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  1. Article: New models to study vulvodynia: Hyperinnervation and nociceptor sensitization in the female genital tract.

    Barry, Christine M / Huilgol, Kalyani K / Haberberger, Rainer V

    Neural regeneration research

    2018  Volume 13, Issue 12, Page(s) 2096–2097

    Language English
    Publishing date 2018-10-14
    Publishing country India
    Document type Journal Article
    ZDB-ID 2388460-5
    ISSN 1876-7958 ; 1673-5374
    ISSN (online) 1876-7958
    ISSN 1673-5374
    DOI 10.4103/1673-5374.241455
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  2. Article ; Online: Clodronate Treatment Prevents Vaginal Hypersensitivity in a Mouse Model of Vestibulodynia.

    Castro, Joel / Harrington, Andrea M / Chegini, Fariba / Matusica, Dusan / Spencer, Nick J / Brierley, Stuart M / Haberberger, Rainer V / Barry, Christine M

    Frontiers in cellular and infection microbiology

    2022  Volume 11, Page(s) 784972

    Abstract: Introduction: Improved understanding of vestibulodynia pathophysiology is required to develop appropriately targeted treatments. Established features include vulvovaginal hyperinnervation, increased nociceptive signalling and hypersensitivity. Emerging ... ...

    Abstract Introduction: Improved understanding of vestibulodynia pathophysiology is required to develop appropriately targeted treatments. Established features include vulvovaginal hyperinnervation, increased nociceptive signalling and hypersensitivity. Emerging evidence indicates macrophage-neuron signalling contributes to chronic pain pathophysiology. Macrophages are broadly classified as M1 or M2, demonstrating pro-nociceptive or anti-nociceptive effects respectively. This study investigates the impact of clodronate liposomes, a macrophage depleting agent, on nociceptive signalling in a mouse model of vestibulodynia.
    Methods: Microinjection of complete Freund's adjuvant (CFA) at the vaginal introitus induced mild chronic inflammation in C57Bl/6J mice. A subgroup was treated with the macrophage depleting agent clodronate. Control mice received saline. After 7 days, immunolabelling for PGP9.5, F4/80+CD11c+ and F4/80+CD206+ was used to compare innervation density and presence of M1 and M2 macrophages respectively in experimental groups. Nociceptive signalling evoked by vaginal distension was assessed using immunolabelling for phosphorylated MAP extracellular signal-related kinase (pERK) in spinal cord sections. Hyperalgesia was assessed by visceromotor response to graded vaginal distension.
    Results: CFA led to increased vaginal innervation (p < 0.05), increased pERK-immunoreactive spinal cord dorsal horn neurons evoked by vaginal-distension (p < 0.01) and enhanced visceromotor responses compared control mice (p < 0.01). Clodronate did not reduce vaginal hyperinnervation but significantly reduced the abundance of M1 and M2 vaginal macrophages and restored vaginal nociceptive signalling and vaginal sensitivity to that of healthy control animals.
    Conclusions: We have developed a robust mouse model of vestibulodynia that demonstrates vaginal hyperinnervation, enhanced nociceptive signalling, hyperalgesia and allodynia. Macrophages contribute to hypersensitivity in this model. Macrophage-sensory neuron signalling pathways may present useful pathophysiological targets.
    MeSH term(s) Animals ; Clodronic Acid/therapeutic use ; Female ; Freund's Adjuvant ; Hyperalgesia/drug therapy ; Mice ; Mice, Inbred C57BL ; Vulvodynia/drug therapy
    Chemical Substances Clodronic Acid (0813BZ6866) ; Freund's Adjuvant (9007-81-2)
    Language English
    Publishing date 2022-01-18
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2619676-1
    ISSN 2235-2988 ; 2235-2988
    ISSN (online) 2235-2988
    ISSN 2235-2988
    DOI 10.3389/fcimb.2021.784972
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  3. Article ; Online: Primary afferent neurons containing calcitonin gene-related peptide but not substance P in forepaw skin, dorsal root ganglia, and spinal cord of mice.

    Kestell, Garreth R / Anderson, Rebecca L / Clarke, Jennifer N / Haberberger, Rainer V / Gibbins, Ian L

    The Journal of comparative neurology

    2015  Volume 523, Issue 17, Page(s) 2555–2569

    Abstract: In mice dorsal root ganglia (DRG), some neurons express calcitonin gene-related peptide (CGRP) without substance P (SP; CGRP(+) SP(-) ). The projections and functions of these neurons are unknown. Therefore, we combined in vitro axonal tracing with ... ...

