@article{pmid40280127,

title = {The gut microbiota promotes pain in fibromyalgia},

author = {Weihua Cai and May Haddad and Rana Haddad and Inbar Kesten and Tseela Hoffman and Reut Laan and Susan Westfall and Manon Defaye and Nasser S Abdullah and Calvin Wong and Nicole Brown and Shannon Tansley and Kevin C Lister and Mehdi Hooshmandi and Feng Wang and Louis-Etienne Lorenzo and Volodya Hovhannisyan and David Ho-Tieng and Vibhu Kumar and Behrang Sharif and Bavanitha Thurairajah and Jonathan Fan and Tali Sahar and Charlotte Clayton and Neil Wu and Ji Zhang and Haggai Bar-Yoseph and Milena Pitashny and Emerson Krock and Jeffrey S Mogil and Masha Prager-Khoutorsky and Philippe Séguéla and Christophe Altier and Irah L King and Yves De Koninck and Nicholas J B Brereton and Emmanuel Gonzalez and Yoram Shir and Amir Minerbi and Arkady Khoutorsky},

doi = {10.1016/j.neuron.2025.03.032},

issn = {1097-4199},

year  = {2025},

date = {2025-07-01},

journal = {Neuron},

volume = {113},

number = {13},

pages = {2161--2175.e13},

abstract = {Fibromyalgia is a prevalent syndrome characterized by widespread pain in the absence of evident tissue injury or pathology, making it one of the most mysterious chronic pain conditions. The composition of the gut microbiota in individuals with fibromyalgia differs from that of healthy controls, but its functional role in the syndrome is unknown. Here, we show that fecal microbiota transplantation from fibromyalgia patients, but not from healthy controls, into germ-free mice induces pain and numerous molecular phenotypes that parallel known changes in fibromyalgia patients, including immune activation and metabolomic profile alterations. Replacing the fibromyalgia microbiota with a healthy microbiota substantially alleviated pain in mice. An open-label trial in women with fibromyalgia (Registry MOH_2021-11-04_010374) showed that transplantation of a healthy microbiota is associated with reduced pain and improved quality of life. We conclude that altered gut microbiota has a role in fibromyalgia pain, highlighting it as a promising target for therapeutic interventions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38277178,

title = {An improved conflict avoidance assay reveals modality-specific differences in pain hypersensitivity across sexes},

author = {Samuel Ferland and Feng Wang and Yves De Koninck and Francesco Ferrini},

doi = {10.1097/j.pain.0000000000003132},

issn = {1872-6623},

year  = {2024},

date = {2024-06-01},

journal = {Pain},

volume = {165},

number = {6},

pages = {1304--1316},

abstract = {Abnormal encoding of somatosensory modalities (ie, mechanical, cold, and heat) are a critical part of pathological pain states. Detailed phenotyping of patients' responses to these modalities have raised hopes that analgesic treatments could one day be tailored to a patient's phenotype. Such precise treatment would require a profound understanding of the underlying mechanisms of specific pain phenotypes at molecular, cellular, and circuitry levels. Although preclinical pain models have helped in that regard, the lack of a unified assay quantifying detailed mechanical, cold, and heat pain responses on the same scale precludes comparing how analgesic compounds act on different sensory phenotypes. The conflict avoidance assay is promising in that regard, but testing conditions require validation for its use with multiple modalities. In this study, we improve upon the conflict avoidance assay to provide a validated and detailed assessment of all 3 modalities within the same animal, in mice. We first optimized testing conditions to minimize the necessary amount of training and to reduce sex differences in performances. We then tested what range of stimuli produce dynamic stimulus-response relationships for different outcome measures in naive mice. We finally used this assay to show that nerve injury produces modality-specific sex differences in pain behavior. Our improved assay opens new avenues to study the basis of modality-specific abnormalities in pain behavior.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38112748,

title = {Assessing spontaneous sensory neuron activity using in vivo calcium imaging},

author = {Sonia Ingram and Kim I Chisholm and Feng Wang and Yves De Koninck and Franziska Denk and George L Goodwin},

