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Brian Samuels, Nathan Hammes, Philip Johnson, Anantha Shekhar; A Potential Role for the Hypothalamic Orexin System in Mediating Intraocular Pressure Fluctuations. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4013.
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© ARVO (1962-2015); The Authors (2016-present)
We have recently shown that chemical stimulation of the dorsomedial/perifornical hypothalamus (DMH/PeF) evokes increases in intraocular pressure (IOP), intracranial pressure (ICP), and the translaminar pressure gradient. The DMH/PeF region receives strong direct and indirect projections from the suprachiasmatic nucleus and has extensive efferent projections to autonomic sympathetic relays. Therefore, the DMH/PeF neurons are ideally situated to modulate circadian fluctuations in IOP. Orexins are a novel class of neuropeptides that play a key role in regulating circadian behaviors as well as neuroendocrine and autonomic functions. Given that orexin containing neurons are located almost exclusively in the DMH/PeF region, we hypothesize that fluctuations in IOP and ICP are regulated, at least in part, by these orexin containing neurons. To test this hypothesis, we examined the effect of a systemically administered orexin 1 receptor antagonist, SB334861 (Tocris), on the increases in IOP and ICP following chemical stimulation of the DMH/PeF with the GABA-A receptor antagonist bicuculline methoidide (BMI).
The cisterna magna space of isoflurane-anesthetized Sprague-Dawley rats (250-300g; n=18) was cannulated for continuous monitoring of ICP. The ICP line was then connected to high sensitivity pressure transducer attached to a PowerLab data acquisition system (AD Instruments). An iCareLab tonometer was used to record IOP every 2 minutes throughout the experiment. Rats received an injection of SB334861 (30mg/kg, i.p.) or vehicle 30 minutes prior to stereotaxic microinjection of BMI (30pmol/75nL) into the DMH/PeF region. The resulting increases in IOP and ICP were then recorded and differences between treatment groups determined by t-test with significance set at P≤0.05.
Compared to vehicle control, pretreatment with the SB33486 attenuated the maximum increase in IOP (13.1±1.9 vs 7.7±1.0 mmHg; p=0.03) but not ICP (5.0±0.5 vs 3.9±0.7 mmHg; p=0.19) following chemical stimulation.
These data are the first to support the hypothesis that orexin neurons located in the DMH/PeF region play a role in mediating circadian fluctuations in IOP, a previously unrecognized function of these specific neurons. Further, these neurons may provide a novel target for future glaucoma therapies aimed at reducing circadian fluctuation of IOP.
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