Many pain syndromes/disorders observed below the head region, such as irritable bowel syndrome (IBS), fibromyalgia, vulvodynia, endometriosis and pelvic pain, have a greater prevalence in women or are female-specific. The long-term goal of our research is to understand biological mechanisms that make women more susceptible to the development of pain syndromes and to enhance our understanding of the sex-related differences in the regulation of pain throughout the life span. Our postulate that estrogen-induced negative regulation of the function of many G protein coupled receptors (GPCRs) such as the opioid receptor like1 (ORL1) and 12-adrenoceptors makes women more susceptible to the development of pain syndromes is both novel and provocative. We will test the hypothesis that estrogen differentially regulates the antinociceptive function of KOR and ORL1 receptors via both genomic mechanisms, involving transcription of receptors and signaling machinery, as well as non-genomic mechanisms, via membrane-associated estrogen receptors.
Aim 1 uses behavioral techniques to determine whether estrogen differentially regulates the antinociceptive function of KOR and ORL1 via genomic as well membrane estrogen receptor (GPR30, ER1, ER2)-mediated non-genomic mechanisms.
Aim 2 uses biochemical techniques to determine estrogen-induced changes in the temporal expression of the KOR and ORL1 genes, affinity of KOR and ORL1 receptors, and coupling to G proteins (Gi/Go).
Aim 3 uses neuroanatomical techniques to determine whether estrogen receptors co-localize with KOR and ORL1 receptors in projection neurons and/or in interneurons in the dorsal horn of the spinal cord. The proposed studies will provide fundamental new knowledge regarding the estrogen-induced differential regulation of the role of KOR and ORL1 in pain suppression in the spinal cord, and a new perspective in the treatment of pain, particularly in women at different phases of their life (pre-puberty, reproductive years, pregnancy, and menopause) and aging men. KOR agonists will be effective analgesics during the reproductive years in women whereas ORL1 agonists will be more effective in postmenopausal women. ORL1 agonists will be effective in adult men but their effectiveness may diminish in aging men as the levels of testosterone decline. Further, antinociception produced by activation of KOR and ORL1 is not linked to addictive side- effects characteristic of other opioid receptor subpopulations.
The goal of our research is to understand biological mechanisms that make women more vulnerable to the development of pain syndromes and enhance our understanding of the sex-related differences in the regulation of pain throughout the life span. This will lead to better pain treatment strategies.
|Robinson Jr, Douglas L; Nag, Subodh; Mokha, Sukhbir S (2016) Estrogen facilitates and the kappa and mu opioid receptors mediate antinociception produced by intrathecal (-)-pentazocine in female rats. Behav Brain Res 312:163-8|
|Nag, Subodh; Mokha, Sukhbir S (2016) Activation of the trigeminal ?2-adrenoceptor produces sex-specific, estrogen dependent thermal antinociception and antihyperalgesia using an operant pain assay in the rat. Behav Brain Res 314:152-8|
|Nag, S; Mokha, S S (2014) Activation of a Gq-coupled membrane estrogen receptor rapidly attenuates ?2-adrenoceptor-induced antinociception via an ERK I/II-dependent, non-genomic mechanism in the female rat. Neuroscience 267:122-34|
|Small, K M; Nag, S; Mokha, S S (2013) Activation of membrane estrogen receptors attenuates opioid receptor-like1 receptor-mediated antinociception via an ERK-dependent non-genomic mechanism. Neuroscience 255:177-90|