@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{pmid32054836,

title = {Enhancing neuronal chloride extrusion rescues α2/α3 GABA-mediated analgesia in neuropathic pain},

author = {Louis-Etienne Lorenzo and Antoine G Godin and Francesco Ferrini and Karine Bachand and Isabel Plasencia-Fernandez and Simon Labrecque and Alexandre A Girard and Dominic Boudreau and Irenej Kianicka and Martin Gagnon and Nicolas Doyon and Alfredo Ribeiro-da-Silva and Yves De Koninck},

doi = {10.1038/s41467-019-14154-6},

issn = {2041-1723},

year  = {2020},

date = {2020-02-01},

journal = {Nat Commun},

volume = {11},

number = {1},

pages = {869},

abstract = {Spinal disinhibition has been hypothesized to underlie pain hypersensitivity in neuropathic pain. Apparently contradictory mechanisms have been reported, raising questions on the best target to produce analgesia. Here, we show that nerve injury is associated with a reduction in the number of inhibitory synapses in the spinal dorsal horn. Paradoxically, this is accompanied by a BDNF-TrkB-mediated upregulation of synaptic GABARs and by an α1-to-α2GABAR subunit switch, providing a mechanistic rationale for the analgesic action of the α2,3GABAR benzodiazepine-site ligand L838,417 after nerve injury. Yet, we demonstrate that impaired Cl extrusion underlies the failure of L838,417 to induce analgesia at high doses due to a resulting collapse in Cl gradient, dramatically limiting the benzodiazepine therapeutic window. In turn, enhancing KCC2 activity not only potentiated L838,417-induced analgesia, it rescued its analgesic potential at high doses, revealing a novel strategy for analgesia in pathological pain, by combined targeting of the appropriate GABAR-subtypes and restoring Cl homeostasis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28634406,

title = {Enhancing KCC2 function counteracts morphine-induced hyperalgesia},

author = {Francesco Ferrini and Louis-Etienne Lorenzo and Antoine G Godin and Miorie Le Quang and Yves De Koninck},

doi = {10.1038/s41598-017-04209-3},

issn = {2045-2322},

year  = {2017},

date = {2017-06-01},

journal = {Sci Rep},

volume = {7},

number = {1},

pages = {3870},

abstract = {Morphine-induced hyperalgesia (MIH) is a severe adverse effect accompanying repeated morphine treatment, causing a paradoxical decrease in nociceptive threshold. Previous reports associated MIH with a decreased expression of the Cl extruder KCC2 in the superficial dorsal horn (SDH) of the spinal cord, weakening spinal GABA/glycine-mediated postsynaptic inhibition. Here, we tested whether the administration of small molecules enhancing KCC2, CLP257 and its pro-drug CLP290, may counteract MIH. MIH was typically expressed within 6-8 days of morphine treatment. Morphine-treated rats exhibited decreased withdrawal threshold to mechanical stimulation and increased vocalizing behavior to subcutaneous injections. Chloride extrusion was impaired in SDH neurons measured as a depolarizing shift in E  under Cl load. Delivering CLP257 to spinal cord slices obtained from morphine-treated rats was sufficient to restore Cl extrusion capacity in SDH neurons. In vivo co-treatment with morphine and oral CLP290 prevented membrane KCC2 downregulation in SDH neurons. Concurrently, co-treatment with CLP290 significantly mitigated MIH and acute administration of CLP257 in established MIH restored normal nociceptive behavior. Our data indicate that enhancing KCC2 activity is a viable therapeutic approach for counteracting MIH. Chloride extrusion enhancers may represent an effective co-adjuvant therapy to improve morphine analgesia by preventing and reversing MIH.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23292683,

title = {Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl⁻ homeostasis},

author = {Francesco Ferrini and Tuan Trang and Theresa-Alexandra M Mattioli and Sophie Laffray and Thomas Del'Guidice and Louis-Etienne Lorenzo and Annie Castonguay and Nicolas Doyon and Wenbo Zhang and Antoine G Godin and Daniela Mohr and Simon Beggs and Karen Vandal and Jean-Martin Beaulieu and Catherine M Cahill and Michael W Salter and Yves De Koninck},

doi = {10.1038/nn.3295},

issn = {1546-1726},

year  = {2013},

date = {2013-02-01},

journal = {Nat Neurosci},

volume = {16},

number = {2},

pages = {183--192},

abstract = {A major unresolved issue in treating pain is the paradoxical hyperalgesia produced by the gold-standard analgesic morphine and other opiates. We found that hyperalgesia-inducing treatment with morphine resulted in downregulation of the K(+)-Cl(-) co-transporter KCC2, impairing Cl(-) homeostasis in rat spinal lamina l neurons. Restoring the anion equilibrium potential reversed the morphine-induced hyperalgesia without affecting tolerance. The hyperalgesia was also reversed by ablating spinal microglia. Morphine hyperalgesia, but not tolerance, required μ opioid receptor-dependent expression of P2X4 receptors (P2X4Rs) in microglia and μ-independent gating of the release of brain-derived neurotrophic factor (BDNF) by P2X4Rs. Blocking BDNF-TrkB signaling preserved Cl(-) homeostasis and reversed the hyperalgesia. Gene-targeted mice in which Bdnf was deleted from microglia did not develop hyperalgesia to morphine. However, neither morphine antinociception nor tolerance was affected in these mice. Our findings dissociate morphine-induced hyperalgesia from tolerance and suggest the microglia-to-neuron P2X4-BDNF-KCC2 pathway as a therapeutic target for preventing hyperalgesia without affecting morphine analgesia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24089642,

title = {Microglia control neuronal network excitability via BDNF signalling},

author = {Francesco Ferrini and Yves De Koninck},

doi = {10.1155/2013/429815},

issn = {1687-5443},

year  = {2013},

date = {2013-01-01},

journal = {Neural Plast},

volume = {2013},

pages = {429815},

abstract = {Microglia-neuron interactions play a crucial role in several neurological disorders characterized by altered neural network excitability, such as epilepsy and neuropathic pain. While a series of potential messengers have been postulated as substrates of the communication between microglia and neurons, including cytokines, purines, prostaglandins, and nitric oxide, the specific links between messengers, microglia, neuronal networks, and diseases have remained elusive. Brain-derived neurotrophic factor (BDNF) released by microglia emerges as an exception in this riddle. Here, we review the current knowledge on the role played by microglial BDNF in controlling neuronal excitability by causing disinhibition. The efforts made by different laboratories during the last decade have collectively provided a robust mechanistic paradigm which elucidates the mechanisms involved in the synthesis and release of BDNF from microglia, the downstream TrkB-mediated signals in neurons, and the biophysical mechanism by which disinhibition occurs, via the downregulation of the K⁺-Cl⁻ cotransporter KCC2, dysrupting Cl⁻ homeostasis, and hence the strength of GABA(A)- and glycine receptor-mediated inhibition. The resulting altered network activity appears to explain several features of the associated pathologies. Targeting the molecular players involved in this canonical signaling pathway may lead to novel therapeutic approach for ameliorating a wide array of neural dysfunctions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}