    Abstract In mice dorsal root ganglia (DRG), some neurons express calcitonin gene-related peptide (CGRP) without substance P (SP; CGRP(+) SP(-) ). The projections and functions of these neurons are unknown. Therefore, we combined in vitro axonal tracing with multiple-labeling immunohistochemistry to neurochemically define these neurons and characterize their peripheral and central projections. Cervical spinal cord, DRG, and forepaw skin were removed from C57Bl/6 mice and multiple-labeled for CGRP, SP, and either marker for the sensory neuron subpopulations transient receptor potential vanilloid type 1 (TRPV1), neurofilament 200 (NF200), or vesicular glutamate transporter 2 (VGluT1). To determine central projections of CGRP(+) SP(-) neurons, Neurobiotin (NB) was applied to the C7 ventral ramus and visualized in DRG and spinal cord sections colabeled for CGRP and SP. Half (50%) of the CGRP-immunoreactive DRG neurons lacked detectable SP and had a mean soma size of 473 ± 14 μm(2) (n = 5); 89% of the CGRP(+) SP(-) neurons expressed NF200 (n = 5), but only 32% expressed TRPV1 (n = 5). Cutaneous CGRP(+) SP(-) fibers were numerous within dermal papillae and around hair shafts (n = 4). CGRP(+) SP(-) boutons were prevalent in lateral lamina I and in lamina IV/V of the dorsal horn (n = 5). NB predominantly labeled fibers penetrating lamina IV/V, 6 ± 3% contained CGRP (n = 5), and 21 ± 2% contained VGluT1 (n = 3). CGRP(+) SP(-) afferent neurons are likely to be non-nociceptive. Their soma size, neurochemical profile, and peripheral and central targets suggest that CGRP(+) SP(-) neurons are polymodal mechanoceptors.
    MeSH term(s) Afferent Pathways/physiology ; Analysis of Variance ; Animals ; Biotin/analogs & derivatives ; Biotin/metabolism ; Calcitonin Gene-Related Peptide/metabolism ; Cell Count ; Female ; Ganglia, Spinal/cytology ; Mice ; Mice, Inbred C57BL ; Neurofilament Proteins/metabolism ; Phosphopyruvate Hydratase/metabolism ; Sensory Receptor Cells/metabolism ; Skin/cytology ; Skin/innervation ; Spinal Cord/cytology ; Substance P/metabolism ; TRPV Cation Channels/metabolism ; Vesicular Glutamate Transport Protein 1/metabolism
    Chemical Substances Neurofilament Proteins ; TRPV Cation Channels ; TRPV1 protein, mouse ; Vesicular Glutamate Transport Protein 1 ; neurobiotin ; neurofilament protein H (108688-71-7) ; Substance P (33507-63-0) ; Biotin (6SO6U10H04) ; Calcitonin Gene-Related Peptide (83652-28-2) ; Phosphopyruvate Hydratase (EC 4.2.1.11)
    Language English
    Publishing date 2015-12-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3086-7
    ISSN 1096-9861 ; 0021-9967 ; 0092-7317
    ISSN (online) 1096-9861
    ISSN 0021-9967 ; 0092-7317
    DOI 10.1002/cne.23804
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  4. Article ; Online: Morphological and neurochemical differences in peptidergic nerve fibers of the mouse vagina.

    Barry, Christine M / Ji, Esther / Sharma, Harman / Beukes, Lara / Vilimas, Patricia I / DeGraaf, Yvette C / Matusica, Dusan / Haberberger, Rainer V

    The Journal of comparative neurology

    2017  Volume 525, Issue 10, Page(s) 2394–2410

    Abstract: The vagina is innervated by a complex arrangement of sensory, sympathetic, and parasympathetic nerve fibers that contain classical transmitters plus an array of neuropeptides and enzymes known to regulate diverse processes including blood flow and ... ...

