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Alleviation of Mechanical Allodynia by 14,15-Epoxyeicosatrienoic Acid in a Central Poststroke Pain Model: Possible Role of Allopregnanolone and δ-Subunit-Containing Gamma-Aminobutyric Acid A Receptors

  • Xuhui Chen
    Affiliations
    Department of Anaesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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  • Zuofan Li
    Affiliations
    Department of Anaesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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  • Bo Zhang
    Affiliations
    Department of Anaesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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  • Rong Hu
    Affiliations
    Department of Anaesthesiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
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  • Jiayan Li
    Affiliations
    Department of Anaesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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  • Miaomiao Feng
    Affiliations
    Department of Anaesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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  • Wenlong Yao
    Affiliations
    Department of Anaesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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  • Chuanhan Zhang
    Affiliations
    Department of Anaesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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  • Li Wan
    Affiliations
    Department of Anaesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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  • Yue Zhang
    Correspondence
    Address reprint requests to Yue Zhang, PhD, MD, Department of Anaesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, 430030, Wuhan, Hubei Province, China.
    Affiliations
    Department of Anaesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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Published:November 27, 2018DOI:https://doi.org/10.1016/j.jpain.2018.11.006

      Highlights

      • Experimental thalamic hemorrhage induced bilateral mechanical allodynia in rats.
      • Central poststroke pain (CPSP) rats exhibited reduced epoxyeicosatrienoic acid (EET), steroidogenic acute regulatory (StAR) protein, allopregnanolone (AP), and δ-subunit-containing gamma-aminobutyric acid A receptor (δGABAAR) levels along the lesion site.
      • 14,15-EET attenuated mechanical allodynia by enhancing StAR-AP-δGABAAR signaling.
      • 14,15-EET showed greater efficacy in the secondary prevention for CPSP than gabapentin.
      • Epoxyeicosatrienoic acids attenuated CPSP by reserving thalamic inhibition through AP-δGABAAR signaling.

      Abstract

      Central poststroke pain (CPSP) is a neuropathic pain syndrome arising after a lesion of the central nervous system owing to cerebrovascular insult. Impaired daily activities and reduced quality of life in people suffering from CPSP justify the need for improved treatment. The detailed mechanism of CPSP is not well understood, but central disinhibition has been suggested. Recent reports indicated that epoxyeicosatrienoic acids (EETs), the cytochrome P450 metabolites of arachidonic acid, promoted neuronal survival after stroke, displayed antinociception in peripheral inflammatory pain, and reduced neuronal excitability in seizure model. Here, we tested the hypothesis that 14,15-EET may attenuate CPSP by suppressing thalamic disinhibition through neurosteroids−δ-subunit-containing gamma-aminobutyric acid A receptors (δGABAAR) signaling. In this study, we used a rat model of thalamic hemorrhagic stroke to induce CPSP. Pain behavioral tests revealed that CPSP rats exhibited mechanical allodynia, starting at day 7 postlesion and lasting at least 4 weeks. Analysis of the perithalamic lesion tissue from the brain of CPSP rats demonstrated a decrease of 14,15-EET content, steroidogenic acute regulatory protein expression, and allopregnanolone (AP) production. This was accompanied by reduced δGABAAR expression in the medial thalamus at 4 weeks postlesion. Intrathalamic injection of exogenous 14,15-EET into the ventral posterior lateral nucleus attenuated mechanical allodynia, induced a marked increase in the abundance of the steroidogenic acute regulatory protein and AP along the lesion site and a concomitant increase in δGABAAR expression in the medial thalamus under CPSP condition. However, this antinociceptive effect could be eliminated by the 5α-reductase inhibitor finasteride or dutasteride or GABAAR antagonist bicuculline. Moreover, compared with the current first-line drug gabapentin for central neuropathic pain, an early treatment of EET showed greater efficacy in the secondary prevention of CPSP. Taken together, this study provided a proof of concept that EETs may have anti-CPSP effect by reserving normal thalamic inhibition through AP-δGABAAR signaling.

