The orexinergic system in the retina: Expression and physiological impact-A review of the literature.

The neuropeptides orexin-A (OXA) and orexin-B (OXB), central orchestrators of arousal and energy homeostasis, are increasingly recognized as key neuromodulators within the vertebrate retina. This review synthesizes current evidence demonstrating a broad extra-hypothalamic expression of the orexin system across retinal neurons, including photoreceptors, bipolar (BCs), amacrine (ACs), and ganglion cells (GCs). We detail a sophisticated, cell-type-specific signaling framework where orexins exert complex, often antagonistic, presynaptic and postsynaptic actions via orexin 1 (OX1R) and orexin 2 (OX2R) receptors. These actions fine-tune signal transmission by potentiating glutamate release from BCs while suppressing GABAergic inhibition from ACs, ultimately modulating retinal output. A central theme emerging is the system's pivotal role in non-image-forming visual functions: OXA enhances the pupillary light reflex (PLR) by increasing the excitability of specific intrinsically photosensitive retinal ganglion cells (M2 ipRGCs), while OXB potentiates scotopic (dim-light) sensitivity by disinhibiting rod bipolar circuits. Furthermore, pharmacological inhibition of orexin receptors affects circadian rhythms in both the retina and hypothalamus. However, the field is marked by intriguing paradoxes, such as the stimulatory effects of receptor antagonists and significant species differences in OX2R expression. We critically evaluate evidence for a tonically active retinal orexin system that interfaces with dopaminergic signaling and circadian photic input. By integrating molecular, cellular, and behavioral findings, this review clarifies how retinal orexinergic modulation serves as a potential crucial interface between light detection, circadian physiology, and systemic arousal, while highlighting critical translational gaps and future research directions.