Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl− homeostasis

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

doi:10.1038/nn.3295

Cited by 366 publications

(418 citation statements)

References 59 publications

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“…Moreover, our experimental set-up allows to monitor, in addition to the development of OIH, the decline of the analgesic response to morphine (tolerance). Presented data support the view that hyperalgesia and tolerance may involve common cellular and molecular mechanisms 8,9 , although this is disputed in the literature 1,[10][11][12] . Finally, this protocol may be similarly adapted to genetically modified mice in order to evaluate the role of individual genes in the modulation of pain.…”

Section: Introductionsupporting

confidence: 72%

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities

Elhabazi¹,

Ayachi²,

Ilien³

et al. 2014

JoVE

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Opioid-induced hyperalgesia and tolerance severely impact the clinical efficacy of opiates as pain relievers in animals and humans. The molecular mechanisms underlying both phenomena are not well understood and their elucidation should benefit from the study of animal models and from the design of appropriate experimental protocols.We describe here a methodological approach for inducing, recording and quantifying morphine-induced hyperalgesia as well as for evidencing analgesic tolerance, using the tail-immersion and tail pressure tests in wild-type mice. As shown in the video, the protocol is divided into five sequential steps. Handling and habituation phases allow a safe determination of the basal nociceptive response of the animals. Chronic morphine administration induces significant hyperalgesia as shown by an increase in both thermal and mechanical sensitivity, whereas the comparison of analgesia time-courses after acute or repeated morphine treatment clearly indicates the development of tolerance manifested by a decline in analgesic response amplitude. This protocol may be similarly adapted to genetically modified mice in order to evaluate the role of individual genes in the modulation of nociception and morphine analgesia. It also provides a model system to investigate the effectiveness of potential therapeutic agents to improve opiate analgesic efficacy.

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Section: Introductionsupporting

confidence: 72%

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities

Elhabazi¹,

Ayachi²,

Ilien³

et al. 2014

JoVE

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“…Future studies are warranted to further the investigation of axonal CASP6 by generating conditional knockout mice to delete CASP6 selectively in nociceptor neurons. Apart from the well-demonstrated chronic role of microglia in regulating neuropathic pain and chronic opioid-induced hyperalgesia (15,16,54), we have demonstrated an acute role of microglia in modulating synaptic plasticity and inflammatory/nociceptive pain that occurs after persistent nociceptive input following inflammation or intense noxious stimulation. Thus, targeting the CASP6/ TNF-α pathway may offer a new approach for the management of inflammatory pain by modulating rapid changes in spinal cord microglia.…”

Section: Figurementioning

confidence: 80%

Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-α secretion

et al. 2014

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Increasing evidence indicates that the pathogenesis of neuropathic pain is mediated through spinal cord microglia activation. The intracellular protease caspase-6 (CASP6) is known to regulate neuronal apoptosis and axonal degeneration; however, the contribution of microglia and CASP6 in modulating synaptic transmission and pain is unclear. Here, we found that CASP6 is expressed specifically in C-fiber axonal terminals in the superficial spinal cord dorsal horn. Animals exposed to intraplantar formalin or bradykinin injection exhibited CASP6 activation in the dorsal horn. Casp6-null mice had normal baseline pain, but impaired inflammatory pain responses. Furthermore, formalin-induced second-phase pain was suppressed by spinal injection of CASP6 inhibitor or CASP6-neutralizing antibody, as well as perisciatic nerve injection of CASP6 siRNA. Recombinant CASP6 (rCASP6) induced marked TNF-α release in microglial cultures, and most microglia within the spinal cord expressed Tnfa. Spinal injection of rCASP6 elicited TNF-α production and microgliadependent pain hypersensitivity. Evaluation of excitatory postsynaptic currents (EPSCs) revealed that rCASP6 rapidly increased synaptic transmission in spinal cord slices via TNF-α release. Interestingly, the microglial inhibitor minocycline suppressed rCASP6 but not TNF-α−induced synaptic potentiation. Finally, rCASP6-activated microglial culture medium increased EPSCs in spinal cord slices via TNF-α. Together, these data suggest that CASP6 released from axonal terminals regulates microglial TNF-α secretion, synaptic plasticity, and inflammatory pain.

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“…While the paradoxical morphine‐induced hyperalgesia occurs via brain‐derived neurotrophic factor‐mediated KCC2 downregulation (Ferrini et al . 2013), an analgesic mode of morphine function via KCC2 upregulation has not been examined. Opioids act via a cognate G q ‐class of opioid GPCRs, and upon activation they enhance PKC signalling postsynaptically in DRG neurons (Mao et al .…”

Section: Discussionmentioning

confidence: 99%

Regulation of neuronal chloride homeostasis by neuromodulators

Mahadevan

Woodin

2016

The Journal of Physiology

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KCC2 is the central regulator of neuronal Cl− homeostasis, and is critical for enabling strong hyperpolarizing synaptic inhibition in the mature brain. KCC2 hypofunction results in decreased inhibition and increased network hyperexcitability that underlies numerous disease states including epilepsy, neuropathic pain and neuropsychiatric disorders. The current holy grail of KCC2 biology is to identify how we can rescue KCC2 hypofunction in order to restore physiological levels of synaptic inhibition and neuronal network activity. It is becoming increasingly clear that diverse cellular signals regulate KCC2 surface expression and function including neurotransmitters and neuromodulators. In the present review we explore the existing evidence that G‐protein‐coupled receptor (GPCR) signalling can regulate KCC2 activity in numerous regions of the nervous system including the hypothalamus, hippocampus and spinal cord. We present key evidence from the literature suggesting that GPCR signalling is a conserved mechanism for regulating chloride homeostasis. This evidence includes: (1) the activation of group 1 metabotropic glutamate receptors and metabotropic Zn2+ receptors strengthens GABAergic inhibition in CA3 pyramidal neurons through a regulation of KCC2; (2) activation of the 5‐hydroxytryptamine type 2A serotonin receptors upregulates KCC2 cell surface expression and function, restores endogenous inhibition in motoneurons, and reduces spasticity in rats; and (3) activation of A3A‐type adenosine receptors rescues KCC2 dysfunction and reverses allodynia in a model of neuropathic pain. We propose that GPCR‐signals are novel endogenous Cl− extrusion enhancers that may regulate KCC2 function.

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Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl− homeostasis

Cited by 366 publications

References 59 publications

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities

Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-α secretion

Regulation of neuronal chloride homeostasis by neuromodulators

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