Activation of Membrane Estrogen Receptors Attenuates NOP-Mediated Tactile Antihypersensitivity in a Rodent Model of Neuropathic Pain
Identifieur interne : 000B45 ( Pmc/Curation ); précédent : 000B44; suivant : 000B46Activation of Membrane Estrogen Receptors Attenuates NOP-Mediated Tactile Antihypersensitivity in a Rodent Model of Neuropathic Pain
Auteurs : Danyeal M. Wright ; Keri M. Small ; Subodh Nag ; Sukhbir S. MokhaSource :
- Brain Sciences [ 2076-3425 ] ; 2019.
Abstract
Women manifest a higher prevalence of several chronic pain disorders compared to men. We demonstrated earlier that estrogen rapidly attenuates nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP)-mediated thermal antinociception through the activation of membrane estrogen receptors (mERs). However, the effect of mER activation on NOP-mediated attenuation of tactile hypersensitivity in a neuropathic model of pain and the underlying mechanisms remain unknown. Following spared nerve injury (SNI), male and ovariectomized (OVX) female rats were intrathecally (i.t.) injected with a selective mER agonist and nociceptin/orphanin FQ (N/OFQ), the endogenous ligand for NOP, and their effects on paw withdrawal thresholds (PWTs) were tested. In addition, spinal cord tissue was used to measure changes in phosphorylated extracellular signal regulated kinase (ERK), protein kinase A (PKA), protein kinase C (PKC), and protein kinase B (Akt) levels. SNI significantly reduced PWTs in males and OVX females, indicating tactile hypersensitivity. N/OFQ restored PWTs, indicating an antihypersensitive effect. Selective mER activation attenuated the effect of N/OFQ in an antagonist-reversible manner. SNI led to a robust increase in the phosphorylation of ERK, PKA, PKC, and Akt. However, mER activation did not further affect it. Thus, we conclude that activation of mERs rapidly abolishes NOP-mediated tactile antihypersensitivity following SNI via an ERK-, PKA-, PKC-, and Akt-independent mechanism.
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DOI: 10.3390/brainsci9060147
PubMed: 31234278
PubMed Central: 6628583
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Activation of Membrane Estrogen Receptors Attenuates NOP-Mediated Tactile Antihypersensitivity in a Rodent Model of Neuropathic Pain</title><author><name sortKey="Wright, Danyeal M" sort="Wright, Danyeal M" uniqKey="Wright D" first="Danyeal M." last="Wright">Danyeal M. Wright</name></author><author><name sortKey="Small, Keri M" sort="Small, Keri M" uniqKey="Small K" first="Keri M." last="Small">Keri M. Small</name></author><author><name sortKey="Nag, Subodh" sort="Nag, Subodh" uniqKey="Nag S" first="Subodh" last="Nag">Subodh Nag</name></author><author><name sortKey="Mokha, Sukhbir S" sort="Mokha, Sukhbir S" uniqKey="Mokha S" first="Sukhbir S." last="Mokha">Sukhbir S. Mokha</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31234278</idno><idno type="pmc">6628583</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628583</idno><idno type="RBID">PMC:6628583</idno><idno type="doi">10.3390/brainsci9060147</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000B45</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000B45</idno><idno type="wicri:Area/Pmc/Curation">000B45</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000B45</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Activation of Membrane Estrogen Receptors Attenuates NOP-Mediated Tactile Antihypersensitivity in a Rodent Model of Neuropathic Pain</title><author><name sortKey="Wright, Danyeal M" sort="Wright, Danyeal M" uniqKey="Wright D" first="Danyeal M." last="Wright">Danyeal M. Wright</name></author><author><name sortKey="Small, Keri M" sort="Small, Keri M" uniqKey="Small K" first="Keri M." last="Small">Keri M. Small</name></author><author><name sortKey="Nag, Subodh" sort="Nag, Subodh" uniqKey="Nag S" first="Subodh" last="Nag">Subodh Nag</name></author><author><name sortKey="Mokha, Sukhbir S" sort="Mokha, Sukhbir S" uniqKey="Mokha S" first="Sukhbir S." last="Mokha">Sukhbir S. Mokha</name></author></analytic><series><title level="j">Brain