PMID- 35323848
OWN - NLM
STAT- MEDLINE
DCOM- 20220502
LR  - 20220716
IS  - 1460-2156 (Electronic)
IS  - 0006-8950 (Print)
IS  - 0006-8950 (Linking)
VI  - 145
IP  - 3
DP  - 2022 Apr 29
TI  - Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across 
      rodent and human models of pathological pain.
PG  - 1124-1138
LID - 10.1093/brain/awab408 [doi]
AB  - The prevalence and severity of many chronic pain syndromes differ across sex, and 
      recent studies have identified differences in immune signalling within spinal 
      nociceptive circuits as a potential mediator. Although it has been proposed that 
      sex-specific pain mechanisms converge once they reach neurons within the 
      superficial dorsal horn, direct investigations using rodent and human preclinical 
      pain models have been lacking. Here, we discovered that in the Freund's adjuvant 
      in vivo model of inflammatory pain, where both male and female rats display 
      tactile allodynia, a pathological coupling between KCC2-dependent disinhibition 
      and N-methyl-D-aspartate receptor (NMDAR) potentiation within superficial dorsal 
      horn neurons was observed in male but not female rats. Unlike males, the 
      neuroimmune mediator brain-derived neurotrophic factor (BDNF) failed to 
      downregulate inhibitory signalling elements (KCC2 and STEP61) and upregulate 
      excitatory elements (pFyn, GluN2B and pGluN2B) in female rats, resulting in no 
      effect of ex vivo brain-derived neurotrophic factor on synaptic NMDAR responses 
      in female lamina I neurons. Importantly, this sex difference in spinal pain 
      processing was conserved from rodents to humans. As in rodents, ex vivo spinal 
      treatment with BDNF downregulated markers of disinhibition and upregulated 
      markers of facilitated excitation in superficial dorsal horn neurons from male 
      but not female human organ donors. Ovariectomy in female rats recapitulated the 
      male pathological pain neuronal phenotype, with BDNF driving a coupling between 
      disinhibition and NMDAR potentiation in adult lamina I neurons following the 
      prepubescent elimination of sex hormones in females. This discovery of sexual 
      dimorphism in a central neuronal mechanism of chronic pain across species 
      provides a foundational step towards a better understanding and treatment for 
      pain in both sexes.
CI  - (c) The Author(s) (2022). Published by Oxford University Press on behalf of the 
      Guarantors of Brain.
FAU - Dedek, Annemarie
AU  - Dedek A
AUID- ORCID: 0000-0002-7215-4928
AD  - Department of Neuroscience, Carleton University, K1S 5B6 Ontario, Canada.
AD  - Neuroscience Program, Ottawa Hospital Research Institute, K1Y 4M9 Ontario, 
      Canada.
FAU - Xu, Jian
AU  - Xu J
AD  - Child Study Center, Yale University School of Medicine, New Haven, CT 06519, USA.
FAU - Lorenzo, Louis-Etienne
AU  - Lorenzo LE
AUID- ORCID: 0000-0002-5514-0049
AD  - CERVO Brain Research Centre, Quebec Mental Health Institute, Quebec G1E 1T2, 
      Canada.
FAU - Godin, Antoine G
AU  - Godin AG
AUID- ORCID: 0000-0003-2417-2563
AD  - CERVO Brain Research Centre, Quebec Mental Health Institute, Quebec G1E 1T2, 
      Canada.
AD  - Department of Psychiatry and Neuroscience, Universite Laval, Quebec G1V 0A6, 
      Canada.
FAU - Kandegedara, Chaya M
AU  - Kandegedara CM
AD  - Department of Neuroscience, Carleton University, K1S 5B6 Ontario, Canada.
AD  - Neuroscience Program, Ottawa Hospital Research Institute, K1Y 4M9 Ontario, 
      Canada.
FAU - Glavina, Genevieve
AU  - Glavina G
AD  - CERVO Brain Research Centre, Quebec Mental Health Institute, Quebec G1E 1T2, 
      Canada.
FAU - Landrigan, Jeffrey A
AU  - Landrigan JA
AD  - Department of Neuroscience, Carleton University, K1S 5B6 Ontario, Canada.
FAU - Lombroso, Paul J
AU  - Lombroso PJ
AD  - Child Study Center, Yale University School of Medicine, New Haven, CT 06519, USA.
FAU - De Koninck, Yves
AU  - De Koninck Y
AUID- ORCID: 0000-0002-5779-9330
AD  - CERVO Brain Research Centre, Quebec Mental Health Institute, Quebec G1E 1T2, 
      Canada.
AD  - Department of Psychiatry and Neuroscience, Universite Laval, Quebec G1V 0A6, 
      Canada.
FAU - Tsai, Eve C
AU  - Tsai EC
AD  - Neuroscience Program, Ottawa Hospital Research Institute, K1Y 4M9 Ontario, 
      Canada.
AD  - Brain and Mind Research Institute, University of Ottawa, Ontario K1N 6N5, Canada.
AD  - Department of Surgery, Division of Neurosurgery, The Ottawa Hospital, Ontario K1Y 
      4E9, Canada.
FAU - Hildebrand, Michael E
AU  - Hildebrand ME
AUID- ORCID: 0000-0002-6845-8013
AD  - Department of Neuroscience, Carleton University, K1S 5B6 Ontario, Canada.
AD  - Neuroscience Program, Ottawa Hospital Research Institute, K1Y 4M9 Ontario, 
      Canada.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Brain
JT  - Brain : a journal of neurology
JID - 0372537
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Symporters)
SB  - IM
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - *Chronic Pain
MH  - Female
MH  - Humans
MH  - Male
MH  - Neurons/metabolism
MH  - Rats
MH  - Sex Characteristics
MH  - *Symporters
PMC - PMC9050559
OTO - NOTNLM
OT  - NMDAR
OT  - inflammatory pain
OT  - pain
OT  - sex difference
OT  - spinal hyperexcitability
EDAT- 2022/03/25 06:00
MHDA- 2022/05/03 06:00
PMCR- 2022/03/23
CRDT- 2022/03/24 12:15
PHST- 2021/06/30 00:00 [received]
PHST- 2021/10/03 00:00 [revised]
PHST- 2021/10/15 00:00 [accepted]
PHST- 2022/03/25 06:00 [pubmed]
PHST- 2022/05/03 06:00 [medline]
PHST- 2022/03/24 12:15 [entrez]
PHST- 2022/03/23 00:00 [pmc-release]
AID - 6551129 [pii]
AID - awab408 [pii]
AID - 10.1093/brain/awab408 [doi]
PST - ppublish
SO  - Brain. 2022 Apr 29;145(3):1124-1138. doi: 10.1093/brain/awab408.