to vehicle (0.9% NaCl, n=5), intravenous administration of AC187 (6 µg/kg) significantly decreased the ongoing spontaneous and dural-evoked firing rates of central trigeminovascular neurons in males (n=4).

Conclusion: Our data support that activation of the AMY₁ receptor modulates the trigeminal nociceptive system and that this effect is most pronounced during the estrus and early diestrus phases of the mesntrual cycle. The data also support selective AMY₁ antagonists as novel and potentially effective targets for the treatment of migraine.