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Signaling Mechanisms in the Neuronal Networks of Pain and Itch
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Glutamate is the essential neurotransmitters in pain pathways. The discovery of the vesicular glutamate transporters (VGLUT1-3) has been a fundamental step on the way to describe glutamate-dependent pain pathways. We used the Cre-lox system to construct conditional knockouts with deficient Vglut2 transmission in specific neuronal populations. We generated a Vglut2f/f;Ht-Pa-Cre line to selectively delete Vglut2 from the peripheral nervous system. These Vglut2 deficient mice showed decreased acute nociceptive responses and were less prone to develop an inflammatory state. They did not develop cold allodynia, or heat hyperalgesia and were less hypersensitive to mechanical stimuli in the PSNL chronic pain model. Further analyses of genes with altered expression after nerve injury, revealed candidates for future studies of chronic pain biomarkers. Interestingly, the Vglut2f/f;Ht-Pa-Cre mice developed an elevated itch behavior.

To investigate more specific neuronal populations, we analyzed mice lacking Vglut2 in the Nav1.8 population, as inflammatory hyperalgesia, cold pain, and noxious mechanosensation have been shown to depend upon Nav1.8Cre positive sensory neurons. We showed that deleting Vglut2 in Nav1.8Cre positive neurons abolished thermal hyperalgesia in persistent inflammatory models and responses to noxious mechanical stimuli. We also demonstrated that substance P and VGLUT2-dependent glutamatergic transmission are co-required for the development of formalin-induced inflammatory pain and heat hyperalgesia in persistent inflammatory states.

Deletion of Vglut2 in a subpopulation of neurons overlapping with the vanilloid receptor (TRPV1) primary afferents in the dorsal root ganglia resulted in a dramatic increase in itch behavior accompanied by a reduced responsiveness to thermal pain. Substance P signaling and VGLUT2-mediated glutamatergic transmission in TRPV1 neurons was co-required for the development of inflammatory pain states. Analyses of an itch phenotype uncovered the pathway within TRPV1 neurons, with VGLUT2 playing a regulatory role and GRPR neurons, which are to plausible converge the itch signal in the spinal cord.

These studies confirmed the essential role of VGLUT2-dependent glutamatergic transmission in acute and persistent pain states and identified the roles of specific subpopulations of primary afferent neurons. Additionally, a novel pain and itch transmission pathway in TRPV1/VGLUT2 positive neurons was identified, which could be part of the gate control of pain.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. , 78 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 833
Keyword [en]
mouse genetics, neuronal network, glutamate, sensory neuron, dorsal root ganglion, pain, itch
National Category
Neurosciences
Research subject
Neuroscience; Molecular Genetics
Identifiers
URN: urn:nbn:se:uu:diva-183255ISBN: 978-91-554-8517-7 (print)OAI: oai:DiVA.org:uu-183255DiVA: diva2:562390
Public defence
2012-12-07, BMC, B22, BMC, Husargatan 3, 75124 Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-11-16 Created: 2012-10-23 Last updated: 2013-01-23Bibliographically approved
List of papers
1. VGLUT2-dependent glutamatergic transmission in primary afferents is required for intact nociception in both acute and persistent pain modalities
Open this publication in new window or tab >>VGLUT2-dependent glutamatergic transmission in primary afferents is required for intact nociception in both acute and persistent pain modalities
2012 (English)In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 153, no 7, 1525-1536 p.Article in journal (Refereed) Published
Abstract [en]

Glutamate is an essential transmitter in pain pathways. However, its broad usage in the central and peripheral nervous system prevents us from designing efficient glutamate-based pain therapies without causing harmful side effects. The discovery of vesicular glutamate transporters (VGLUT1-3) has been a crucial step in describing specific glutamatergic neuronal subpopulations and glutamate-dependent pain pathways. To assess the role of VGLUT2-mediated glutamatergic contribution to pain transmission from the entire primary sensory population, we crossed our Vglut2(f/f) line with the Ht-Pa-Cre line. Such Vglut2-deficient mice showed significantly decreased, but not completely absent, acute nociceptive responses. The animals were less prone to develop an inflammatory-related state of pain and were, in the partial sciatic nerve ligation chronic pain model, much less hypersensitive to mechanical stimuli and did not develop cold allodynia or heat hyperalgesia. To take advantage of this neuropathic pain-resistant model, we analyzed Vglut2-dependent transcriptional changes in the dorsal spinal cord after nerve injury, which revealed several novel candidate target genes potentially relevant for the development of neuropathic pain therapeutics. Taken together, we conclude that VGLUT2 is a major mediator of nociception in primary afferents, implying that glutamate is the key somatosensory neurotransmitter. 

