Implications of the Mu-opioid receptor single nucleotide polymorphism on the regulation of the HPA axis
Open Access
- Author:
- Marsan, Lynnsay A
- Graduate Program:
- Neuroscience
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- September 09, 2014
- Committee Members:
- Robert Harold Bonneau, Dissertation Advisor/Co-Advisor
Robert Harold Bonneau, Committee Chair/Co-Chair
Patricia Sue Grigson Kennedy, Committee Member
Andras Hajnal, Committee Member
Jianxun Song, Committee Member
Sarah Rebstock, Special Member - Keywords:
- neuroendocrinology
HPA axis
mu-opioid receptor
stress - Abstract:
- The activation of the hypothalamic-pituitary-adrenal (HPA) axis is modulated, in part, by the μ-opioid receptor. A relatively common single nucleotide polymorphism (SNP) (A118G) has been identified in the human μ-opioid receptor (OPRM1) gene and results in the replacement of the amino acid asparagine (N), with aspartic acid (D) at residue 40 (N40D). The objective of this study was to use a novel mouse line (A112G) that is representative of the human A118G SNP to evaluate the impact of the A112G SNP on HPA axis activation in adult male and female mice in response to acute and chronic restraint stress. Using radioimmunoassay (RIA), it was determined that this A112G SNP alters the HPA axis response, and thus corticosterone (CORT) production, to both acute and chronic psychological stress. These results indicate that although the A112G SNP contributes to stress reactivity by altering the functionality of the HPA axis, it does not disrupt the circadian rhythm as measured by serum-derived CORT. A112G heterozygous (AG) and homozygous (GG) mice exhibit higher CORT levels in response to stress than do wild-type (AA) mice. This SNP also has a dimorphic component, as CORT levels in response to chronic stress are significantly higher in females, especially in AG mice. It was also determined that stress-induced hypothalamic expression of the μ-opioid receptor protein (MOPR), as measured by immunohistochemistry and mRNA quantification, is higher in GG mice as compared to both AA and AG mice. Additionally, pathology analysis revealed that chronic stress-induced physiological damages are less severe in GG mice, indicating a protective effect of the A112G SNP in response to stress. Together these findings suggest that although the A112G SNP increases the CORT response to psychological stress, it also initiates a compensatory protective mechanism by increasing μ-opioid receptor expression in mice harboring the SNP.