doi = {10.1097/j.pain.0000000000003116},

issn = {1872-6623},

year  = {2024},

date = {2024-05-01},

journal = {Pain},

volume = {165},

number = {5},

pages = {1131--1141},

abstract = {Heightened spontaneous activity in sensory neurons is often reported in individuals living with chronic pain. It is possible to study this activity in rodents using electrophysiology, but these experiments require great skill and can be prone to bias. Here, we have examined whether in vivo calcium imaging with GCaMP6s can be used as an alternative approach. We show that spontaneously active calcium transients can be visualised in the fourth lumbar dorsal root ganglion (L4 DRG) through in vivo imaging in a mouse model of inflammatory pain. Application of lidocaine to the nerve, between the inflamed site and the DRG, silenced spontaneous firing and revealed the true baseline level of calcium for spontaneously active neurons. We used these data to train a machine learning algorithm to predict when a neuron is spontaneously active. We show that our algorithm is accurate in 2 different models of pain: intraplantar complete Freund adjuvant and antigen-induced arthritis, with accuracies of 90.0% ±1.2 and 85.9% ±2.1, respectively, assessed against visual inspection by an experienced observer. The algorithm can also detect neuronal activity in imaging experiments generated in a different laboratory using a different microscope configuration (accuracy = 94.0% ±2.2). We conclude that in vivo calcium imaging can be used to assess spontaneous activity in sensory neurons and provide a Google Colaboratory Notebook to allow anyone easy access to our novel analysis tool, for the assessment of spontaneous neuronal activity in their own imaging setups.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37551444,

title = {Restoring neuronal chloride extrusion reverses cognitive decline linked to Alzheimer's disease mutations},

author = {Iason Keramidis and Brendan B McAllister and Julien Bourbonnais and Feng Wang and Dominique Isabel and Edris Rezaei and Romain Sansonetti and Phil Degagne and Justin P Hamel and Mojtaba Nazari and Samsoon Inayat and Jordan C Dudley and Annie Barbeau and Lionel Froux and Marie-Eve Paquet and Antoine G Godin and Majid H Mohajerani and Yves De Koninck},

doi = {10.1093/brain/awad250},

issn = {1460-2156},

year  = {2023},

date = {2023-12-01},

journal = {Brain},

volume = {146},

number = {12},

pages = {4903--4915},

abstract = {Disinhibition during early stages of Alzheimer's disease is postulated to cause network dysfunction and hyperexcitability leading to cognitive deficits. However, the underlying molecular mechanism remains unknown. Here we show that, in mouse lines carrying Alzheimer's disease-related mutations, a loss of neuronal membrane potassium-chloride cotransporter KCC2, responsible for maintaining the robustness of GABAA-mediated inhibition, occurs pre-symptomatically in the hippocampus and prefrontal cortex. KCC2 downregulation was inversely correlated with the age-dependent increase in amyloid-β 42 (Aβ42). Acute administration of Aβ42 caused a downregulation of membrane KCC2. Loss of KCC2 resulted in impaired chloride homeostasis. Preventing the decrease in KCC2 using long term treatment with CLP290 protected against deterioration of learning and cortical hyperactivity. In addition, restoring KCC2, using short term CLP290 treatment, following the transporter reduction effectively reversed spatial memory deficits and social dysfunction, linking chloride dysregulation with Alzheimer's disease-related cognitive decline. These results reveal KCC2 hypofunction as a viable target for treatment of Alzheimer's disease-related cognitive decline; they confirm target engagement, where the therapeutic intervention takes place, and its effectiveness.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35579957,

title = {mTORC2 mediates structural plasticity in distal nociceptive endings that contributes to pain hypersensitivity following inflammation},

author = {Calvin Wong and Omer Barkai and Feng Wang and Carolina Thörn Perez and Shaya Lev and Weihua Cai and Shannon Tansley and Noosha Yousefpour and Mehdi Hooshmandi and Kevin C Lister and Mariam Latif and A Claudio Cuello and Masha Prager-Khoutorsky and Jeffrey S Mogil and Philippe Séguéla and Yves De Koninck and Alfredo Ribeiro-da-Silva and Alexander M Binshtok and Arkady Khoutorsky},

doi = {10.1172/JCI152635},

issn = {1558-8238},

year  = {2022},

date = {2022-08-01},

journal = {J Clin Invest},

volume = {132},

number = {15},

abstract = {The encoding of noxious stimuli into action potential firing is largely mediated by nociceptive free nerve endings. Tissue inflammation, by changing the intrinsic properties of the nociceptive endings, leads to nociceptive hyperexcitability and thus to the development of inflammatory pain. Here, we showed that tissue inflammation-induced activation of the mammalian target of rapamycin complex 2 (mTORC2) triggers changes in the architecture of nociceptive terminals and leads to inflammatory pain. Pharmacological activation of mTORC2 induced elongation and branching of nociceptor peripheral endings and caused long-lasting pain hypersensitivity. Conversely, nociceptor-specific deletion of the mTORC2 regulatory protein rapamycin-insensitive companion of mTOR (Rictor) prevented inflammation-induced elongation and branching of cutaneous nociceptive fibers and attenuated inflammatory pain hypersensitivity. Computational modeling demonstrated that mTORC2-mediated structural changes in the nociceptive terminal tree are sufficient to increase the excitability of nociceptors. Targeting mTORC2 using a single injection of antisense oligonucleotide against Rictor provided long-lasting alleviation of inflammatory pain hypersensitivity. Collectively, we showed that tissue inflammation-induced activation of mTORC2 causes structural plasticity of nociceptive free nerve endings in the epidermis and inflammatory hyperalgesia, representing a therapeutic target for inflammatory pain.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36337346,

