Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain

Coull, Jeffrey A. M.; Boudreau, Dominic; Bachand, Karine; Prescott, Steven A.; Nault, Francine; Sı́k, Attila; Koninck, Paul De; Koninck, Yves De

doi:10.1038/nature01868

Cited by 986 publications

(909 citation statements)

References 27 publications

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“…In contrast, pathophysiological activity associated with epilepsy, neuropathic pain, and neurodevelopmental disorders all involve a breakdown of KCC2‐mediated Cl − homeostasis (Coull et al . 2003; Tao et al . 2012; He et al .…”

Section: Introductionmentioning

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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Section: Introductionmentioning

confidence: 99%

Regulation of neuronal chloride homeostasis by neuromodulators

Mahadevan

Woodin

2016

The Journal of Physiology

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“…The altered inhibitory responses initiated by P2X4R stimulation in microglia unmasks low threshold input to lamina I, thereby driving the phenotypic switch in their response properties. This phenotypic switch caused spinal lamina I neurons to relay innocuous mechanical input, increase discharge to a noxious stimulus, and display spontaneous activity [18,42]. The changes in output of the lamina I neurons may be interpreted as providing a neural substrate for neuropathic pain.…”

Section: Introductionmentioning

confidence: 99%

P2X4 purinoceptor signaling in chronic pain

Trang

Salter

2012

Purinergic Signalling

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ATP, acting via P2 purinergic receptors, is a known mediator of inflammatory and neuropathic pain. There is increasing evidence that the ATP-gated P2X4 receptor (P2X4R) subtype is a locus through which activity of spinal microglia and peripheral macrophages instigate pain hypersensitivity caused by inflammation or by injury to a peripheral nerve. The present article highlights the recent advances in our understanding of microglia-neuron interactions in neuropathic pain by focusing on the signaling and regulation of the P2X4R. We will also develop a framework for understanding converging lines of evidence for involvement of P2X4Rs expressed on macrophages in peripheral inflammatory pain.

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“…This increased expression appears to be specific since P2X4 receptor protein expression is not increased in neurons or astrocytes following trauma or injury [27,41]. Several intracellular signaling pathways have been implicated in the upregulation of P2X4 receptor expression including the PI3K/AKT pathway [42], and lyn kinase via an associated fibronectin/integrin mechanism [43][44][45][46][47][48][49].…”

Section: P2x4 Receptorsmentioning

confidence: 99%

“…Intrathecal infusion of ATP-stimulated microglia cells that express P2X4 receptors also produces allodynia in normal rats [27]. This action appears to be mediated by increased intracellular Cl − concentrations in lamina I neurons that is dependent on brain-derived neurotrophic factor (BDNF) and neurotropin (TrkB) receptor signaling pathways [45,47]. P2X4 receptor stimulation results in down-stream signaling involving PIP2, PIP3, and p38 MAPK and subsequent release of BDNF [48,49].…”

Section: P2x4 Receptorsmentioning

confidence: 99%

P2X receptor antagonists for pain management: examination of binding and physicochemical properties

Gum

Wakefield

Jarvis

2011

Purinergic Signalling

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Enhanced sensitivity to noxious stimuli and the perception of non-noxious stimuli as painful are hallmark sensory perturbations associated with chronic pain. It is now appreciated that ATP, through its actions as an excitatory neurotransmitter, plays a prominent role in the initiation and maintenance of chronic pain states. Mechanistically, the ability of ATP to drive nociceptive sensitivity is mediated through direct interactions at neuronal P2X3 and P2X2/3 receptors. Extracellular ATP also activates P2X4, P2X7, and several P2Y receptors on glial cells within the spinal cord, which leads to a heightened state of neural-glial cell interaction in ongoing pain states. Following the molecular identification of the P2 receptor superfamilies, selective small molecule antagonists for several P2 receptor subtypes were identified, which have been useful for investigating the role of specific P2X receptors in preclinical chronic pain models. More recently, several P2X receptor antagonists have advanced into clinical trials for inflammation and pain. The development of orally bioavailable blockers for ion channels, including the P2X receptors, has been traditionally difficult due to the necessity of combining requirements for target potency and selectivity with suitable absorption distribution, metabolism, and elimination properties. Recent studies on the physicochemical properties of marketed orally bioavailable drugs, have identified several parameters that appear critical for increasing the probability of achieving suitable bioavailability, central nervous system exposure, and acceptable safety necessary for clinical efficacy. This review provides an overview of the antinociceptive pharmacology of P2X receptor antagonists and the chemical diversity and drug-like properties for emerging antagonists of P2X3, P2X2/3, P2X4, and P2X7 receptors. Keywords

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Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain

Cited by 986 publications

References 27 publications

Regulation of neuronal chloride homeostasis by neuromodulators

Regulation of neuronal chloride homeostasis by neuromodulators

P2X4 purinoceptor signaling in chronic pain

P2X receptor antagonists for pain management: examination of binding and physicochemical properties

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