      Perspective

      Agents targeting EETs may serve as potential therapeutic options for stroke, the use of which at the initial period could not only block further nerve damage but also prevent the occurrence of CPSP.

      Key words

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      References

        • Abdu E
        • Bruun DA
        • Yang D
        • Yang J
        • Inceoglu B
        • Hammock BD
        • Alkayed NJ
        • Lein PJ
        Epoxyeicosatrienoic acids enhance axonal growth in primary sensory and cortical neuronal cell cultures.
        J Neurochem. 2011; 117: 632-642
        • Akyuz G
        • Kuru P
        Systematic review of central post stroke pain: What is happening in the central nervous system?.
        Am J Phys Med Rehabil. 2016; 95: 618-627
        • Bonin RP
        • Labrakakis C
        • Eng DG
        • Whissell PD
        • De Koninck Y
        • Orser BA
        Pharmacological enhancement of delta-subunit-containing GABA(A) receptors that generate a tonic inhibitory conductance in spinal neurons attenuates acute nociception in mice.
        Pain. 2011; 152: 1317-1326
        • Brenneis C
        • Sisignano M
        • Coste O
        • Altenrath K
        • Fischer MJ
        • Angioni C
        • Fleming I
        • Brandes RP
        • Reeh PW
        • Woolf CJ
        • Geisslinger G
        • Scholich K
        Soluble epoxide hydrolase limits mechanical hyperalgesia during inflammation.
        Mol Pain. 2011; 7: 78
        • Carver CM
        • Reddy DS
        Neurosteroid structure-activity relationships for functional activation of extrasynaptic deltaGABA(A) receptors.
        J Pharmacol Exp Ther. 2016; 357: 188-204
        • Casey KL
        • Geisser M
        • Lorenz J
        • Morrow TJ
        • Paulson P
        • Minoshima S
        Psychophysical and cerebral responses to heat stimulation in patients with central pain, painless central sensory loss, and in healthy persons.
        Pain. 2012; 153: 331-341
        • Castel A
        • Helie P
        • Beaudry F
        • Vachon P
        Bilateral central pain sensitization in rats following a unilateral thalamic lesion may be treated with high doses of ketamine.
        BMC Vet Res. 2013; 9: 59
        • Chandra D
        • Jia F
        • Liang J
        • Peng Z
        • Suryanarayanan A
        • Werner DF
        • Spigelman I
        • Houser CR
        • Olsen RW
        • Harrison NL
        • Homanics GE
        GABAA receptor alpha 4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol.
        Proc Natl Acad Sci U S A. 2006; 103: 15230-15235
        • Chen CC
        • Chuang YF
        • Huang AC
        • Chen CK
        • Chang YJ
        The antalgic effects of non-invasive physical modalities on central post-stroke pain: A systematic review.
        J Phys Ther Sci. 2016; 28: 1368-1373
        • Clark BJ
        • Soo SC
        • Caron KM
        • Ikeda Y
        • Parker KL
        • Stocco DM
        Hormonal and developmental regulation of the steroidogenic acute regulatory protein.
        Mol Endocrinol. 1995; 9: 1346-1355
        • Cohen SP
        • Mao J
        Neuropathic pain: Mechanisms and their clinical implications.
        BMJ. 2014; 348: f7656
        • De Vloo P
        • Morlion B
        • van Loon J
        • Nuttin B
        Animal models for central poststroke pain: A critical comprehensive review.
        Pain. 2017; 158: 17-29
        • Guedes AG
        • Morisseau C
        • Sole A
        • Soares JH
        • Ulu A
        • Dong H
        • Hammock BD
        Use of a soluble epoxide hydrolase inhibitor as an adjunctive analgesic in a horse with laminitis.
        Vet Anaesth Analg. 2013; 40: 440-448