title = {Distribution of acid-sensing ion channel subunits in human sensory neurons contrasts with that in rodents},

author = {Melina Papalampropoulou-Tsiridou and Stephanie Shiers and Feng Wang and Antoine G Godin and Theodore J Price and Yves De Koninck},

doi = {10.1093/braincomms/fcac256},

issn = {2632-1297},

year  = {2022},

date = {2022-01-01},

journal = {Brain Commun},

volume = {4},

number = {6},

pages = {fcac256},

abstract = {Acid-sensing ion channels (ASICs) play a critical role in nociception in human sensory neurons. Four genes ( and ) encoding multiple subunits through alternative splicing have been identified in humans. Real time-PCR experiments showed strong expression of three subunits , , and  in human dorsal root ganglia; however, their detailed expression pattern in different neuronal populations has not been investigated yet. In the current study, using an  hybridization approach (RNAscope), we examined the presence of , , and  mRNA in three subpopulations of human dorsal root ganglia neurons. Our results revealed that  and  were present in the vast majority of dorsal root ganglia neurons, while  was only expressed in less than half of dorsal root ganglia neurons. The distribution pattern of the three  subunits was the same across the three populations of dorsal root ganglia neurons examined, including neurons expressing the REarranged during Transfection (RET) receptor tyrosine kinase, calcitonin gene-related peptide, and a subpopulation of nociceptors expressing Transient Receptor Potential Cation Channel Subfamily V Member 1. These results strongly contrast the expression pattern of  in mice since our previous study demonstrated differential distribution of  among the various subpopulation of dorsal root ganglia neurons. Given the distinct acid-sensitivity and activity dynamics among different ASIC channels, the expression differences between human and rodents should be taken under consideration when evaluating the translational potential and efficiency of drugs targeting ASICs in rodent studies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32573694,

title = {Neuronal interleukin-1 receptors mediate pain in chronic inflammatory diseases},

author = {Benoit Mailhot and Marine Christin and Nicolas Tessandier and Chaudy Sotoudeh and Floriane Bretheau and Roxanne Turmel and Ève Pellerin and Feng Wang and Cyril Bories and Charles Joly-Beauparlant and Yves De Koninck and Arnaud Droit and Francesca Cicchetti and Grégory Scherrer and Eric Boilard and Reza Sharif-Naeini and Steve Lacroix},

doi = {10.1084/jem.20191430},

issn = {1540-9538},

year  = {2020},

date = {2020-09-01},

journal = {J Exp Med},

volume = {217},

number = {9},

abstract = {Chronic pain is a major comorbidity of chronic inflammatory diseases. Here, we report that the cytokine IL-1β, which is abundantly produced during multiple sclerosis (MS), arthritis (RA), and osteoarthritis (OA) both in humans and in animal models, drives pain associated with these diseases. We found that the type 1 IL-1 receptor (IL-1R1) is highly expressed in the mouse and human by a subpopulation of TRPV1+ dorsal root ganglion neurons specialized in detecting painful stimuli, termed nociceptors. Strikingly, deletion of the Il1r1 gene specifically in TRPV1+ nociceptors prevented the development of mechanical allodynia without affecting clinical signs and disease progression in mice with experimental autoimmune encephalomyelitis and K/BxN serum transfer-induced RA. Conditional restoration of IL-1R1 expression in nociceptors of IL-1R1-knockout mice induced pain behavior but did not affect joint damage in monosodium iodoacetate-induced OA. Collectively, these data reveal that neuronal IL-1R1 signaling mediates pain, uncovering the potential benefit of anti-IL-1 therapies for pain management in patients with chronic inflammatory diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32769979,

title = {Differential chloride homeostasis in the spinal dorsal horn locally shapes synaptic metaplasticity and modality-specific sensitization},

author = {Francesco Ferrini and Jimena Perez-Sanchez and Samuel Ferland and Louis-Etienne Lorenzo and Antoine G Godin and Isabel Plasencia-Fernandez and Martin Cottet and Annie Castonguay and Feng Wang and Chiara Salio and Nicolas Doyon and Adalberto Merighi and Yves De Koninck},

