Nonselective innervation of lamina I projection neurons by cocaine‐ and amphetamine‐regulated transcript peptide (CART)‐immunoreactive fibres in the rat spinal dorsal horn

Kozsurek, Márk; Lukácsi, Erika; Fekete, Csaba; Puskár, Zita

doi:10.1111/j.1460-9568.2009.06773.x

Cited by 10 publications

(7 citation statements)

References 94 publications

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“…The receptor of CART is yet unknown, but it has been suggested to potentiate spinal pain transmission [50] . A previous study in mice reported that ∼50% of the peptidergic nerve terminals in lamina I of the dorsal horn also contain CART [51] . We found high CART expression levels in a small subpopulation of sensory neurons by HCS microscopy (2.9±0.1%, n = 3, total of 11091 neurons, Fig.…”

Section: Resultsmentioning

confidence: 96%

“…CART has been shown to potentiate spinal N-methyl-D-aspartate (NMDA)-mediated nociceptive transmission [50] , [81] . Detailed studies on spinal cord sections of mice demonstrated that ∼50% of the peptidergic nerve terminals also contain CART [51] , [82] . Here we demonstrate that CART is expressed at high levels in a tiny subpopulation (≈ 3%) of sensory neurons co-expressing TRPV1.…”

Section: Discussionmentioning

confidence: 99%

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Subgroup-Elimination Transcriptomics Identifies Signaling Proteins that Define Subclasses of TRPV1-Positive Neurons and a Novel Paracrine Circuit

et al. 2014

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Normal and painful stimuli are detected by specialized subgroups of peripheral sensory neurons. The understanding of the functional differences of each neuronal subgroup would be strongly enhanced by knowledge of the respective subgroup transcriptome. The separation of the subgroup of interest, however, has proven challenging as they can hardly be enriched. Instead of enriching, we now rapidly eliminated the subgroup of neurons expressing the heat-gated cation channel TRPV1 from dissociated rat sensory ganglia. Elimination was accomplished by brief treatment with TRPV1 agonists followed by the removal of compromised TRPV1(+) neurons using density centrifugation. By differential microarray and sequencing (RNA-Seq) based expression profiling we compared the transcriptome of all cells within sensory ganglia versus the same cells lacking TRPV1 expressing neurons, which revealed 240 differentially expressed genes (adj. p<0.05, fold-change>1.5). Corroborating the specificity of the approach, many of these genes have been reported to be involved in noxious heat or pain sensitization. Beyond the expected enrichment of ion channels, we found the TRPV1 transcriptome to be enriched for GPCRs and other signaling proteins involved in adenosine, calcium, and phosphatidylinositol signaling. Quantitative population analysis using a recent High Content Screening (HCS) microscopy approach identified substantial heterogeneity of expressed target proteins even within TRPV1-positive neurons. Signaling components defined distinct further subgroups within the population of TRPV1-positive neurons. Analysis of one such signaling system showed that the pain sensitizing prostaglandin PGD2 activates DP1 receptors expressed predominantly on TRPV1(+) neurons. In contrast, we found the PGD2 producing prostaglandin D synthase to be expressed exclusively in myelinated large-diameter neurons lacking TRPV1, which suggests a novel paracrine neuron-neuron communication. Thus, subgroup analysis based on the elimination rather than enrichment of the subgroup of interest revealed proteins that define subclasses of TRPV1-positive neurons and suggests a novel paracrine circuit.

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Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Subgroup-Elimination Transcriptomics Identifies Signaling Proteins that Define Subclasses of TRPV1-Positive Neurons and a Novel Paracrine Circuit

et al. 2014

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“…Quantitative analysis of the % of CGRP and NF200 nerve fibers co-expressing TrkA was adapted from previous methodologies (Herrero-Herranz et al, 2008, Kozsurek et al, 2009). Images were acquired with a 60× objective, under which it was possible to distinguish individual axons.…”