        • Hanada T
        • Kurihara T
        • Tokudome M
        • Tokimura H
        • Arita K
        • Miyata A
        Development and pharmacological verification of a new mouse model of central post-stroke pain.
        Neurosci Res. 2014; 78: 72-80
        • Harizi H
        • Corcuff JB
        • Gualde N
        Arachidonic-acid-derived eicosanoids: Roles in biology and immunopathology.
        Trends Mol Med. 2008; 14: 461-469
        • Imig JD
        • Simpkins AN
        • Renic M
        • Harder DR
        Cytochrome P450 eicosanoids and cerebral vascular function.
        Expert Rev Mol Med. 2011; 13: e7
        • Inceoglu B
        • Jinks SL
        • Ulu A
        • Hegedus CM
        • Georgi K
        • Schmelzer KR
        • Wagner K
        • Jones PD
        • Morisseau C
        • Hammock BD
        Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct analgesic pathways.
        Proc Natl Acad Sci U S A. 2008; 105: 18901-18906
        • Inceoglu B
        • Zolkowska D
        • Yoo HJ
        • Wagner KM
        • Yang J
        • Hackett E
        • Hwang SH
        • Lee KS
        • Rogawski MA
        • Morisseau C
        • Hammock BD
        Epoxy fatty acids and inhibition of the soluble epoxide hydrolase selectively modulate GABA mediated neurotransmission to delay onset of seizures.
        Plos One. 2013; 8: e80922
        • Kim JH
        • Greenspan JD
        • Coghill RC
        • Ohara S
        • Lenz FA
        Lesions limited to the human thalamic principal somatosensory nucleus (ventral caudal) are associated with loss of cold sensations and central pain.
        J Neurosci. 2007; 27: 4995-5004
        • Kim JS
        Pharmacological management of central post-stroke pain: a practical guide.
        CNS Drugs. 2014; 28: 787-797
        • Klit H
        • Finnerup NB
        • Jensen TS
        Central post-stroke pain: Clinical characteristics, pathophysiology, and management.
        Lancet Neurol. 2009; 8: 857-868
        • Klit H
        • Finnerup NB
        • Overvad K
        • Andersen G
        • Jensen TS
        Pain following stroke: A population-based follow-up study.
        Plos One. 2011; 6: e27607
        • Kuan YH
        • Shih HC
        • Tang SC
        • Jeng JS
        • Shyu BC
        Targeting P(2)X(7) receptor for the treatment of central post-stroke pain in a rodent model.
        Neurobiol Dis. 2015; 78: 134-145
        • Kumar G
        • Soni CR
        Central post-stroke pain: Current evidence.
        J Neurol Sci. 2009; 284: 10-17
        • Liu JP
        • He YT
        • Duan XL
        • Suo ZW
        • Yang X
        • Hu XD
        Enhanced activities of delta subunit-containing gabaa receptors blocked spinal long-term potentiation and attenuated formalin-induced spontaneous pain.
        Neuroscience. 2018; 371: 155-165
        • Liu X
        • Davis CM
        • Alkayed NJ
        P450 eicosanoids and reactive oxygen species interplay in brain injury and neuroprotection.
        Antioxid Redox Signal. 2017; https://doi.org/10.1089/ars.2017.7056
        • Liu Y
        • Wan Y
        • Fang Y
        • Yao E
        • Xu S
        • Ning Q
        • Zhang G
        • Wang W
        • Huang X
        • Xie M
        Epoxyeicosanoid signaling provides multi-target protective effects on neurovascular unit in rats after focal ischemia.
        J Mol Neurosci. 2016; 58: 254-265
        • Maekawa M
        • Watanabe A
        • Iwayama Y
        • Kimura T
        • Hamazaki K
        • Balan S
        • Ohba H
        • Hisano Y
        • Nozaki Y
        • Ohnishi T
        • Toyoshima M
        • Shimamoto C
        • Iwamoto K
        • Bundo M
        • Osumi N
        • Takahashi E
        • Takashima A
