Date of Award


Document Type

Open Access Dissertation


Biomedical Science

First Advisor

Sarah Sweitzer,


Sickle cell disease (SCD) is a common genetic blood disorders that is characterized by painful vaso-occlusive episodes (VOEs), which are the major cause of hospitalizations for these patients. One of the mechanisms that may contribute to the development of painful VOEs is the imbalance between vasoconstrictors and vasodilators. This thesis focuses on the vasoconstrictors endothelin-1 (ET-1), which is elevated during VOEs and is pro-nociceptive, and angiotensin II (Ang II) and the vasodilator apelin, which has anti-nociceptive properties. This thesis tested two hypotheses: 1) an imbalance between the vasoconstrictive and pro-nociceptive systems and vasodilatory and anti-nociceptive systems contributes to pain in children with SCD and 2) the pain associated with VOEs in SCD involves the contralateral sensitizing effects of ET-1 through central mechanisms. The first aim of this thesis explored the impact of an imbalance between apelin and either endothelin or Ang II on pain measures in children with SCD. The second aim determined the pain neuroaxis location of the sensitizing/desensitizing effect of ET-1 and the effect of endothelin system activation on the apelin system. The last aim explored associations between genetic variability in the apelin receptor gene and pain measures. An imbalance between apelin and endothelin was correlated with underlying baseline pain and the frequency of VOEs while Ang II was correlated with acute procedural pain. In our models of acute VOEs, the mechanism responsible for the contralateral sensitizing effect of ET-1 is, at least in part, mediated centrally in the spinal cord. In contrast, at the level of the primary afferent neuron, repeated exposure to ET-1 has a desensitizing effect. Furthermore in a sex-dependent manner, activation of the endothelin system decreased the peripheral apelin system with a concomitant increase in the central apelin system. Single nucleotide polymorphisms in the apelin receptor gene in children with SCD had strong trends for associations with indirect pain measures, namely increases in health care utilization. Overall, these results support the postulates that contralateral sensitizing effects of ET-1 occurs through central mechanisms in the spinal cord and that an imbalance between the vasoconstrictive and pronociceptive systems and vasodilatory and antinociceptive systems may contribute to pain associated with SCD.


© 2014, Terika Smith

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