doi = {10.1038/s41467-020-17824-y},

issn = {2041-1723},

year  = {2020},

date = {2020-08-01},

journal = {Nat Commun},

volume = {11},

number = {1},

pages = {3935},

abstract = {GABA/glycine-mediated neuronal inhibition critically depends on intracellular chloride (Cl) concentration which is mainly regulated by the K-Cl co-transporter 2 (KCC2) in the adult central nervous system (CNS). KCC2 heterogeneity thus affects information processing across CNS areas. Here, we uncover a gradient in Cl extrusion capacity across the superficial dorsal horn (SDH) of the spinal cord (laminae I-II: LI-LII), which remains concealed under low Cl load. Under high Cl load or heightened synaptic drive, lower Cl extrusion is unveiled in LI, as expected from the gradient in KCC2 expression found across the SDH. Blocking TrkB receptors increases KCC2 in LI, pointing to differential constitutive TrkB activation across laminae. Higher Cl lability in LI results in rapidly collapsing inhibition, and a form of activity-dependent synaptic plasticity expressed as a continuous facilitation of excitatory responses. The higher metaplasticity in LI as compared to LII differentially affects sensitization to thermal and mechanical input. Thus, inconspicuous heterogeneity of Cl extrusion across laminae critically shapes plasticity for selective nociceptive modalities.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32508593,

title = {Differential Expression of Acid - Sensing Ion Channels in Mouse Primary Afferents in Naïve and Injured Conditions},

author = {Melina Papalampropoulou-Tsiridou and Simon Labrecque and Antoine G Godin and Yves De Koninck and Feng Wang},

doi = {10.3389/fncel.2020.00103},

issn = {1662-5102},

year  = {2020},

date = {2020-01-01},

journal = {Front Cell Neurosci},

volume = {14},

pages = {103},

abstract = {Injury and inflammation cause tissue acidosis, which is a common feature of various painful conditions. Acid-Sensing Ion channels (ASICs) are amongst the main excitatory channels activated by extracellular protons and expressed in the nervous system. Six transcripts of ASIC subunits including ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, and ASIC4 are encoded by four genes (Asic1-4) and have been identified in rodents. Most ASIC subunits are present at substantial levels in primary sensory neurons of dorsal root ganglia (DRG) except for ASIC4. However, their expression pattern in DRG neurons remains largely unclear, mainly due to the lack of antibodies with appropriate specificity. In this study, we examined in detail the expression pattern of ASIC1-3 subunits, including splice variants, in different populations of DRG neurons in adult mice using an  hybridization technique (RNAscope) with high sensitivity and specificity. We found that in naïve condition, all five subunits examined were expressed in the majority of myelinated, NF200-immunoreactive, DRG neurons (NF200). However, ASIC subunits showed a very different expression pattern among non-myelinated DRG neuronal subpopulations: ASIC1 and ASIC3 were only expressed in CGRP-immunoreactive neurons (CGRP), ASIC2a was mostly expressed in the majority of IB4-binding neurons (IB4), while ASIC2b was expressed in almost all non-myelinated DRG neurons. We also found that at least half of sensory neurons expressed multiple types of ASIC subunits, indicating prevalence of heteromeric channels. In mice with peripheral nerve injury, the expression level of ASIC1a and ASIC1b in L4 DRG and ASIC3 in L5 DRG were altered in CGRP neurons, but not in IB4 neurons. Furthermore, the pattern of change varied among DRGs depending on their segmental level, which pointed to differential regulatory mechanisms between afferent types and anatomical location. The distinct expression pattern of ASIC transcripts in naïve condition, and the differential regulation of ASIC subunits after peripheral nerve injury, suggest that ASIC subunits are involved in separate sensory modalities.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29768200,

title = {Sensory Afferents Use Different Coding Strategies for Heat and Cold},

author = {Feng Wang and Erik Bélanger and Sylvain L Côté and Patrick Desrosiers and Steven A Prescott and Daniel C Côté and Yves De Koninck},

doi = {10.1016/j.celrep.2018.04.065},

issn = {2211-1247},

year  = {2018},

date = {2018-05-01},

journal = {Cell Rep},

volume = {23},

number = {7},

pages = {2001--2013},

abstract = {Primary afferents transduce environmental stimuli into electrical activity that is transmitted centrally to be decoded into corresponding sensations. However, it remains unknown how afferent populations encode different somatosensory inputs. To address this, we performed two-photon Ca imaging from thousands of dorsal root ganglion (DRG) neurons in anesthetized mice while applying mechanical and thermal stimuli to hind paws. We found that approximately half of all neurons are polymodal and that heat and cold are encoded very differently. As temperature increases, more heating-sensitive neurons are activated, and most individual neurons respond more strongly, consistent with graded coding at population and single-neuron levels, respectively. In contrast, most cooling-sensitive neurons respond in an ungraded fashion, inconsistent with graded coding and suggesting combinatorial coding, based on which neurons are co-activated. Although individual neurons may respond to multiple stimuli, our results show that different stimuli activate distinct combinations of diversely tuned neurons, enabling rich population-level coding.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}