        • Yoshikawa T
        Polyunsaturated fatty acid deficiency during neurodevelopment in mice models the prodromal state of schizophrenia through epigenetic changes in nuclear receptor genes.
        Transl Psychiatry. 2017; 7: e1229
        • Maguire J
        • Mody I
        Neurosteroid synthesis-mediated regulation of GABA(A) receptors: relevance to the ovarian cycle and stress.
        J Neurosci. 2007; 27: 2155-2162
        • Maguire JL
        • Stell BM
        • Rafizadeh M
        • Mody I
        Ovarian cycle-linked changes in GABA(A) receptors mediating tonic inhibition alter seizure susceptibility and anxiety.
        Nat Neurosci. 2005; 8: 797-804
        • Marowsky A
        • Burgener J
        • Falck JR
        • Fritschy JM
        • Arand M
        Distribution of soluble and microsomal epoxide hydrolase in the mouse brain and its contribution to cerebral epoxyeicosatrienoic acid metabolism.
        Neuroscience. 2009; 163: 646-661
        • Mensah-Nyagan AG
        • Bouzobra F
        • Meyer L
        • Taleb O
        • Patte-Mensah C
        Neurosteroids as neuroprotectors of pain neural pathways.
        Eur Neuropsychopharm. 2016; 262: S122-S123
        • Artemenko IP
        • Zhao D
        • Hales DB
        • Hales KH
        • Jefcoate CR
        Mitochondrial processing of newly synthesized steroidogenic acute regulatory protein (StAR), but not total StAR, mediates cholesterol transfer to cytochrome P450 side chain cleavage enzyme in adrenal cells.
        J Biol Chem. 2001; 276: 46583-46596
        • Miller WL
        Mechanism of StAR's regulation of mitochondrial cholesterol import.
        Mol Cell Endocrinol. 2007; 265-266: 46-50
        • Montes C
        • Magnin M
        • Maarrawi J
        • Frot M
        • Convers P
        • Mauguiere F
        • Garcia-Larrea L
        Thalamic thermo-algesic transmission: ventral posterior (VP) complex versus VMpo in the light of a thalamic infarct with central pain.
        Pain. 2005; 113: 223-232
        • Patte-Mensah C
        • Meyer L
        • Taleb O
        • Mensah-Nyagan AG
        Potential role of allopregnanolone for a safe and effective therapy of neuropathic pain.
        Prog Neurobiol. 2014; 113: 70-78
        • Peyron R
        Functional brain imaging: what has it brought to our understanding of neuropathic pain? A special focus on allodynic pain mechanisms.
        Pain. 2016; 157: S67-S71
        • Pillarisetti S
        • Khanna I
        A multimodal disease modifying approach to treat neuropathic pain–inhibition of soluble epoxide hydrolase (sEH).
        Drug Discov Today. 2015; 20: 1382-1390
        • Reddy DS
        Neurosteroids: Endogenous role in the human brain and therapeutic potentials.
        Prog Brain Res. 2010; 186: 113-137
        • Renic M
        • Klaus JA
        • Omura T
        • Kawashima N
        • Onishi M
        • Miyata N
        • Koehler RC
        • Harder DR
        • Roman RJ
        Effect of 20-HETE inhibition on infarct volume and cerebral blood flow after transient middle cerebral artery occlusion.
        J Cereb Blood Flow Metab. 2009; 29: 629-639
        • Sasso O
        • Russo R
        • Vitiello S
        • Raso GM
        • D'Agostino G
        • Iacono A
        • Rana GL
        • Vallee M
        • Cuzzocrea S
        • Piazza PV
        • Meli R
        • Calignano A
        Implication of allopregnanolone in the antinociceptive effect of N-palmitoylethanolamide in acute or persistent pain.
        Pain. 2012; 153: 33-41
        • Schneider C
        • Pratt DA
        • Porter NA
        • Brash AR
        Control of oxygenation in lipoxygenase and cyclooxygenase catalysis.
        Chem Biol. 2007; 14: 473-488
        • Shih HC
