Allopregnanolone levels are inversely associated with self-reported pain symptoms in U.S. Iraq and Afghanistan-Era veterans: Implications for biomarkers and therapeutics

MIRECC Workgroup, Jennifer C. Naylor, Jason D. Kilts, Steven T. Szabo, Charlotte E. Dunn, Francis J. Keefe, Larry A. Tupler, Lawrence J. Shampine, Rajendra A. Morey, Jennifer L. Strauss, Robert M. Hamer, H. Ryan Wagner, Jean C. Beckham, Mira Brancu, Patrick S. Calhoun, John A. Fairbank, Harold S. Kudler, Scott D. Moore, Kristy A. Straits-Troster, Richard D. Weiner & 1 others Christine E. Marx

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Abstract

Background and Objectives. Pain symptoms are common among Iraq/Afghanistan-era veterans, many of whom continue to experience persistent pain symptoms despite multiple pharmacological interventions. Preclinical data suggest that neurosteroids such as allopregnanolone demonstrate pronounced analgesic properties, and thus represent logical biomarker candidates and therapeutic targets for pain. Allopregnanolone is also a positive GABAA receptor modulator with anxiolytic, anticonvulsant, and neuroprotective actions in rodent models. We previously reported inverse associations between serum allopregnanolone levels and self-reported pain symptom severity in a pilot study of 82 male veterans. Methods. The current study investigates allopregnanolone levels in a larger cohort of 485 male Iraq/ Afghanistan-era veterans to attempt to replicate these initial findings. Pain symptoms were assessed by items from the Symptom Checklist-90-R (SCL-90-R) querying headache, chest pain, muscle soreness, and low back pain over the past 7 days. Allopregnanolone levels were quantified by gas chromatography/mass spectrometry. Results. Associations between pain ratings and allopregnanolone levels were examined with Poisson regression analyses, controlling for age and smoking. Bivariate nonparametric Mann- Whitney analyses examining allopregnanolone levels across high and low levels of pain were also conducted. Allopregnanolone levels were inversely associated with muscle soreness [P50.0028], chest pain [P50.032], and aggregate total pain (sum of all four pain items) [P50.0001]. In the bivariate analyses, allopregnanolone levels were lower in the group reporting high levels of muscle soreness [P50.001]. Conclusions. These findings are generally consistent with our prior pilot study and suggest that allopregnanolone may function as an endogenous analgesic. Thus, exogenous supplementation with allopregnanolone could have therapeutic potential. The characterization of neurosteroid profiles may also have biomarker utility.

LanguageEnglish (US)
Pages25-32
Number of pages8
JournalPain Medicine (United States)
Volume17
Issue number1
DOIs
StatePublished - Jan 1 2016

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Pregnanolone
Afghanistan
Iraq
Veterans
Biomarkers
Pain
Myalgia
Therapeutics
Chest Pain
Neurotransmitter Agents
Analgesics
Anti-Anxiety Agents
GABA-A Receptors
Low Back Pain
Checklist
Anticonvulsants
Gas Chromatography-Mass Spectrometry
Headache
Rodentia

Keywords

  • Allopregnanolone
  • GABA
  • Neurosteroid
  • Pain
  • Veteran

ASJC Scopus subject areas

  • Clinical Neurology
  • Anesthesiology and Pain Medicine

Cite this

@article{132f299b6fb84d1fbf57ccef47622476,
title = "Allopregnanolone levels are inversely associated with self-reported pain symptoms in U.S. Iraq and Afghanistan-Era veterans: Implications for biomarkers and therapeutics",
abstract = "Background and Objectives. Pain symptoms are common among Iraq/Afghanistan-era veterans, many of whom continue to experience persistent pain symptoms despite multiple pharmacological interventions. Preclinical data suggest that neurosteroids such as allopregnanolone demonstrate pronounced analgesic properties, and thus represent logical biomarker candidates and therapeutic targets for pain. Allopregnanolone is also a positive GABAA receptor modulator with anxiolytic, anticonvulsant, and neuroprotective actions in rodent models. We previously reported inverse associations between serum allopregnanolone levels and self-reported pain symptom severity in a pilot study of 82 male veterans. Methods. The current study investigates allopregnanolone levels in a larger cohort of 485 male Iraq/ Afghanistan-era veterans to attempt to replicate these initial findings. Pain symptoms were assessed by items from the Symptom Checklist-90-R (SCL-90-R) querying headache, chest pain, muscle soreness, and low back pain over the past 7 days. Allopregnanolone levels were quantified by gas chromatography/mass spectrometry. Results. Associations between pain ratings and allopregnanolone levels were examined with Poisson regression analyses, controlling for age and smoking. Bivariate nonparametric Mann- Whitney analyses examining allopregnanolone levels across high and low levels of pain were also conducted. Allopregnanolone levels were inversely associated with muscle soreness [P50.0028], chest pain [P50.032], and aggregate total pain (sum of all four pain items) [P50.0001]. In the bivariate analyses, allopregnanolone levels were lower in the group reporting high levels of muscle soreness [P50.001]. Conclusions. These findings are generally consistent with our prior pilot study and suggest that allopregnanolone may function as an endogenous analgesic. Thus, exogenous supplementation with allopregnanolone could have therapeutic potential. The characterization of neurosteroid profiles may also have biomarker utility.",
keywords = "Allopregnanolone, GABA, Neurosteroid, Pain, Veteran",
author = "{MIRECC Workgroup} and Naylor, {Jennifer C.} and Kilts, {Jason D.} and Szabo, {Steven T.} and Dunn, {Charlotte E.} and Keefe, {Francis J.} and Tupler, {Larry A.} and Shampine, {Lawrence J.} and Morey, {Rajendra A.} and Strauss, {Jennifer L.} and Hamer, {Robert M.} and Wagner, {H. Ryan} and Beckham, {Jean C.} and Mira Brancu and Calhoun, {Patrick S.} and Fairbank, {John A.} and Kudler, {Harold S.} and Moore, {Scott D.} and Straits-Troster, {Kristy A.} and Weiner, {Richard D.} and Marx, {Christine E.}",
year = "2016",
month = "1",
day = "1",
doi = "10.1111/pme.12860",
language = "English (US)",
volume = "17",
pages = "25--32",
journal = "Pain Medicine (United States)",
issn = "1526-2375",
publisher = "Wiley-Blackwell",
number = "1",

