Differential ATF3 expression in dorsal root ganglion neurons reveals the profile of primary afferents engaged by diverse noxious chemical stimuli

Bráz, Joao; Basbaum, Allan I.

doi:10.1016/j.pain.2010.05.005

Cited by 136 publications

(134 citation statements)

References 64 publications

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“…3D). This finding is consistent with the engagement of all primary afferents by formalin (27), making the VGLUT2+ cell population dispensable. In summary, cKO mice showed reduced responsiveness to acute stimulation with noxious heat, mechanical, and chemical stimuli.…”

Section: Deficits In Acute Mechanical Pain and Capsaicin Response In supporting

confidence: 88%

VGLUT2 expression in primary afferent neurons is essential for normal acute pain and injury-induced heat hypersensitivity

Scherrer

Low

Wang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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110

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Dorsal root ganglia (DRG) neurons, including the nociceptors that detect painful thermal, mechanical, and chemical stimuli, transmit information to spinal cord neurons via glutamatergic and peptidergic neurotransmitters. However, the specific contribution of glutamate to pain generated by distinct sensory modalities or injuries is not known. Here we generated mice in which the vesicular glutamate transporter 2 (VGLUT2) is ablated selectively from DRG neurons. We report that conditional knockout (cKO) of the Slc17a6 gene encoding VGLUT2 from the great majority of nociceptors profoundly decreased VGLUT2 mRNA and protein in these neurons, and reduced firing of lamina I spinal cord neurons in response to noxious heat and mechanical stimulation. In behavioral assays, cKO mice showed decreased responsiveness to acute noxious heat, mechanical, and chemical (capsaicin) stimuli, but responded normally to cold stimulation and in the formalin test. Strikingly, although tissue injury-induced heat hyperalgesia was lost in the cKO mice, mechanical hypersensitivity developed normally. In a model of nerve injuryinduced neuropathic pain, the magnitude of heat hypersensitivity was diminished in cKO mice, but both the mechanical allodynia and the microgliosis generated by nerve injury were intact. These findings suggest that VGLUT2 expression in nociceptors is essential for normal perception of acute pain and heat hyperalgesia, and that heat and mechanical hypersensitivity induced by peripheral injury rely on distinct (VGLUT2 dependent and VGLUT2 independent, respectively) primary afferent mechanisms and pathways.nociceptor | inflammatory pain | electrophysiology | neuroanatomy P rimary afferent neurons of the dorsal root ganglia (DRG) detect a wide range of stimulus modalities and intensities (1). This is particularly true for nociceptors, which are the neurons specialized to detect noxious stimuli. Not only do subsets of nociceptors express different repertoires of neuropeptides, receptors, and ion channels, but they also project to different laminae in the spinal cord where they engage different CNS circuits (2-4). Importantly, studies in rodents in which different nociceptor populations have been deleted revealed remarkably selective behavioral deficits (e.g., heat, mechanical, or chemical pain), demonstrating the existence of behaviorally relevant peripheral-labeled lines for different modalities of pain (5-8).Whether the modality-specific contribution of sensory neurons to acute pain and to injury-induced hypersensitivity states is also manifest at the level of the different neurotransmitters expressed by these neurons is still not known. Interestingly, previous pharmacological and genetic studies that disrupted neuropeptide function did not find a modality-specific loss of pain processing (9). Here we turned our attention to glutamate, which is presumed to be released by all DRG neurons to activate second-order spinal cord neurons.Because pharmacological blockade of glutamate signaling would nonselectively inhibit the centr...

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Section: Deficits In Acute Mechanical Pain and Capsaicin Response In supporting

confidence: 88%

VGLUT2 expression in primary afferent neurons is essential for normal acute pain and injury-induced heat hypersensitivity

Scherrer

Low

Wang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

110

102

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“…In contrast, the high thermal coefficient of glutamate release on Vc neurons suggests a relatively narrow set of potential molecular drivers, chiefly the most sensitive thermoTRPs (Caterina 2007); the best-characterized member of these is TRPV1. TRPV1 is expressed throughout the trigeminal afferents, extending to their presynaptic terminals in the superficial Vc, thereby identifying primary afferent fibers (Bae et al 2004;Braz and Basbaum 2010;Cavanaugh et al 2011a,b;Davies and North 2009;Jennings et al 2003). In our system, 70% of Vc neurons were CAP-sensitive (i.e., TRPV1ϩ).…”

