Date of Award

1-1-2009

Document Type

Campus Access Dissertation

Department

Pharmacology, Physiology and Neuroscience

Sub-Department

Biomedical Science

First Advisor

Sarah M. Sweitzer

Abstract

Painful vaso-occlusive episodes (VOEs) in children with sickle cell can begin as early as 2-6 months of age and is the most common reason for hospitalization in this patient population. Although the majority of the medical community acknowledges that infants experience pain, there is still concern regarding the safety of using analgesics and anesthetics in infants. This thesis has developed an animal model using Endothelin-1 (ET-1), a peptide that is involved in vaso-occlusive crisis, to investigate the cellular and molecule mechanisms by which painful VOEs in infancy results in a physiological "memory" of pain. Administration of ET-1 during infancy results in nociceptive sensitization in male rats and nociceptive de-sensitization in female rats via modulation of endothelin-B (ETB) receptor. This thesis focuses on the hypothesis that exposure to ET-1 early in development alters nociception later in development via sex-dependent regulation of the ETB receptor. Three specific aims were undertaken to test this hypothesis. In Specific Aim 1, a behavioral characterization of age- and sex-specific ET-1 induced nociception was completed. In Specific Aim 2, the molecular mechanism by which ET-1 alters acute nociception was identified. In Specific Aim 3, the role of gonadal hormones in ET-1 induced sensitization/de-sensitization was determined. For males, ET-1 exposure resulted in systemic alterations in sensitization, down-regulation in ETB receptor expression and changes in ETB:ETA receptor ratio. Pretreatment with morphine or the androgen receptor antagonist, flutamide, attenuated ET-1 induced sensitization in males. For females, ET-1 exposure resulted in local de-sensitization and dermatome specific sensitization, local up-regulation of ETB receptor expression and changes in ETB:ETA receptor ratio. Pretreatment with morphine or the estrogen receptor antagonist, fulvestrant, did not prevent local ET-1 induced de-sensitization in females. Understanding the role of endothelin receptors in pain sensitization and de-sensitization is a critical first step in determining whether the ET system is a viable therapeutic target to minimize pain and prevent pain-induced sensitization in infants.

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