Newly Published
Pain Medicine  |   April 2020
Distinct Function of Estrogen Receptors in the Rodent Anterior Cingulate Cortex in Pain-related Aversion
Author Notes
  • From the State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, Department of Translational Neuroscience, Jing’an District Centre Hospital of Shanghai, Institutes of Brain Science, Institutes of Integrative Medicine, Fudan University, Shanghai 200032, China (K.-K.Z., L.-Q.C., Y.Y., Q.-L.C., Y.-L.T., S.-S.L., H.C., Y.-Q.Z.); the Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai 200433, China (X.X.); and the First Rehabilitation Hospital of Shanghai, Tongji University School of Medicine, Shanghai 200090, China (L.Z.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • K.-K.Z. and X.X. contributed equally to this article.
    K.-K.Z. and X.X. contributed equally to this article.×
  • Submitted for publication May 4, 2019. Accepted for publication March 16, 2020.
    Submitted for publication May 4, 2019. Accepted for publication March 16, 2020.×
  • Correspondence: Address correspondence to Dr. Zhang: Institutes of Brain Science, Fudan University, 1202 Mingdao Building, 131 Dong’an Road, Shanghai 200032, China. yuqiuzhang@fudan.edu.cn, Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Pain Medicine / Central and Peripheral Nervous Systems / Pain Medicine
Pain Medicine   |   April 2020
Distinct Function of Estrogen Receptors in the Rodent Anterior Cingulate Cortex in Pain-related Aversion
Anesthesiology Newly Published on April 22, 2020. doi:https://doi.org/10.1097/ALN.0000000000003324
Anesthesiology Newly Published on April 22, 2020. doi:https://doi.org/10.1097/ALN.0000000000003324
Abstract

Background: Brain-derived estrogen is implicated in pain-related aversion; however, which estrogen receptors mediate this effect remains unclear. This study hypothesized that the different estrogen receptors in the rostral anterior cingulate cortex play distinct roles in pain-related aversion.

Methods: Formalin-induced conditioned place avoidance and place escape/avoidance paradigms were used to evaluate pain-related aversion in rodents. Immunohistochemistry and Western blotting were used to detect estrogen receptor expression. Patch-clamp recordings were used to examine N-methyl-d-aspartate–mediated excitatory postsynaptic currents in rostral anterior cingulate cortex slices.

Results: The administration of the estrogen receptor-β antagonist 4-(2-phenyl-5,7-bis [trifluoromethyl] pyrazolo [1,5-a] pyrimidin-3-yl) phenol (PHTPP) or the G protein–coupled estrogen receptor-1 antagonist (3aS*,4R*,9bR*)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta [c] quinolone (G15) but not the estrogen receptor-α antagonist 1,3-bis (4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy) phenol]-1H-pyrazole dihydrochloride (MPP) into the rostral anterior cingulate cortex blocked pain-related aversion in rats (avoidance score, mean ± SD: 1,3-bis [4-hydroxyphenyl]-4-methyl-5-(4-[2-piperidinylethoxy] phenol)-1H-pyrazole dihydrochloride (MPP): 47.0 ± 18.9%, 4-(2-phenyl-5,7-bis [trifluoromethyl] pyrazolo [1,5-a] pyrimidin-3-yl) phenol (PHTPP): −7.4 ± 20.6%, and [3aS*,4R*,9bR*]-4-[6-bromo-1,3-benzodioxol-5-yl]-3a,4,5,9b-3H-cyclopenta [c] quinolone (G15): −4.6 ± 17.0% vs. vehicle: 46.5 ± 12.2%; n = 7 to 9; P < 0.0001). Consistently, estrogen receptor-β knockdown but not estrogen receptor-α knockdown by short-hairpin RNA also inhibited pain-related aversion in mice (avoidance score, mean ± SD: estrogen receptor-α–short-hairpin RNA: 26.0 ± 7.1% and estrogen receptor-β–short-hairpin RNA: 6.3 ± 13.4% vs. control short-hairpin RNA: 29.1 ± 9.1%; n = 7 to 10; P < 0.0001). Furthermore, the direct administration of the estrogen receptor-β agonist 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN) or the G protein–coupled estrogen receptor-1 agonist (±)-1-([3aR*,4S*,9bS*]-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta [c]quinolin-8-yl)-ethanone (G1) into the rostral anterior cingulate cortex resulted in conditioned place avoidance (avoidance score, mean ± SD: 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN): 35.3 ± 9.5% and (±)-1-([3aR*,4S*,9bS*]-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta [c]quinolin-8-yl)-ethanone (G1): 43.5 ± 22.8% vs. vehicle: 0.3 ± 14.9%; n = 8; P < 0.0001) but did not affect mechanical or thermal sensitivity. The activation of the estrogen receptor-β/protein kinase A or G protein–coupled estrogen receptor-1/protein kinase B pathway elicited the long-term potentiation of N-methyl-d-aspartate–mediated excitatory postsynaptic currents.

Conclusions: These findings indicate that estrogen receptor-β and G protein–coupled estrogen receptor-1 but not estrogen receptor-α in the rostral anterior cingulate cortex contribute to pain-related aversion by modulating N-methyl-d-aspartate receptor–mediated excitatory synaptic transmission.

Editor’s Perspective:

What We Already Know about This Topic:

  • Estrogen produced within the central nervous system may modulate pain in both males and females

  • Estrogen receptors within the rostral anterior cingulate cortex modulate pain-related behaviors in rodent pain models

What This Article Tells Us That Is New:

  • Blockade of the estrogen receptor-β but not the estrogen receptor-α reduced pain-related aversion in rats, a model of the affective components of pain

  • Administration of an estrogen receptor-β agonist to the rostral anterior cingulate cortex caused conditioned place aversion without altering mechanical or thermal sensitivity

  • Estrogen receptor-β may be a key receptor controlling the affective components of pain-related behaviors in laboratory models