Differential modulation of nociceptive dural input to [hypocretin] orexin A and B receptor activation in the posterior hypothalamic area

Abstract

The novel neuropeptides orexin A and B are selectively synthesised in the lateral and posterior hypothalamus and are involved in hypothalamic regulation of autonomic and neuroendocrine functions. Recent findings point also to a role in nociception. As the posterior hypothalamus is involved in the central modulation of nociception we studied the effects of hypocretin/orexin receptor activation in the posterior hypothalamic area (PH) of the rat on dural nociceptive input. Orexins were microinjected into the PH and the effects on responses of neurones in the caudal trigeminal nucleus studied. Injection of orexin A decreased the A- and C-fibre responses to dural electrical stimulation as well as spontaneous activity. Responses to noxious thermal stimulation of the facial skin were also decreased by orexin A. Injection of orexin B into the PH, however, elicited increased responses to dural stimulation in A- and C-fibre responses and resulted in increased spontaneous activity. Responses to facial thermal stimulation were also increased by orexin B. Control injection of saline into the PH had no significant effect. The results show a differential modulation of dural nociceptive input by orexin A and B receptor activation in the PH. The results support the role of the PH in the nociceptive processing of meningeal input. As both peptides are also involved in hypothalamic regulation of neuroendocrine and autonomic functions, orexinergic mechanisms in the PH may provide a link for endocrine and autonomic changes as well as nociceptive phenomena seen in primary headache disorders.

Erratum to: Why does Sleep Stop Migraine?

“…Stimulation of the superior saggital sinus, an experimental maneuver for activating pathways relevant to migraine was shown to activate neurons in the posterior hypothalamus [70] Injection of OX-A or OX-B into the posterior hypothalamus has been shown to differentially modulate nociceptive dural input to the TNC. Micro-injection of OX-A elicited an anti-nociceptive effect reducing A and C fiber responses to dural stimulation and spontaneous activity, in agreement with other analgesia studies whereas interestingly OX-B activation elicited the opposite "pro-nociceptive" effect enhancing nociceptive transmission and convergent sensory responses to facial thermal stimulation [71]. Most recently novel dual OX-1R/OX-2R receptor antagonists that have been developed for the treatment of primary insomnia [72] have been used to probe the pharmacology of the trigeminal system rather than the peptide orexin agonists.…”

Hypothalamic Deep Brain Stimulation in Positron Emission Tomography

“…Conversely, electrical stimulation of the superior sagittal sinus activates the supra-optic nucleus and posterior hypothalamic area (Benjamin et al, 2004) [a monosynaptic pathway connecting the hypothalamus and trigeminal nucleus has been documented (Malick et al, 2000)]. The posterior hypothalamus is able to both decrease and enhance nociceptive responses in the trigeminal nucleus caudalis (Bartsch et al, 2004). In humans, stereotactic thermocoagulation of the posteromedial hypothalamus has been successfully used to treat otherwise intractable cancer pain (Sano et al, 1975) Using PET, we investigated 10 patients successfully treated with hypothalamic DBS for intractable CH.…”

Update on future headache treatments

“…Integral to sleep and eating, Orexins are peptides that can alter the function of specific processes of the trigeminovascular system associated with migraine [64,65]. Orexin B, when injected into the posterior hypothalamus, can increase responses to dural stimulation in the A-and C-fiber input neurons and resulted in increased spontaneous activity [66].…”