Sciences</title><idno type="eISSN">2076-3425</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Women manifest a higher prevalence of several chronic pain disorders compared to men. We demonstrated earlier that estrogen rapidly attenuates nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP)-mediated thermal antinociception through the activation of membrane estrogen receptors (mERs). However, the effect of mER activation on NOP-mediated attenuation of tactile hypersensitivity in a neuropathic model of pain and the underlying mechanisms remain unknown. Following spared nerve injury (SNI), male and ovariectomized (OVX) female rats were intrathecally (i.t.) injected with a selective mER agonist and nociceptin/orphanin FQ (N/OFQ), the endogenous ligand for NOP, and their effects on paw withdrawal thresholds (PWTs) were tested. In addition, spinal cord tissue was used to measure changes in phosphorylated extracellular signal regulated kinase (ERK), protein kinase A (PKA), protein kinase C (PKC), and protein kinase B (Akt) levels. SNI significantly reduced PWTs in males and OVX females, indicating tactile hypersensitivity. N/OFQ restored PWTs, indicating an antihypersensitive effect. Selective mER activation attenuated the effect of N/OFQ in an antagonist-reversible manner. SNI led to a robust increase in the phosphorylation of ERK, PKA, PKC, and Akt. However, mER activation did not further affect it. Thus, we conclude that activation of mERs rapidly abolishes NOP-mediated tactile antihypersensitivity following SNI via an ERK-, PKA-, PKC-, and Akt-independent mechanism.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Edlund, M J" uniqKey="Edlund M">M.J. Edlund</name></author><author><name sortKey="Martin, B C" uniqKey="Martin B">B.C. Martin</name></author><author><name sortKey="Fan, M Y" uniqKey="Fan M">M.-Y. Fan</name></author><author><name sortKey="Devries, A" uniqKey="Devries A">A. Devries</name></author><author><name sortKey="Braden, J B" uniqKey="Braden J">J.B. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Brain Sci</journal-id><journal-id journal-id-type="iso-abbrev">Brain Sci</journal-id><journal-id journal-id-type="publisher-id">brainsci</journal-id><journal-title-group><journal-title>Brain Sciences</journal-title></journal-title-group><issn pub-type="epub">2076-3425</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31234278</article-id><article-id pub-id-type="pmc">6628583</article-id><article-id pub-id-type="doi">10.3390/brainsci9060147</article-id><article-id pub-id-type="publisher-id">brainsci-09-00147</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Activation of Membrane Estrogen Receptors Attenuates NOP-Mediated Tactile Antihypersensitivity in a Rodent Model of Neuropathic Pain</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-7632-0161</contrib-id><name><surname>Wright</surname><given-names>Danyeal M.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Small</surname><given-names>Keri M.</given-names></name></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-8834-4278</contrib-id><name><surname>Nag</surname><given-names>Subodh</given-names></name><xref rid="c1-brainsci-09-00147" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><name><surname>Mokha</surname><given-names>Sukhbir S.</given-names></name></contrib></contrib-group><aff id="af1-brainsci-09-00147">Department of Biochemistry, Cancel Biology, Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA;<email>dheckard@mmc.edu</email> (D.M.W.);<email>kerimcleansmall@gmail.com</email> (K.M.S.);<email>smokha@mmc.edu</email> (S.S.M.)</aff><author-notes><corresp id="c1-brainsci-09-00147"><label>*</label>Correspondence: <email>snag@mmc.edu</email>; Tel.: +1-615-327-6926</corresp></author-notes><pub-date pub-type="epub"><day>21</day><month>6</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>6</month><year>2019</year></pub-date><volume>9</volume><issue>6</issue><elocation-id>147</elocation-id><history><date date-type="received"><day>31</day><month>5</month><year>2019</year></date><date date-type="accepted"><day>19</day><month>6</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 by the authors.