Control of Nociception in the Spinal Cord

Summary

Principal Investigator: Sukhbir S Mokha
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2007-08-01 - 2015-08-31
more information: NIH RePORT

Top Publications

  1. pmc Activation of membrane estrogen receptors attenuates opioid receptor-like1 receptor-mediated antinociception via an ERK-dependent non-genomic mechanism
    K M Small
    Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA
    Neuroscience 255:177-90. 2013
  2. pmc Activation of a Gq-coupled membrane estrogen receptor rapidly attenuates α2-adrenoceptor-induced antinociception via an ERK I/II-dependent, non-genomic mechanism in the female rat
    S Nag
    Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, United States Electronic address
    Neuroscience 267:122-34. 2014

Research Grants

  1. Endogenous Cannabinoids and Brain Function
    Aron H Lichtman; Fiscal Year: 2013
  2. Prepubertal Stress, Windows of Risk &Sex Bias for Affective Disturbance
    C NEILL NEILL EPPERSON; Fiscal Year: 2013
  3. Mechanisms of Opioid Receptor Interactions
    GEORGE LATIMER WILCOX; Fiscal Year: 2013
  4. OPIOID MECHANISMS OF ANALGESIA
    Donna L Hammond; Fiscal Year: 2013
  5. Economic Status, Health, &Well-Being Over the Life Course and Across Generations
    Vicki A Freedman; Fiscal Year: 2013
  6. Sex-dependent tolerance and withdrawal mechanisms
    Alan R Gintzler; Fiscal Year: 2013
  7. N-type Calcium Channels in Nociceptive Neurons
    Diane Lipscombe; Fiscal Year: 2013
  8. NEUROPEPTIDERGIC INHIBITION OF SPINAL PAIN TRANSMISSION
    Bradley K Taylor; Fiscal Year: 2013
  9. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
  10. Estrogen Modulation of Bursting Activity in GnRH Neurons
    Oline K Ronnekleiv; Fiscal Year: 2013

Detail Information

Publications2

  1. pmc Activation of membrane estrogen receptors attenuates opioid receptor-like1 receptor-mediated antinociception via an ERK-dependent non-genomic mechanism
    K M Small
    Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA
    Neuroscience 255:177-90. 2013
    ..Taken together, the data are consistent with the interpretations that mER activation attenuates ORL1-mediated antinociception through a non-genomic, ERK 2-dependent mechanism in females...
  2. pmc Activation of a Gq-coupled membrane estrogen receptor rapidly attenuates α2-adrenoceptor-induced antinociception via an ERK I/II-dependent, non-genomic mechanism in the female rat
    S Nag
    Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, United States Electronic address
    Neuroscience 267:122-34. 2014
    ....

Research Grants30

  1. Endogenous Cannabinoids and Brain Function
    Aron H Lichtman; Fiscal Year: 2013
    ..Ultimately, the knowledge gained from this basic research will yield novel therapeutic targets that can be exploited with the pharmacological agents developed here. PROGRAM CHARACTERISTICS ..
  2. Prepubertal Stress, Windows of Risk &Sex Bias for Affective Disturbance
    C NEILL NEILL EPPERSON; Fiscal Year: 2013
    ..The Center would provide an intellectual platform with important resources to encourage established investigators, and their mentees, to consider sex and gender as crucial factors in their research. ..
  3. Mechanisms of Opioid Receptor Interactions
    GEORGE LATIMER WILCOX; Fiscal Year: 2013
    ..The information gained from these studies may identify new therapeutic analgesic combinations and combination receptor targets leading toward reduction of dependence liabilities of analgesic treatments. ..
  4. OPIOID MECHANISMS OF ANALGESIA
    Donna L Hammond; Fiscal Year: 2013
    ..Insights gain from this work will guide the development of new, more effective pharmacotherapies or cognitive approaches for the relief of persistent pain. ..
  5. Economic Status, Health, &Well-Being Over the Life Course and Across Generations
    Vicki A Freedman; Fiscal Year: 2013
    ..abstract_text> ..
  6. Sex-dependent tolerance and withdrawal mechanisms
    Alan R Gintzler; Fiscal Year: 2013
    ..Eluci- dation of sex-dependent aspects of addictive states should profoundly influence their medical management and help to maximize the effectiveness of pain control strategies that are utilized in women as well as men. ..
  7. N-type Calcium Channels in Nociceptive Neurons
    Diane Lipscombe; Fiscal Year: 2013
    ..By studying a novel form of the N-type calcium channel in the pain pathway, our studies of novel knock-in mice should lead to new strategies for inhibiting the activity of this N-type calcium channel and alleviating pain sufferers. ) ..
  8. NEUROPEPTIDERGIC INHIBITION OF SPINAL PAIN TRANSMISSION
    Bradley K Taylor; Fiscal Year: 2013
    ..Such studies are critical not only to determine whether NPY is a natural long-lasting analgesic that reduces the duration of pain, but also to harness its therapeutic potential towards the development of new analgesic drugs. ..
  9. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  10. Estrogen Modulation of Bursting Activity in GnRH Neurons
    Oline K Ronnekleiv; Fiscal Year: 2013
    ..It is envisioned that the results from the proposed experiments will help mold a cellular model of burst firing of GnRH neurons, pulsatile neurosecretion, and ultimately ovulation in the female. ..
  11. Center for Reproductive Science and Medicine
    Pamela L Mellon; Fiscal Year: 2013
    ..The SCCPIR Human Ovary Tissue Bank provides tissue to NIH-funded investigators nation-wide. ..
  12. NEW MODALITIES FOR TREATMENT OF PAIN AND DRUG ABUSE
    Victor J Hruby; Fiscal Year: 2013
    ....
  13. Molecular and Cellular Therapies for Muscular Dystrophy
    Stanley C Froehner; Fiscal Year: 2013
    ..The mechanism of NPC1 phenotype amelioration and its applicability to LGMDs will be studied. Two core facilities will serve the participating laboratories. ..
  14. Development of a Novel Class for Opioid Drugs
    NIKOLAY DOKHOLYAN; Fiscal Year: 2013
    ..The long-term goal of this effort is to develop novel opioids that evoke high potency analgesia without deleterious short- or long-term consequences. ..
  15. Prolonged activation of endogenous opioid analgesia after inflammation
    Gregory Corder; Fiscal Year: 2013
    ..to successfully compete for strong post-doctoral positions and ultimately, a successful career in research science and teaching beginning with a tenure-track position in a strong medical research university environment: ..
  16. BETA ENDORPHIN NEURONS AND THE CONTROL OF HOMEOSTASIS
    MARTIN JEFFREY KELLY; Fiscal Year: 2013
    ....