}

TY - JOUR

T1 - Allopregnanolone levels are inversely associated with self-reported pain symptoms in U.S. Iraq and Afghanistan-Era veterans

T2 - Pain Medicine (United States)

AU - MIRECC Workgroup

AU - Naylor,Jennifer C.

AU - Kilts,Jason D.

AU - Szabo,Steven T.

AU - Dunn,Charlotte E.

AU - Keefe,Francis J.

AU - Tupler,Larry A.

AU - Shampine,Lawrence J.

AU - Morey,Rajendra A.

AU - Strauss,Jennifer L.

AU - Hamer,Robert M.

AU - Wagner,H. Ryan

AU - Beckham,Jean C.

AU - Brancu,Mira

AU - Calhoun,Patrick S.

AU - Fairbank,John A.

AU - Kudler,Harold S.

AU - Moore,Scott D.

AU - Straits-Troster,Kristy A.

AU - Weiner,Richard D.

AU - Marx,Christine E.

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Background and Objectives. Pain symptoms are common among Iraq/Afghanistan-era veterans, many of whom continue to experience persistent pain symptoms despite multiple pharmacological interventions. Preclinical data suggest that neurosteroids such as allopregnanolone demonstrate pronounced analgesic properties, and thus represent logical biomarker candidates and therapeutic targets for pain. Allopregnanolone is also a positive GABAA receptor modulator with anxiolytic, anticonvulsant, and neuroprotective actions in rodent models. We previously reported inverse associations between serum allopregnanolone levels and self-reported pain symptom severity in a pilot study of 82 male veterans. Methods. The current study investigates allopregnanolone levels in a larger cohort of 485 male Iraq/ Afghanistan-era veterans to attempt to replicate these initial findings. Pain symptoms were assessed by items from the Symptom Checklist-90-R (SCL-90-R) querying headache, chest pain, muscle soreness, and low back pain over the past 7 days. Allopregnanolone levels were quantified by gas chromatography/mass spectrometry. Results. Associations between pain ratings and allopregnanolone levels were examined with Poisson regression analyses, controlling for age and smoking. Bivariate nonparametric Mann- Whitney analyses examining allopregnanolone levels across high and low levels of pain were also conducted. Allopregnanolone levels were inversely associated with muscle soreness [P50.0028], chest pain [P50.032], and aggregate total pain (sum of all four pain items) [P50.0001]. In the bivariate analyses, allopregnanolone levels were lower in the group reporting high levels of muscle soreness [P50.001]. Conclusions. These findings are generally consistent with our prior pilot study and suggest that allopregnanolone may function as an endogenous analgesic. Thus, exogenous supplementation with allopregnanolone could have therapeutic potential. The characterization of neurosteroid profiles may also have biomarker utility.

AB - Background and Objectives. Pain symptoms are common among Iraq/Afghanistan-era veterans, many of whom continue to experience persistent pain symptoms despite multiple pharmacological interventions. Preclinical data suggest that neurosteroids such as allopregnanolone demonstrate pronounced analgesic properties, and thus represent logical biomarker candidates and therapeutic targets for pain. Allopregnanolone is also a positive GABAA receptor modulator with anxiolytic, anticonvulsant, and neuroprotective actions in rodent models. We previously reported inverse associations between serum allopregnanolone levels and self-reported pain symptom severity in a pilot study of 82 male veterans. Methods. The current study investigates allopregnanolone levels in a larger cohort of 485 male Iraq/ Afghanistan-era veterans to attempt to replicate these initial findings. Pain symptoms were assessed by items from the Symptom Checklist-90-R (SCL-90-R) querying headache, chest pain, muscle soreness, and low back pain over the past 7 days. Allopregnanolone levels were quantified by gas chromatography/mass spectrometry. Results. Associations between pain ratings and allopregnanolone levels were examined with Poisson regression analyses, controlling for age and smoking. Bivariate nonparametric Mann- Whitney analyses examining allopregnanolone levels across high and low levels of pain were also conducted. Allopregnanolone levels were inversely associated with muscle soreness [P50.0028], chest pain [P50.032], and aggregate total pain (sum of all four pain items) [P50.0001]. In the bivariate analyses, allopregnanolone levels were lower in the group reporting high levels of muscle soreness [P50.001]. Conclusions. These findings are generally consistent with our prior pilot study and suggest that allopregnanolone may function as an endogenous analgesic. Thus, exogenous supplementation with allopregnanolone could have therapeutic potential. The characterization of neurosteroid profiles may also have biomarker utility.

KW - Allopregnanolone

KW - GABA

KW - Neurosteroid

KW - Pain

KW - Veteran

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U2 - 10.1111/pme.12860

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