To determine the effects of the 5-HT_1F receptor agonist lasmiditan in a preclinical model of trigeminal autonomic cephalalgias.

Lasmiditan, a 5-HT_1F receptor agonist has demonstrated preclinical and clinical efficacy for the treatment of migraine. However, its potential efficacy in preclinical models of trigeminal autonomic cephalalgias, including cluster headache is undetermined.

Male Sprague-Dawley rats (n=32) were anesthetized with isoflurane and maintained with propofol infusion (33-50mg/kg/h). A small burr hole permitted placement of a tungsten stimulating electrode in the superior salivatory nucleus (SSN) to evoke parasympathetic outflow and trigeminal nociception. A laser Doppler probe positioned on the anterior choroid of the eye recorded changes in choroidal blood flow as a surrogate readout of parasympathetic-induced lacrimation. In a subset of experiments, a C1 laminectomy was performed to record SSN-evoked trigeminal nociception. Following baseline responses to SSN stimulation, animals were intravenously infused with saline or lasmiditan (5mg/kg) and SSN-evoked responses recorded for 90 minutes.

Lasmiditan had no significant effect on choroidal blood flow responses to SSN stimulation when compared to saline-treated rats (χ²₍₁₀₎=3.3, p=0.975). However, lasmiditan significantly inhibited SSN-evoked trigeminal nociception, compared to saline-treated rats (F_10,100=9.6, p<0.0001). Neuronal responses were inhibited 20 minutes post lasmiditan, maximally by 40% at 45 minutes and remained reduced for the remainder of the 90 minute recording window.

The data highlights a clear action for lasmiditan in a validated preclinical model of trigeminal autonomic cephalalgias. Given the proven translational efficacy of this model, the data supports the potential utility of lasmiditan clinically for trigeminal autonomic cephalalgias, including cluster headache.