The periaqueductal grey (PAG) region of the brainstem is a known modulator of somatic pain transmission. Migraine is likely to be due to episodic brain dysfunction in pathways involved in the control of pain and other sensory modalities, such as light and sound. To investigate the influence of the PAG on pain transmission from intracranial structures, we examined spinal trigeminal neuronal activity in response to PAG stimulation in a model of trigeminovascular nociception in the cat. Evoked trigeminal neuronal activity in the spinal cord was reversibly inhibited by stimulation of the PAG. The effect was robust with a mean reduction in evoked activity of -61+/-21%. This effect could be seen both ipsilateral and contralateral to the side of PAG stimulation and was well localised to the ventrolateral PAG. These data demonstrate that a role of the PAG is to inhibit afferent trigeminal nociceptive traffic. Considered with neurosurgical and human functional imaging studies, these data support the notion that brainstem dysfunction might lead to disinhibition of trigeminal afferents and be important in the pain process of migraines.