The orexins and their involvement in the modulation of trigeminovascular nociceptive transmission

Migraine is a common and disabling condition that affects up to 15% of the population. This thesis sought to explore a possible role of the orexins in migraine by investigating aspects of their effect on trigeminovascular physiology. The orexins are two neuropeptides synthesised in the lateral and posterior hypothalamic nuclei that have recently been implicated in the modulation of nociceptive processing. To investigate a possible role of the orexins in the pathophysiology of migraine, different animal models of trigeminovascular activation were used to identify possible modulatory functions. Intravital microscopy uses dilation of dural blood vessel as a measure of trigeminal nerve activation, and thus compounds inhibiting the vasodilator response have the potential to inhibit trigeminovascular nociceptive transmission. Orexin A, but not B was able to significantly inhibit the observed dilation, an effect reversed by the selective orexin 1 (OXi) receptor antagonist SB-334867. Central modulatory roles of the orexins were investigated using electrophysiological methods. Orexin A and B and SB-334867 were given intravenously, or microinjected into the ventrolateral PAG (vlPAG) of the anaesthetised rat, and the responses of trigeminocervical complex (TCC) neurons to a variety of stimuli examined. Orexin A inhibited trigeminal neurons in the TCC when given intravenously or microinjected into the vlPAG, via activation of the OXi receptor. Orexin B demonstrated a differential effect, resulting in a facilitation of trigeminal neuronal firing when microinjected into the vlPAG. The orexinergic system was also investigated in the feline model of trigeminovascular activation via stimulation of the SSS. Double-labelled immunohistochemistry for Fos and orexin A or B was utilised to identify orexinergic neurons that are activated in the hypothalamus in response to trigeminovascular activation. A subpopulation of orexin synthesising neurons were shown to be activated in response to SSS stimulation, demonstrating that either efferent or afferent nociceptive transmission from the hypothalamus may involve orexinergic systems