    Abstract The vagina is innervated by a complex arrangement of sensory, sympathetic, and parasympathetic nerve fibers that contain classical transmitters plus an array of neuropeptides and enzymes known to regulate diverse processes including blood flow and nociception. The neurochemical characteristics and distributions of peptide-containing nerves in the mouse vagina are unknown. This study used multiple labeling immunohistochemistry, confocal maging and analysis to investigate the presence and colocalization of the peptides vasoactive intestinal polypeptide (VIP), calcitonin-gene related peptide (CGRP), substance P (SP), neuropeptide tyrosine (NPY), and the nitric oxide synthesizing enzyme neuronal nitric oxide synthase (nNOS) in nerve fibers of the murine vaginal wall. We compared cervical and vulvar areas of the vagina in young nullipara and older multipara C57Bl/6 mice, and identified differences including that small ganglia were restricted to cervical segments, epithelial fibers were mainly present in vulvar segments and most nerve fibers were found in the lamina propria of the cervical region of the vagina, where a higher number of fibers containing immunoreactivity for VIP, CGRP, SP, or nNOS were found. Two populations of VIP-containing fibers were identified: fibers containing CGRP and fibers containing VIP but not CGRP. Differences between young and older mice were present in multiple layers of the vaginal wall, with older mice showing overall loss of innervation of epithelium of the proximal vagina and reduced proportions of VIP, CGRP, and SP containing nerve fibers in the distal epithelium. The distal vagina also showed increased vascularization and perivascular fibers containing NPY. Immunolabeling of ganglia associated with the vagina indicated the likely origin of some peptidergic fibers. Our results reveal regional differences and age- or parity-related changes in innervation of the mouse vagina, effecting the distribution of neuropeptides with diverse roles in function of the female genital tract.
    Language English
    Publishing date 2017-07-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3086-7
    ISSN 1096-9861 ; 0021-9967 ; 0092-7317
    ISSN (online) 1096-9861
    ISSN 0021-9967 ; 0092-7317
    DOI 10.1002/cne.24214
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  5. Article ; Online: Peptidergic nerve fibers in the urethra: Morphological and neurochemical characteristics in female mice of reproductive age.

    Barry, Christine M / Ji, Esther / Sharma, Harman / Yap, Pauline / Spencer, Nicholas J / Matusica, Dusan / Haberberger, Rainer V

    Neurourology and urodynamics

    2017  Volume 37, Issue 3, Page(s) 960–970

    Abstract: Background: Peptidergic nerve fibers provide important contributions to urethral function. Urethral innervation of female mice is not well documented.: Aims: To determine the distribution and projection sites of nerve fibers immunoreactive for ... ...

    Abstract Background: Peptidergic nerve fibers provide important contributions to urethral function. Urethral innervation of female mice is not well documented.
    Aims: To determine the distribution and projection sites of nerve fibers immunoreactive for vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), substance P (SP), and neuropeptide Y (NPY) in the urethra of wild-type control mice and compare innervation characteristics between the proximal and distal urethra of young nullipara and older multipara mice. Furthermore, to identify the location and neurochemical coding of the spinal afferent nerve endings in the urethra, whose sensory neurons reside in lumbosacral dorsal root ganglia (DRG).
    Methods: Multiple labeling immunohistochemistry of urethral sections of nulliparous (6-8 weeks old), and multiparous (9-12 months old) mice, and anterograde axonal tracing from L5-S2 (DRG) in vivo.
    Results: Abundant VIP-, CGRP-, SP-, and NPY-immunoreactive nerve fibers were identified in the adventitia, muscularis, and lamina propria of proximal and distal segments of the urethra. A proportion of fibers were closely associated with blood vessels, glands, and cells immunoreactive for PGP9.5. The epithelium contained abundant nerve fibers immunoreactive for CGRP and/or SP. Epithelial innervation was increased in the distal urethra of multipara mice. Abundant fibers were traced from L5-S2 DRG to all urethral regions.
    Conclusions: We present the first identification of spinal afferent endings in the urethra. Peptidergic nerve fibers, including multiple populations of spinal afferents, provide rich innervation of the female mouse urethra. The morphology of fibers in the epithelium and other regions suggests multiple nerve-cell interactions impacting on urethral function.
    MeSH term(s) Animals ; Calcitonin Gene-Related Peptide/metabolism ; Female ; Ganglia, Spinal/metabolism ; Immunohistochemistry ; Mice ; Nerve Fibers/metabolism ; Neuropeptide Y/metabolism ; Substance P/metabolism ; Urethra/innervation ; Urethra/metabolism ; Vasoactive Intestinal Peptide/metabolism
    Chemical Substances Neuropeptide Y ; Substance P (33507-63-0) ; Vasoactive Intestinal Peptide (37221-79-7) ; Calcitonin Gene-Related Peptide (JHB2QIZ69Z)
    Language English
    Publishing date 2017-10-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 604904-7
    ISSN 1520-6777 ; 0733-2467
    ISSN (online) 1520-6777
    ISSN 0733-2467
    DOI 10.1002/nau.23434
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  6. Article ; Online: Innervation Changes Induced by Inflammation in the Murine Vagina.