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>Women manifest a higher prevalence of several chronic pain disorders compared to men. We demonstrated earlier that estrogen rapidly attenuates nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP)-mediated thermal antinociception through the activation of membrane estrogen receptors (mERs). However, the effect of mER activation on NOP-mediated attenuation of tactile hypersensitivity in a neuropathic model of pain and the underlying mechanisms remain unknown. Following spared nerve injury (SNI), male and ovariectomized (OVX) female rats were intrathecally (i.t.) injected with a selective mER agonist and nociceptin/orphanin FQ (N/OFQ), the endogenous ligand for NOP, and their effects on paw withdrawal thresholds (PWTs) were tested. In addition, spinal cord tissue was used to measure changes in phosphorylated extracellular signal regulated kinase (ERK), protein kinase A (PKA), protein kinase C (PKC), and protein kinase B (Akt) levels. SNI significantly reduced PWTs in males and OVX females, indicating tactile hypersensitivity. N/OFQ restored PWTs, indicating an antihypersensitive effect. Selective mER activation attenuated the effect of N/OFQ in an antagonist-reversible manner. SNI led to a robust increase in the phosphorylation of ERK, PKA, PKC, and Akt. However, mER activation did not further affect it. Thus, we conclude that activation of mERs rapidly abolishes NOP-mediated tactile antihypersensitivity following SNI via an ERK-, PKA-, PKC-, and Akt-independent mechanism.</p></abstract><kwd-group><kwd>nociceptin/orphanin FQ receptor</kwd><kwd>neuropathic pain</kwd><kwd>spinal cord</kwd><kwd>spared nerve injury</kwd><kwd>analgesia</kwd></kwd-group></article-meta></front><floats-group><fig id="brainsci-09-00147-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Intrathecally administered (β-estradiol 6-(<italic>O</italic>-carboxymethyl) oxime/bovine serum albumin (BSA)) (E<sub>2</sub>BSA) rapidly attenuated nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP)-mediated antihypersensitivity in ovariectomized (OVX) rats: (<bold>a</bold>) Spared nerve injury (SNI) significantly reduced paw withdrawal thresholds (PWTs) compared to the sham group. N/OFQ (10 nM) increased PWTs in both the sham and SNI groups. Co-administration with E<sub>2</sub>BSA (0.5 mM) abolished the N/OFQ-induced increase in PWTs. Pretreatment with membrane estrogen receptor (mER) antagonist (ICI 182,780 and G-15 cocktail) restored an N/OFQ-induced increase in PWTs. (<bold>b</bold>) the area under the curve (AUC) analysis confirmed these effects, with a significantly reduced AUC in the SNI group, N/OFQ significantly increasing it, and E<sub>2</sub>BSA attenuating the effect of N/OFQ in an antagonist-reversible manner. Here, * <italic>p</italic> < 0.05 compared to veh + veh; # <italic>p</italic> < 0.05 compared to veh + N/OFQ; $ <italic>p</italic> < 0.05 compared to E<sub>2</sub>BSA + N/OFQ.</p></caption><graphic xlink:href="brainsci-09-00147-g001"></graphic></fig><fig id="brainsci-09-00147-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Intrathecally administered E<sub>2</sub>BSA rapidly attenuated NOP-mediated antihypersensitivity in male rats. (<bold>a</bold>) SNI significantly reduced PWTs compared to the sham group. N/OFQ (10 nM) increased PWTs in both the sham and SNI groups. Co-administration of E<sub>2</sub>BSA (0.5 mM) abolished the N/OFQ-induced increase in PWTs. Pretreatment with mER antagonist (ICI 182,780 and G-15 cocktail) restored an N/OFQ-induced increase in PWTs. (<bold>b</bold>) AUC analysis confirmed these effects, with a significantly reduced AUC in the SNI groups, N/OFQ significantly increasing it, and E<sub>2</sub>BSA attenuating the effect of N/OFQ in an antagonist-reversible manner. Here, * <italic>p</italic> < 0.05 compared to veh + veh; # <italic>p</italic> < 0.05 compared to veh + N/OFQ; $ <italic>p</italic> < 0.05 compared to E<sub>2</sub>BSA + N/OFQ.