Determining the biological basis for phenotypic sex differences in kappa opioid receptor function

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The kappa opioid receptor (KOR) is one of four related opioid receptor proteins in vertebrates. KOR agonists are both analgesic and dysphoric. I have shown previously that a portion of KOR analgesia is due to engagement of dysphoric pathways leading to stress-induced analgesia. Therefore, systemic KOR analgesia is mediated by a convergence of these analgesic and stress pathways. The KOR system is also notable for a prominent sex-difference, where females show significantly less analgesia than males. It is unknown if a similar sexual dichotomy exists in the stress effects of KOR agonists, and how this might impact KOR analgesia. Sexually dimorphic traits can be due to either the influence of gonadal hormones (testosterone or estrogen) or the complement of genes expressed on the X or Y chromosome. Historically, removal of the gonads (testes or ovaries) has been used to examine sex differences. However, the influence of genes expressed on the sex chromosomes cannot be revealed by this approach, because the sex chromosomes are only ever expressed with their appropriate gonad (X with ovaries, Y with testes). To overcome this limitation, I employ two innovative genetic approaches to manipulate the expression of sex chromosome with gonadal hormones. I test the hypothesis that females exhibit lower KOR-mediated analgesia due to differences in the stress response mediated by X chromosome genes. For the first aim, I test the hypothesis that differences in KOR analgesia are due to differences in stress response by using a variety of behavioral tests of pain and anxiety in combination with pharmacological manipulation of the stress response. In the second aim, I will use transgenic mouse models to isolate and assess the contribution of gonadal hormones and sex chromosomes in mediating these sex differences. These models manipulate the expression of X and Y chromosomes with the gonads (i.e: generate XX mice with testes and XY mice with ovaries). This powerful tool allows me to test, simultaneously, the impact of gonadal hormones and sex chromosomes on the observed sex difference. It is now widely accepted that normal and pathological brain function exhibits important yet poorly understood sex differences. This study directly addresses this issue by examining the neurobiological basis for the difference in KOR function between males and females. Insights gleaned from these experiments can be used to illuminate fundamental differences in stress and pain processing between males and females. Not only will this information improve our understanding of basic neurobiology in females, but will improve the development of future therapies for pain and analgesia in both sexes. Finally, this research program will allow me to establish breeding colonies for these genetic models, thus positioning my lab to be a an elite training environment examining the mechanistic basis for sex differences across many phenotypic modalities.