Section: Discussionmentioning

confidence: 74%

Physiological temperatures drive glutamate release onto trigeminal superficial dorsal horn neurons

Largent-Milnes

Hegarty

Aicher

et al. 2014

Journal of Neurophysiology

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Largentϩ , thermal, and chemical stimuli. The present study investigated the relationships among the spontaneous release of glutamate, temperature, and TRPV1 localization at synapses in the Vc. Spontaneous excitatory postsynaptic currents (sEPSCs) were recorded from Vc neurons (n ϭ 151) in horizontal brain-stem slices obtained from Sprague-Dawley rats. Neurons had basal sEPSC rates that fell into two distinct frequency categories: High (Ն10 Hz) or Low (Ͻ10 Hz) at 35°C. Of all recorded neurons, those with High basal release rates (67%) at near-physiological temperatures greatly reduced their sEPSC rate when cooled to 30°C without amplitude changes. Such responses persisted during blockade of action potentials indicating that the High rate of glutamate release arises from presynaptic thermal mechanisms. Neurons with Low basal frequencies (33%) showed minor thermal changes in sEPSC rate that were abolished after addition of TTX, suggesting these responses were indirect and required local circuits. Activation of TRPV1 with capsaicin (100 nM) increased miniature EPSC (mEPSC) frequency in 70% of neurons, but half of these neurons had Low basal mEPSC rates and no temperature sensitivity. Our evidence indicates that normal temperatures (35-37°C) drive spontaneous excitatory synaptic activity within superficial Vc by a mechanism independent of presynaptic action potentials. Thus thermally sensitive inputs on superficial Vc neurons may tonically activate these neurons without afferent stimulation.trigeminal nucleus caudalis; temperature; TRPV1; spontaneous release; electrophysiology

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“…By evaluating several markers for pain induction and nerve damage, including p-ERK, activating transcription factor 3 (ATF3) and Iba1 (Ma & Quirion 2002;Ivanavicius et al 2007;Bráz & Basbaum 2010;Maeda et al 2010), this model was used to demonstrate the anatomical and functional phenotypes of neuropathic pain (Lee et al 2014).…”

Section: Adenoviral Vector-mediated Animal Models Of Neuropathic Painmentioning

confidence: 99%

Novel animal models of GARS-associated neuropathy by overexpression of mutant GARS using an adenoviral vector

Jeong

Song

et al. 2015

Animal Cells and Systems

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Glycyl-tRNA synthetase (GARS)-associated neuropathy caused by a mutation in GARS is a hereditary axonal neuropathy involving motor functional impairment. In this review, we describe a novel GARS-associated mouse neuropathy model produced using an adenovirus vector system containing a neuron-specific promoter. These adenovirus vector-mediated animal models are based on GARS mutations and have been generated by viral delivery of GARS proteins to the long peripheral axons of mice. Using the highly efficient adenoviral vector system, the overexpression of mutated GARS proteins in animals is sufficient to induce the same phenotypes seen in patients, such as neuropathic pain and motor function impairment. Adenoviral vector-mediated animal models have been used to demonstrate the cellular distribution patterns of GARS mutants and their induced molecular changes. In addition, the GARS-associated neuropathy model has demonstrated that neuroinflammation mediated by microglial activation is a disease phenotype-causing factor. Thus, these adenoviral vector-mediated animal models provide valuable insights into GARS-associated axonopathy and may contribute to the development of therapeutic approaches.

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Differential ATF3 expression in dorsal root ganglion neurons reveals the profile of primary afferents engaged by diverse noxious chemical stimuli

Cited by 136 publications

References 64 publications

VGLUT2 expression in primary afferent neurons is essential for normal acute pain and injury-induced heat hypersensitivity

VGLUT2 expression in primary afferent neurons is essential for normal acute pain and injury-induced heat hypersensitivity

Physiological temperatures drive glutamate release onto trigeminal superficial dorsal horn neurons

Novel animal models of GARS-associated neuropathy by overexpression of mutant GARS using an adenoviral vector

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