</p></caption><graphic xlink:href="brainsci-09-00147-g002"></graphic></fig><fig id="brainsci-09-00147-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Selective activation of ERα attenuated NOP-mediated antihypersensitivity in OVX rats: (<bold>a</bold>) SNI significantly reduced PWTs compared to the sham group. Intrathecal administration of N/OFQ (10 nM) significantly increased paw withdrawal thresholds, whereas propylpyrazoletriol (PPT) (100 nM), the selective ERα agonist, attenuated the N/OFQ-induced increase in PWTs. Pretreatment with mER antagonist (ICI 182,780) restored an N/OFQ-induced increase in PWTs. (<bold>b</bold>) AUC analysis confirmed these effects, with a significantly reduced AUC in SNI groups, N/OFQ significantly increasing it, and PPT attenuating the effect of N/OFQ in an antagonist-reversible manner. Here, * <italic>p</italic> < 0.05 compared to veh + veh; # <italic>p</italic> < 0.05 compared to veh + N/OFQ; $ <italic>p</italic> < 0.05 compared to PPT + N/OFQ.</p></caption><graphic xlink:href="brainsci-09-00147-g003"></graphic></fig><fig id="brainsci-09-00147-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Selective activation of ERα in male rats rapidly attenuated NOP-mediated antihypersensitivity: (<bold>a</bold>) SNI significantly reduced PWTs compared to the sham group. N/OFQ (10 nM) increased PWTs in both the sham and SNI groups. PPT (100 nM) abolished the N/OFQ-induced increase in PWTs. Pretreatment with mER antagonist (ICI 182,780) restored an N/OFQ-induced increase in PWTs. (<bold>b</bold>) AUC analysis confirmed these effects, with a significantly reduced AUC in the SNI groups, N/OFQ significantly increasing it, and PPT attenuating the effect of N/OFQ in an antagonist-reversible manner. Here, * <italic>p</italic> < 0.05 compared to veh + veh; # <italic>p</italic> < 0.05 compared to veh + N/OFQ; $ <italic>p</italic> < 0.05 compared to PPT + N/OFQ.</p></caption><graphic xlink:href="brainsci-09-00147-g004"></graphic></fig><fig id="brainsci-09-00147-f005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>Selective activation of ERβ attenuated NOP-mediated antihypersensitivity in OVX female rats: (<bold>a</bold>) SNI of the sciatic nerve significantly reduced PWTs compared to the sham group. Intrathecal administration of N/OFQ (10 nM) significantly increased paw withdrawal thresholds, and diarylpropionitrile (DPN) (100 nM), the selective ERβ agonist, attenuated the N/OFQ-induced increase in PWTs. Pretreatment with mER antagonist (ICI 182,780) restored the N/OFQ-induced increase in PWTs. (<bold>b</bold>) AUC analysis confirmed these effects, with a significantly reduced AUC in SNI groups, N/OFQ significantly increasing it, and DPN attenuating the effect of N/OFQ in an antagonist-reversible manner. Here, * <italic>p</italic> < 0.05 compared to veh + veh; # <italic>p</italic> < 0.05 compared to veh + N/OFQ; $, <italic>p</italic> < 0.05 compared to DPN + N/OFQ.</p></caption><graphic xlink:href="brainsci-09-00147-g005"></graphic></fig><fig id="brainsci-09-00147-f006" orientation="portrait" position="float"><label>Figure 6</label><caption><p>Selective activation of ERβ in male rats rapidly attenuated NOP-mediated antihypersensitivity: (<bold>a</bold>) SNI significantly reduced PWTs compared to the sham group. N/OFQ (10 nM) increased PWTs in both the sham and SNI groups. DPN (100 nM) abolished the N/OFQ-induced increase in PWTs. Pretreatment with mER antagonist (ICI 182,780) restored an N/OFQ-induced increase in PWTs. (<bold>b</bold>) AUC analysis confirmed these effects, with a significantly reduced AUC in SNI groups, N/OFQ significantly increasing it, and DPN attenuating the effect of N/OFQ in an antagonist-reversible manner. Here, * <italic>p</italic> < 0.05 compared to veh + veh; #, <italic>p</italic> < 0.05 compared to veh + N/OFQ; $, <italic>p</italic> < 0.05 compared to DPN + N/OFQ.