Section: Methodsmentioning

confidence: 99%

The majority of myelinated and unmyelinated sensory nerve fibers that innervate bone express the tropomyosin receptor kinase A

et al. 2011

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Although skeletal pain is a leading cause of chronic pain and disability, relatively little is known about the specific populations of nerve fibers that innervate the skeleton. Recent studies have reported that therapies blocking nerve growth factor (NGF) or its cognate receptor, tropomyosin receptor kinase A (TrkA) are efficacious in attenuating skeletal pain. A potential factor to consider when assessing the analgesic efficacy of targeting NGF-TrkA signaling in a pain state is the fraction of NGF-responsive TrkA+ nociceptors that innervate the tissue from which the pain is arising, as this innervation and the analgesic efficacy of targeting NGF-TrkA signaling may vary considerably from tissue to tissue. To explore this in the skeleton, tissue slices and whole mount preparations of the normal, adult mouse femur were analyzed using immunohistochemistry and confocal microscopy. Analysis of these preparations revealed that 80% of the unmyelinated/thinly myelinated sensory nerve fibers that express calcitonin gene-related peptide (CGRP) and innervate the periosteum, mineralized bone and bone marrow also express TrkA. Similarly, the majority of myelinated sensory nerve fibers that express neurofilament 200 kDa (NF200) which innervate the periosteum, mineralized bone and bone marrow also co-express TrkA. In the normal femur, the relative density of CGRP+, NF200+ and TrkA+ sensory nerve fibers per unit volume is: periosteum > bone marrow > mineralized bone > cartilage with the respective relative densities being 100: 2: 0.1: 0. The observation that the majority of sensory nerve fibers innervating the skeleton express TrkA+, may in part explain why therapies that block NGF/TrkA pathway are highly efficacious in attenuating skeletal pain.

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“…75 Cocaine-and amphetamine-regulated transcript peptide is a neuropeptide expressed in areas involved in pain processing, including peptidergic C fibers, primary afferents that terminate in the superficial laminae of the spinal cord. 42,43 Mechanistically, CARTp/GPR160-induced central sensitization is driven by activation of the mitogen-activated protein kinases (MAPKs) and extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB). 75 It is well-documented that MAPK activation in the spinal cord is an integral component of neuroinflammatory process and a mechanistic hallmark of various persistent pain states.…”

Section: Introductionmentioning

confidence: 99%

Behavioral characterization of G-protein-coupled receptor 160 knockout mice

Schafer,

Giancotti,

Davis

et al. 2024

Pain

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Neuropathic pain is a devastating condition where current therapeutics offer little to no pain relief. Novel nonnarcotic therapeutic targets are needed to address this growing medical problem. Our work identified the G-protein-coupled receptor 160 (GPR160) as a potential target for therapeutic intervention. However, the lack of small-molecule ligands for GPR160 hampers our understanding of its role in health and disease. To address this void, we generated a global Gpr160 knockout (KO) mouse using CRISPR-Cas9 genome editing technology to validate the contributions of GPR160 in nociceptive behaviors in mice. Gpr160 KO mice are healthy and fertile, with no observable physical abnormalities. Gpr160 KO mice fail to develop behavioral hypersensitivities in a model of neuropathic pain caused by constriction of the sciatic nerve. On the other hand, responses of Gpr160 KO mice in the hot-plate and tail-flick assays are not affected. We recently deorphanized GPR160 and identified cocaine- and amphetamine-regulated transcript peptide (CARTp) as a potential ligand. Using Gpr160 KO mice, we now report that the development of behavioral hypersensitivities after intrathecal or intraplantar injections of CARTp are dependent on GPR160. Cocaine- and amphetamine-regulated transcript peptide plays a role in various affective behaviors, such as anxiety, depression, and cognition. There are no differences in learning, memory, and anxiety between Gpr160 KO mice and their age-matched and sex-matched control floxed mice. Results from these studies support the pronociceptive roles of CARTp/GPR160 and GPR160 as a potential therapeutic target for treatment of neuropathic pain.

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Nonselective innervation of lamina I projection neurons by cocaine‐ and amphetamine‐regulated transcript peptide (CART)‐immunoreactive fibres in the rat spinal dorsal horn

Cited by 10 publications

References 94 publications

Subgroup-Elimination Transcriptomics Identifies Signaling Proteins that Define Subclasses of TRPV1-Positive Neurons and a Novel Paracrine Circuit

Subgroup-Elimination Transcriptomics Identifies Signaling Proteins that Define Subclasses of TRPV1-Positive Neurons and a Novel Paracrine Circuit

The majority of myelinated and unmyelinated sensory nerve fibers that innervate bone express the tropomyosin receptor kinase A

Behavioral characterization of G-protein-coupled receptor 160 knockout mice

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