Morphine-Associated Cerebral Vascular Dysfunction in the Context of Alzheimer’s Disease

In Alzheimer’s disease (AD), progressive cognitive decline is closely linked to β-amyloid–mediated disruption of cerebral vascular integrity. Opioid, a purported cerebral vasodilator, is a commonly prescribed analgesic in this population, and approximately half of all AD/ADRD patients use them for pain management. Clinically, dementia patients treated with strong opioids exhibit a ~27% increase in mortality, raising concern that opioid–vascular interactions may exacerbate cerebrovascular vulnerability in AD. However, the mechanisms by which opioids alter the function of penetrating arterioles, the bottlenecks of cerebral parenchymal circulation, remain unknown. We hypothesized that amyloid-β pathology in AD impairs morphine-mediated vasodilation, compromising the ability of penetrating arterioles to autoregulate. Using pressure myography, we assessed real-time lumen diameter changes in isolated penetrating arterioles exposed to 1 μM morphine. In healthy Sprague–Dawley rats, morphine induced a vasodilation that was endothelium-dependent in penetrating arterioles, as the dilation was eliminated after endothelium denudation (8.9 ± 2.4% vs. 0.3 ± 0.3%, endothelium-intact vs. denuded; p = 0.007, n = 9). In rTg-DI, transgenic rat model of AD, morphine-evoked dilation was markedly reduced and remained unchanged following endothelial stripping (2.8 ± 2.2% vs. 1.9 ± 1.9%, intact vs. denuded; p = 0.748, n = 9). Notably, in penetrating arterioles from rTg-DI and endothelium-denuded arterioles from Sprague-Dawley rats, morphine also elicited vasoconstriction. In arterioles from rTg-DI rats, removal of the endothelium did not alter this vasoconstriction (7.6 ± 2.7% vs. 7.2 ± 2.8%, intact vs. denuded; p = 0.915, n = 9). In endothelium-denuded arterioles from Sprague-Dawley rats, constriction to morphine was similar to that observed in rTg-DI rats (8.3 ± 3.4%, denuded; n = 9). Myogenic reactivity, an ex vivo assessment of cerebral vascular autoregulation, was not affected by morphine in penetrating arterioles from Sprague-Dawley rats. On the other hand, morphine significantly impaired autoregulation in penetrating arterioles of rTg-DI rats, particularly at intraluminal pressures < 60 mmHg, observed as increased myogenic tone. Together, these findings suggest that, in healthy conditions, morphine indeed induces dilation of brain penetrating arterioles in an endothelium-dependent manner. However, without a functional endothelium, morphine instead causes constriction. Further, in rTg-DI, endothelial dysfunction shifts morphine responses towards constriction, which may increase the risk of lethal cerebrovascular accidents in this patient population. NIH/NINDS 1R01NS126752-01A1 R01 AG073230 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.