</p></caption><graphic xlink:href="brainsci-09-00147-g006"></graphic></fig><fig id="brainsci-09-00147-f007" orientation="portrait" position="float"><label>Figure 7</label><caption><p>Selective activation of GPR30 attenuated NOP-mediated antihypersensitivity in OVX female rats: (<bold>a</bold>) SNI significantly reduced PWTs compared to the sham group. N/OFQ (10 nM) increased PWTs in both the sham and SNI groups. Co-administration of N/OFQ with G-1 (0.25 nM), the selective agonist for GPR30, abolished the N/OFQ-induced increase in PWTs. Pretreatment with GPR30 antagonist (G-15) restored an N/OFQ-induced increase in PWTs. (<bold>b</bold>) AUC analysis confirmed these effects, with a significantly reduced AUC in the SNI groups, N/OFQ significantly increasing it, and G-1 attenuating the effect of N/OFQ in an antagonist-reversible manner. Here, * <italic>p</italic> < 0.05 compared to veh + veh; #, <italic>p</italic> < 0.05 compared to veh + N/OFQ; $, <italic>p</italic> < 0.05 compared to G-1 + N/OFQ.</p></caption><graphic xlink:href="brainsci-09-00147-g007"></graphic></fig><fig id="brainsci-09-00147-f008" orientation="portrait" position="float"><label>Figure 8</label><caption><p>Selective activation of GPR30 attenuated NOP-mediated antihypersensitivity in male animals: (<bold>a</bold>) SNI significantly reduced PWTs compared to the sham group. N/OFQ (10 nM) increased PWTs in both the sham and SNI groups. G-1 (0.25 nM) abolished the N/OFQ-induced increase in PWTs. Pretreatment with GPR30 antagonist (G-15) restored an N/OFQ-induced increase in PWTs. (<bold>b</bold>) AUC analysis confirmed these effects, with a significantly reduced AUC in the SNI groups, N/OFQ significantly increasing it, and G-1 attenuating the effect of N/OFQ in an antagonist-reversible manner. Here, * <italic>p</italic> < 0.05 compared to veh + veh; #, <italic>p</italic> < 0.05 compared to veh + N/OFQ; $, <italic>p</italic> < 0.05 compared to G-1 + N/OFQ.</p></caption><graphic xlink:href="brainsci-09-00147-g008"></graphic></fig><fig id="brainsci-09-00147-f009" orientation="portrait" position="float"><label>Figure 9</label><caption><p>Selective activation of Gq-mER attenuated NOP-mediated antihypersensitivity in OVX rats: (<bold>a</bold>) SNI of the sciatic nerve significantly reduced PWTs compared to the sham group. Intrathecal administration of N/OFQ (10 nM) significantly increased PWTs, whereas STX (10 nM), the selective agonist for Gq-mER, attenuated the N/OFQ-induced increase in PWTs. Pretreatment with mER antagonist (ICI 182,780) restored an N/OFQ-induced increase in PWTs. (<bold>b</bold>) AUC analysis confirmed these effects, with a significantly reduced AUC in the SNI groups, N/OFQ significantly increasing it, and STX attenuating the effect of N/OFQ in an antagonist-reversible manner. Here, * <italic>p</italic> < 0.05 compared to veh + veh; #, <italic>p</italic> < 0.05 compared to veh + N/OFQ; $, <italic>p</italic> < 0.05 compared to STX + N/OFQ.</p></caption><graphic xlink:href="brainsci-09-00147-g009"></graphic></fig><fig id="brainsci-09-00147-f010" orientation="portrait" position="float"><label>Figure 10</label><caption><p><bold>Figure 10</bold>. NOP-mediated antihypersensitivity was rapidly attenuated by Gq-mER activation in male rats: (<bold>a</bold>) SNI significantly reduced PWTs compared to the sham group. N/OFQ (10 nM) increased PWTs in both the sham and SNI groups. STX (10 nM) abolished the N/OFQ-induced increase in PWTs. Pretreatment with mER antagonist (ICI 182,780) restored an N/OFQ-induced increase in PWTs. (<bold>b</bold>) AUC analysis confirmed these effects, with a significantly reduced AUC in the SNI groups, N/OFQ significantly increasing it, and STX attenuating the effect of N/OFQ in an antagonist-reversible manner. Here, * <italic>p</italic> < 0.05 compared to veh + veh; # <italic>p</italic> < 0.05 compared to veh + N/OFQ; $, <italic>p</italic> < 0.05 compared to STX + N/OFQ. Taken together, these behavioral data suggest that simultaneous or selective activation of any spinal mER rapidly attenuated spinal NOP-mediated antinociception in the sham groups and tactile antihypersensitivity in the nerve-injured OVX female and male rats.</p></caption><graphic xlink:href="brainsci-09-00147-g010"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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