Posterior hypothalamic modulation of ocular‐responsive trigeminal subnucleus caudalis neurons is mediated by Orexin‐A and Orexin1 receptors

Abstract

Orexin-A (OxA) is synthesized in posterior and lateral regions of the hypothalamus and contributes to homeostatic regulation of body functions including pain modulation. To determine if orexinergic mechanisms contribute to posterior hypothalamus (PH)-induced modulation of ocular input to subnucleus caudalis/upper cervical (Vc/C1) neurons, the orexin-1 receptor antagonist SB334867 was applied to the dorsal brainstem surface prior to PH disinhibition, by bicuculline methiodide, in male rats under isoflurane anesthesia. Ocular input to Vc/C1 units by bright light or hypertonic saline was markedly reduced by PH disinhibition and reversed completely by local Vc/C1 application of SB334867. OxA applied to the Vc/C1 surface mimicked the effects of PH disinhibition in a dose-dependent manner. OxA-induced inhibition was prevented by co-application of SB334867, but not by the orexin-2 receptor antagonist TCS Ox2 29. PH disinhibition and local OxA application also reduced the high threshold convergent cutaneous receptive field area of ocular units, suggesting widespread effects on somatic input to Vc/C1 ocular units. Vc/C1 application of OxA or SB334867 alone did not affect the background discharge of ocular units and suggested that the PH-OxA influence on ocular unit activity was not tonically active. Vc/C1 application of OxA or SB334867 alone also did not alter mean arterial pressure, whereas PH disinhibition evoked prompt and sustained increases. These results suggest that stimulus-evoked increases in PH outflow acts through OxA and orexin-1 receptors to alter the encoding properties of trigeminal brainstem neurons responsive to input from the ocular surface and deep tissues of the eye.

Current understanding of photophobia, visual networks and headaches

“…Ocular pain may then result from mechanical stimulation of sensitized trigeminal nociceptors innervating dilated eye vasculature (34,35) (Figure 3). Activation of these trigeminal nociceptors can further amplify photophobia through trigeminal-autonomic reflex (12) and hypothalamic facilitation of trigeminal activity (103,104). These complementary mechanisms are thought to play a major role in the type of photophobia associated with inflammation of the uvea (iris, ciliary body and choroid), corneal damage and other prechiasmal pathologies (13,15,32,105).…”

Upregulation of calcitonin gene-related peptide, neuronal nitric oxide synthase, and phosphorylated extracellular signal-regulated kinase 1/2 in the trigeminal ganglion after bright light stimulation of the eye in rats

“…A light intensity of 2,000-10,000 lux was used for light therapy in most human studies (62). In most animal studies, however, 500-50,000 lux was used to activate light-responsive neurons in the central nervous system: the posterior thalamus (19), rostral ventromedial medulla (5), and Vc (20,43). In this study, an intensity of 20,000 lux was able to modulate the peripheral nervous system, and the accumulation of daily bright light exposure was not immense.…”

“…Bright light stimulation of the eye activates Vc neurons via the TG in rats (20,43), and Vc neuronal activity is suppressed by intravitreal injection of a NOS inhibitor (44). This suggests that activation of Vc neurons by bright light stimulation is mediated via TG neurons.…”

Multi-dimensional role of the parabrachial nucleus in regulating pain-related affective disturbances in trigeminal neuropathic pain

“…In contrast, hypothalamic orexinergic neurons were found to project to the Vc [85]. A recent study has demonstrated that activity of orexinergic receptors can modulate nociceptive information processing in the superficial layer of the Vc [86]. The above findings about the reciprocal connections between the PBN and lateral hypothalamus suggest that orexinergic neurons that receive excitatory inputs from the lateral PBN might exacerbate the vicious interactions between sleep disturbance and nociceptive sensitivity in trigeminal neuropathic pain [87].…”