    Sharma, Harman / Ji, Esther / Yap, Pauline / Vilimas, Pat / Kyloh, Melinda / Spencer, Nicholas J / Haberberger, Rainer V / Barry, Christine M

    Neuroscience

    2017  Volume 372, Page(s) 16–26

    Abstract: Vulvodynia is a prevalent chronic pain disorder associated with high medical costs and often ineffective treatments. The major pathological feature is proliferation of vaginal nerve fibers. This study aimed to develop a highly reproducible animal model ... ...

    Abstract Vulvodynia is a prevalent chronic pain disorder associated with high medical costs and often ineffective treatments. The major pathological feature is proliferation of vaginal nerve fibers. This study aimed to develop a highly reproducible animal model to study neuroproliferation in the vagina and aid the identification of appropriately targeted treatments for conditions such as vulvodynia. Mild chronic inflammation was induced using microinjection of complete Freund's adjuvant in the distal vagina of C57Bl/6 mice. Control mice received saline. Inflammation and innervation density were assessed at 7 and 28 days after a single administration or 14 days following repeated administration of complete Freund's adjuvant or saline. Histochemistry and blinded-analysis of images were used to assess vaginal morphology (H & E) and abundance of macrophages (CD68-labeling), mast cells (toluidine blue staining, mast cell tryptase-immunoreactivity), blood vessels (αSMA-immunoreactivity) and nerve fibers immunoreactive for the pan-neuronal marker PGP9.5. Subpopulations of nerve fibers were identified using immunoreactivity for calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY). Single administration of complete Freund's adjuvant resulted in vaginal swelling, macrophage infiltration, vascular proliferation and increased abundance of nerve fibers immunoreactive for CGRP, SP, VIP and/or PGP9.5 but not NPY, evident at seven days. Inflammation further increased following repeated administration of complete Freund's adjuvant but nerve fiber proliferation did not. Nerve fiber proliferation continued to be evident at 28 days. The inter-individual differences within each treatment group were small, indicating that this model may be useful to study mechanisms underlying vaginal nerve fiber proliferation associated with inflammation.
    MeSH term(s) Animals ; Calcitonin Gene-Related Peptide/metabolism ; Edema/immunology ; Edema/pathology ; Female ; Freund's Adjuvant ; Inflammation/pathology ; Inflammation/physiopathology ; Mice, Inbred C57BL ; Neovascularization, Pathologic/immunology ; Neovascularization, Pathologic/pathology ; Nerve Fibers/immunology ; Nerve Fibers/pathology ; Substance P/metabolism ; Time Factors ; Vagina/blood supply ; Vagina/immunology ; Vagina/innervation ; Vagina/pathology ; Vasoactive Intestinal Peptide/metabolism
    Chemical Substances Substance P (33507-63-0) ; Vasoactive Intestinal Peptide (37221-79-7) ; Calcitonin Gene-Related Peptide (83652-28-2) ; Freund's Adjuvant (9007-81-2)
    Language English
    Publishing date 2017-12-30
    Publishing country United States
    Document type Journal Article
    ZDB-ID 196739-3
    ISSN 1873-7544 ; 0306-4522
    ISSN (online) 1873-7544
    ISSN 0306-4522
    DOI 10.1016/j.neuroscience.2017.12.026
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  7. Article ; Online: Extracellular and intracellular sphingosine-1-phosphate distinctly regulates exocytosis in chromaffin cells.

    Jiang, Zhong-Jiao / Delaney, Taylor L / Zanin, Mark P / Haberberger, Rainer V / Pitson, Stuart M / Huang, Jian / Alford, Simon / Cologna, Stephanie M / Keating, Damien J / Gong, Liang-Wei

    Journal of neurochemistry

    2019  Volume 149, Issue 6, Page(s) 729–746

    Abstract: Sphingosine-1-phosphate (S1P) is an essential bioactive sphingosine lipid involved in many neurological disorders. Sphingosine kinase 1 (SphK1), a key enzyme for S1P production, is concentrated in presynaptic terminals. However, the role of S1P/SphK1 ... ...