        • Kuan YH
        • Shyu BC
        Targeting brain-derived neurotrophic factor in the medial thalamus for the treatment of central poststroke pain in a rodent model.
        Pain. 2017; 158: 1302-1313
        • Siniscalchi A
        • Gallelli L
        • De Sarro G
        • Malferrari G
        • Santangelo E
        Antiepileptic drugs for central post-stroke pain management.
        Pharmacol Res. 2012; 65: 171-175
        • Stell BM
        • Brickley SG
        • Tang CY
        • Farrant M
        • Mody I
        Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by delta subunit-containing GABAA receptors.
        Proc Natl Acad Sci U S A. 2003; 100: 14439-14444
        • Wagner K
        • Lee KS
        • Yang J
        • Hammock BD
        Epoxy fatty acids mediate analgesia in murine diabetic neuropathy.
        Eur J Pain. 2017; 21: 456-465
        • Wang X
        • Shen CL
        • Dyson MT
        • Yin X
        • Schiffer RB
        • Grammas P
        • Stocco DM
        The involvement of epoxygenase metabolites of arachidonic acid in cAMP-stimulated steroidogenesis and steroidogenic acute regulatory protein gene expression.
        J Endocrinol. 2006; 190: 871-878
        • Wasserman JK
        • Koeberle PD
        Development and characterization of a hemorrhagic rat model of central post-stroke pain.
        Neuroscience. 2009; 161: 173-183
        • Watson CJ
        Insular balance of glutamatergic and GABAergic signaling modulates pain processing.
        Pain. 2016; 157: 2194-2207
        • Wu CH
        • Shyue SK
        • Hung TH
        • Wen S
        • Lin CC
        • Chang CF
        • Chen SF
        Genetic deletion or pharmacological inhibition of soluble epoxide hydrolase reduces brain damage and attenuates neuroinflammation after intracerebral hemorrhage.
        J Neuroinflammation. 2017; 14: 230
        • Xu R
        • Wang S
        • Li W
        • Liu Z
        • Tang J
        • Tang X
        Activation of peroxisome proliferator-activated receptor-gamma by a 12/15-lipoxygenase product of arachidonic acid: a possible neuroprotective effect in the brain after experimental intracerebral hemorrhage.
        J Neurosurg. 2017; 127: 522-531
        • Yang Y
        • Yang F
        • Yang F
        • Li CL
        • Wang Y
        • Li Z
        • Lu YF
        • Yu YQ
        • Fu H
        • He T
        • Sun W
        • Wang RR
        • Chen J
        Gabapentinoid insensitivity after repeated administration is associated with down-regulation of the alpha(2)delta-1 subunit in rats with central post-stroke pain hypersensitivity.
        Neurosci Bull. 2016; 32: 41-50
        • Zhang N
        • Peng Z
        • Tong X
        • Lindemeyer AK
        • Cetina Y
        • Huang CS
        • Olsen RW
        • Otis TS
        • Houser CR
        Decreased surface expression of the delta subunit of the GABAA receptor contributes to reduced tonic inhibition in dentate granule cells in a mouse model of fragile X syndrome.
        Exp Neurol. 2017; 297: 168-178
        • Zhang W
        • Otsuka T
        • Sugo N
        • Ardeshiri A
        • Alhadid YK
        • Iliff JJ
        • DeBarber AE
        • Koop DR
        • Alkayed NJ
        Soluble epoxide hydrolase gene deletion is protective against experimental cerebral ischemia.
        Stroke. 2008; 39: 2073-2078
        • Zhang Y
        • Hong G
        • Lee KS
        • Hammock BD
        • Gebremedhin D
        • Harder DR
        • Koehler RC
        • Sapirstein A
        Inhibition of soluble epoxide hydrolase augments astrocyte release of vascular endothelial growth factor and neuronal recovery after oxygen-glucose deprivation.
        J Neurochem. 2017; 140: 814-825