Sex differences in GABAA signaling in the periaqueductal gray induced by persistent inflammation

Karen J. Tonsfeldt, Katherine L. Suchland, Kathleen A. Beeson, Janet D. Lowe, Minghua Li, Susan Ingram

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The ventrolateral periaqueductal gray (vlPAG) is a key structure in the descending pain modulatory circuit. Activation of the circuit occurs via disinhibition of GABAergic inputs onto vlPAG output neurons. In these studies, we tested the hypothesis that GABAergic inhibition is increased during persistent inflammation, dampening activation of the descending circuit from the vlPAG. Our results indicate that persistent inflammation induced by Complete Freund’s adjuvant (CFA) modulates GABA signaling differently in male and female rats. CFA treatment results in increased presynaptic GABA release but decreased high-affinity tonic GABAA currents in female vlPAG neurons. These effects are not observed in males. The tonic currents in the vlPAG are dependent on GABA transporter activity and are modulated by agonists that activate GABAA receptors containing the δ subunit. The GABAA δ agonist THIP (gaboxadol) induced similar amplitude currents in naive and CFA-treated rats. In addition, a positive allosteric modulator of the GABAA δ subunit, DS2 (4-chloro-N-[2-(2-thienyl)imidazo[1,2-a]pyridin-3-yl]benzamide), increased tonic currents. These results indicate that GABAA δ receptors remain on the cell surface but are less active in CFA-treated female rats. In vivo behavior studies showed that morphine induced greater antinociception in CFA-treated females that was reversed with microinjections of DS2 directly into the vlPAG. DS2 did not affect morphine antinociception in naive or CFA-treated male rats. Together, these data indicate that sex-specific adaptations in GABAA receptor signaling modulate opioid analgesia in persistent inflammation. Antagonists of GABAA δ receptors may be a viable strategy for reducing pain associated with persistent inflammation, particularly in females.

Original languageEnglish (US)
Pages (from-to)1669-1681
Number of pages13
JournalJournal of Neuroscience
Volume36
Issue number5
DOIs
StatePublished - Feb 3 2016

Fingerprint

Periaqueductal Gray
Freund's Adjuvant
Sex Characteristics
GABA-A Receptors
Inflammation
gamma-Aminobutyric Acid
Morphine
GABA Plasma Membrane Transport Proteins
GABA-A Receptor Agonists
Neurons
Pain
Microinjections
Analgesia
Opioid Analgesics

Keywords

  • Chronic pain
  • Descending pain control
  • GABA
  • Opioid
  • Sex difference
  • Tonic current

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Sex differences in GABAA signaling in the periaqueductal gray induced by persistent inflammation. / Tonsfeldt, Karen J.; Suchland, Katherine L.; Beeson, Kathleen A.; Lowe, Janet D.; Li, Minghua; Ingram, Susan.

In: Journal of Neuroscience, Vol. 36, No. 5, 03.02.2016, p. 1669-1681.

Research output: Contribution to journalArticle

Tonsfeldt, Karen J. ; Suchland, Katherine L. ; Beeson, Kathleen A. ; Lowe, Janet D. ; Li, Minghua ; Ingram, Susan. / Sex differences in GABAA signaling in the periaqueductal gray induced by persistent inflammation. In: Journal of Neuroscience. 2016 ; Vol. 36, No. 5. pp. 1669-1681.
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