Keyword
Mouse genetics, Neuronal network, Glutamate, Sensory neuron, Dorsal root ganglia, Pain, Itch
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-177579 (URN)10.1016/j.pain.2012.04.017 (DOI)000305423700027 ()
Available from: 2012-07-16 Created: 2012-07-16 Last updated: 2017-12-07Bibliographically approved
2. A sensory subpopulation depends on vesicular glutamate transporter 2 for mechanical pain, and together with substance P, inflammatory pain
Open this publication in new window or tab >>A sensory subpopulation depends on vesicular glutamate transporter 2 for mechanical pain, and together with substance P, inflammatory pain
Show others...
2011 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 14, 5789-5794 p.Article in journal (Refereed) Published
Abstract [en]

Ablating or functionally compromising sets of sensory neurons has provided important insights into peripheral modality-specific wiring in the somatosensory system. Inflammatory hyperalgesia, cold pain, and noxious mechanosensation have all been shown to depend upon Na(v)1.8-positive sensory neurons. The release of fast-acting neurotransmitters, such as glutamate, and more slowly released neuropeptides, such as substance P (SP), contribute to the diversified responses to external stimuli. Here we show that deleting Vglut2 in Na(v)1.8(Cre)-positive neurons compromised mechanical pain and NGF-induced thermal hyperalgesia, whereas tactile-evoked sensation, thermal, formalin-evoked, and chronic neuropathic pain were normal. However, when Vglut2(f/f); Na(v)1.8(Cre) mice were injected with a SP antagonist before the formalin test, the second phase pain response was nearly completely abolished, whereas in control mice, the pain response was unaffected. Our results suggest that VGLUT2-dependent signaling originating from Na(v)1.8-positive neurons is a principal sensing mechanism for mechanical pain and, together with SP, inflammatory pain. These data define sets of primary afferents associated with specific modalities and provide useful genetic tools with which to analyze the pathways that are activated by functionally distinct neuronal populations and transmitters.

Keyword
dorsal root ganglia, mouse genetics, neuronal network, co-transmission, sensory signaling
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-152814 (URN)10.1073/pnas.1013602108 (DOI)000289265300058 ()
Available from: 2011-05-03 Created: 2011-05-02 Last updated: 2017-12-11Bibliographically approved
3. VGLUT2-Dependent Sensory Neurons in the TRPV1 Population Regulate Pain and Itch
Open this publication in new window or tab >>VGLUT2-Dependent Sensory Neurons in the TRPV1 Population Regulate Pain and Itch
Show others...
2010 (English)In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 68, no 3, 529-542 p.Article in journal (Refereed) Published
Abstract [en]

The natural response to itch sensation is to scratch, which relieves the itch through an unknown mechanism. Interaction between pain and itch has been frequently demonstrated, and the selectivity hypothesis of itch, based on data from electrophysiological and behavioral experiments, postulates the existence of primary pain afferents capable of repressing itch. Here, we demonstrate that deletion of vesicular glutamate transporter (VGLUT) 2 in a subpopulation of neurons partly overlapping with the vanilloid receptor (TRPV1) primary afferents resulted in a dramatic increase in itch behavior accompanied by a reduced responsiveness to thermal pain. The increased itch behavior was reduced by administration of antihistaminergic drugs and by genetic deletion of the gastrin-releasing peptide receptor, demonstrating a dependence on VGLUT2 to maintain normal levels of both histaminergic and nonhistaminergic itch. This study establishes that VGLUT2 is a major player in TRPV1 thermal nociception and also serves to regulate a normal itch response.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-135327 (URN)10.1016/j.neuron.2010.09.016 (DOI)000284255800019 ()
Available from: 2010-12-08 Created: 2010-12-06 Last updated: 2017-12-11Bibliographically approved
4. Cooperative roles of glutamate and Substance P in TRPV1 neurons
Open this publication in new window or tab >>Cooperative roles of glutamate and Substance P in TRPV1 neurons
(English)Manuscript (preprint) (Other academic)
Keyword
mouse genetics, neuronal network, glutamate, sensory neuron, dorsal root ganglia, Trpv1, pain, Substance P, hyperalgesia, inflammation
National Category
Neurosciences
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:uu:diva-182960 (URN)
Available from: 2012-10-19 Created: 2012-10-19 Last updated: 2013-01-23
5. Glutamate and gastrin releasing peptide, but not substance P, are crucial for itch transmission via the TRPV1 population
Open this publication in new window or tab >>Glutamate and gastrin releasing peptide, but not substance P, are crucial for itch transmission via the TRPV1 population
(English)Manuscript (preprint) (Other academic)
Keyword
mouse genetics, neuronal network, glutamate, sensory neuron, dorsal root ganglia, Trpv1, itch, GRP
National Category
Medical and Health Sciences Neurosciences
Identifiers
urn:nbn:se:uu:diva-183254 (URN)
Available from: 2012-10-23 Created: 2012-10-23 Last updated: 2013-01-23

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