Vagal afferent modulation of spinal trigeminal neuronal responses to dural electrical stimulation in rats

Vagus nerve stimulation (VNS) is an approved antiepileptic and antidepressant treatment, which has recently shown promise as a therapy for drug-resistant primary headaches. Specific neurobiological mechanisms underlying its anticephalgic action are not elucidated, partly because of the deficiency of research-related findings. The spinal trigeminal nucleus (STN) plays a prominent role in pathophysiology of headaches by modulating pain transmission from intracranial structures to higher centers of the brain. To determine whether vagal stimulation may affect trigeminovascular nociception, we investigated the effects of VNS on the STN neuronal activity in the animal model of headache. In anesthetized rats the spike activity of the STN neurons with convergent orofacial and meningeal inputs was monitored, and the changes in neuronal responses to electrical stimulation of the dura mater under preconditioning or under continuous electrical stimulation of the left cervical vagus nerve were studied. Preconditioning vagal afferent stimulation (200-ms train of pulses at 30 Hz applied before each dural stimulus) did not produce substantial changes in the STN spike activity. However, continuous VNS with frequency of 10 Hz in 48% of cases significantly suppressed trigeminal neuronal responses to dural electrical stimulation. In line with the decrease in evoked activity, the VNS-induced depression of ongoing neuronal firing was observed. Although the inhibitory effect was prevailing, 29.5% of STN neurons were facilitated by VNS, whereas 22.5% were unresponsive to the stimulation. These results provide an evidence of VNS-induced modulation of trigeminovascular nociception, and therefore contribute to a deeper understanding of neurophysiological mechanisms underlying effects of vagal stimulation in chronic drug-resistant headaches.