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Differential effects of orexin receptors-1 and 2 on IOP and ICP responses to hypothalamic activation
Arthur DeCarlo, Johanna Lee Henry, Izabela Caliman, Rafael Grytz, Philip L Johnson, Brian C Samuels;
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© ARVO (1962-2015); The Authors (2016-present)
The hypothalamus is a highly connected region of the brain with broad endocrine, behavioral and autonomic roles. The orexin/hypocretin system of neurotransmitters and receptors affect many of these hypothalamic functions and the orexin receptor system has been localized in high density within the hypothalamus, in particular the dorsomedial hypothalamic (DMH) and perifornical (PeF) regions. We have shown that intraocular pressure (IOP) rises when stimulating the DMH/PeF region, and our goal was to evaluate orexin receptor antagonists in IOP and ICP modulation.
A crossover design in SD rats (n=13) compared the effects of the orexin-1 and -2 receptor (ORX1 and ORX2) antagonists C56 and JNJ 103, respectively. Localized hypothalamic activation was achieved by microinjection of the GABAA receptor antagonist bicuculline methiodide (BMI; 30 pmoles/75 nL). Response outcomes were heart rate (HR), mean arterial pressure (BP), body temperature (Temp), intracranial pressure (ICP) and IOP. In Arm A of this study design, animals were pretreated 70 min prior to BMI injection with subcutaneous (subQ) vehicle administration. After responses returned to baseline (55 min) the animals were pre-treated subQ a second time with either the vehicle, or with C56, or with JNJ 103 (Arm B). After 70 min, physiological responses to a second, identical hypothalamic BMI injection were then obtained (Arm B).
Comparing mean responses from only Arm B suggested that pre-treatment with C56 was associated with significantly higher HR, BP and IOP responses to BMI relative to control animals. In contrast, animals pre-treated with JNJ 103 demonstrated lower ICP and IOP responses to BMI than controls. In a matched pairs analysis, subtracting the response in Arm B from the Arm A response within each animal, the data suggested that JNJ 103 was associated with a significant lowering of HR, BP, ICP, Temp, and IOP responses in Arm B relative to Arm A compared to control animals. In contrast, pretreatment with C56 in Arm B was associated with significant raising of HR and BP responses compared to control animals.
Pre-treatment with the ORX2 antagonist JNJ 103 lowered both ICP and IOP responses to activation of the DMH/PeF region, thus attenuating the translaminar pressure difference. The orexin system, and particularly ORX2 receptors, may have promise as novel targets for the management of glaucoma.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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