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Brainstem Opioidergic System Is Involved in Early Response to Experimental SAH

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Abstract

Subarachnoid hemorrhage (SAH) is a form of stroke with high rates of mortality and permanent disability for patients who survive the initial event. Previous research has focused on delayed cerebral vasospasm of large conduit arteries as the cause of poor long-term outcomes after SAH. New evidence suggests that acute failure to restore cerebral blood flow (CBF) after SAH may be setting the stage for delayed ischemic neurological deficits. Our lab previously demonstrated that the rostral ventromedial medulla (RVM), an autonomic and sensorimotor integration center, is important for maintaining CBF after experimental SAH. In this study, we have demonstrated that ablation of μ-opioid receptor containing cells with dermorphin conjugates in the RVM results in a high mortality rate after experimental SAH and, in survivors, causes a dramatic decrease in CBF. Further, locally blocking the μ-opioid receptor with the antagonist naltrexone attenuated the reduction in CBF secondary to experimental SAH. Saturating μ-opioid receptors with the agonist [d-Ala(2),NMe-Phe(4),Gly-ol(5)]-encephalin (DAMGO) had no effect. Taken together, these results suggest that SAH activates opioidergic signaling in the RVM with a resultant reduction in CBF. Further, cells in the RVM that contain μ-opioid receptors are important for survival after acute SAH. We propose that failure of the RVM μ-opioid receptor cells to initiate the compensatory CBF response sets the stage for acute and delayed ischemic injury following SAH.

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Acknowledgments

The authors thank Seksiri Arttamangkul, Vollum Institute, and Mary Heinricher, OHSU.

Conflict of Interest

Justin S. Cetas, Robin McFarlane, Kassi Kronfeld, Phoebe Smitasin, Jesse J. Liu, and Jeffrey S. Raskin declare that they have no conflict of interest.

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Authors and Affiliations

  1. Portland VA Medical Center, Oregon Health & Science University, Portland, OR, 97239, USA

    Justin S. Cetas

  2. Department of Neurological Surgery, Oregon Health & Science University, Portland, OR, 97239, USA

    Justin S. Cetas, Robin McFarlane, Kassi Kronfeld, Phoebe Smitasin, Jesse J. Liu & Jeffrey S. Raskin

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  1. Justin S. Cetas
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Correspondence to Justin S. Cetas.

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Cetas, J.S., McFarlane, R., Kronfeld, K. et al. Brainstem Opioidergic System Is Involved in Early Response to Experimental SAH. Transl. Stroke Res. 6, 140–147 (2015). https://doi.org/10.1007/s12975-014-0378-2

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