    Abstract Sphingosine-1-phosphate (S1P) is an essential bioactive sphingosine lipid involved in many neurological disorders. Sphingosine kinase 1 (SphK1), a key enzyme for S1P production, is concentrated in presynaptic terminals. However, the role of S1P/SphK1 signaling in exocytosis remains elusive. By detecting catecholamine release from single vesicles in chromaffin cells, we show that a dominant negative SphK1 (SphK1
    MeSH term(s) Animals ; Chromaffin Cells/metabolism ; Exocytosis/physiology ; Female ; Lysophospholipids/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Sphingosine/analogs & derivatives ; Sphingosine/metabolism
    Chemical Substances Lysophospholipids ; sphingosine 1-phosphate (26993-30-6) ; Sphingosine (NGZ37HRE42)
    Language English
    Publishing date 2019-05-08
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80158-6
    ISSN 1471-4159 ; 0022-3042 ; 1474-1644
    ISSN (online) 1471-4159
    ISSN 0022-3042 ; 1474-1644
    DOI 10.1111/jnc.14703
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  8. Article ; Online: Sensory innervation of the external genital tract of female guinea pigs and mice.

    Vilimas, Patricia I / Yuan, Shi-Yong / Haberberger, Rainer V / Gibbins, Ian L

    The journal of sexual medicine

    2011  Volume 8, Issue 7, Page(s) 1985–1995

    Abstract: Introduction: The structural and neurochemical characterization of the sensory innervation of the external genitalia of females is poorly known.: Aims:   To immunohistochemically map the sensory innervation of external genitalia and surrounding ... ...

    Abstract Introduction: The structural and neurochemical characterization of the sensory innervation of the external genitalia of females is poorly known.
    Aims:   To immunohistochemically map the sensory innervation of external genitalia and surrounding structures of female guinea pigs and mice.
    Methods: Large-diameter sensory fibers, presumably mechanoreceptors, were identified by their immunoreactivity to neuron-specific enolase (NSE) or vesicular glutamate transporter 1 (VGluT1). Peptidergic sensory fibers, presumably unmyelinated nociceptors, were identified by their immunoreactivity to calcitonin gene-related peptide (CGRP), substance P, or both. Multiple-labelled tissues were examined with high-resolution confocal microscopy.
    Main outcome measures: Microscopic identification of sensory endings, including potential nociceptors, characteristic of the external genitalia.
    Results: Large complex nerve endings immunoreactive for NSE and VGluT1 were abundant in dermal papillae of the clitoris. Each large ending was accompanied by one or two fine fibers immunoreactive for CGRP but neither substance P nor VGluT1. More simple NSE-immunoreactive endings occurred within dermal papillae in non-hairy skin of the labia and anal canal but were rare in pudendal or perineal hairy skin. Fine intra-epithelial fibers immunoreactive for NSE but not CGRP were abundant in hairy skin but rare in non-hairy genital skin and the clitoris. Only fine varicose fibers immunoreactive for both CGRP and substance P occurred in connective tissue underlying the mucosal epithelium of cervix and endometrium.
    Conclusion: Compared with surrounding tissues, the sensory innervation of the clitoris is highly specialized. The coactivation of nociceptors containing CGRP but not substance P within each mechanoreceptor complex could be the explanation of pain disorders of the external genitalia.
    MeSH term(s) Anal Canal/innervation ; Animals ; Calcitonin Gene-Related Peptide/metabolism ; Clitoris/metabolism ; Dermis/innervation ; Female ; Genitalia, Female/innervation ; Guinea Pigs ; Immunohistochemistry ; Mice ; Microscopy, Confocal ; Nociceptors/metabolism ; Perineum/innervation ; Phosphopyruvate Hydratase/metabolism ; Sensory Receptor Cells/metabolism ; Substance P/metabolism ; Vesicular Glutamate Transport Protein 1/metabolism
    Chemical Substances Vesicular Glutamate Transport Protein 1 ; Substance P (33507-63-0) ; Calcitonin Gene-Related Peptide (83652-28-2) ; Phosphopyruvate Hydratase (EC 4.2.1.11)
    Language English
    Publishing date 2011-07
    Publishing country Netherlands
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2251959-2
    ISSN 1743-6109 ; 1743-6095
    ISSN (online) 1743-6109
    ISSN 1743-6095
    DOI 10.1111/j.1743-6109.2011.02258.x
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  9. Article ; Online: Non-peptidergic small diameter primary afferents expressing VGluT2 project to lamina I of mouse spinal dorsal horn.

    Clarke, Jennifer N / Anderson, Rebecca L / Haberberger, Rainer V / Gibbins, Ian L

    Molecular pain

    2011  Volume 7, Page(s) 95

    Abstract: Background: Unmyelinated primary afferent nociceptors are commonly classified into two main functional types: those expressing neuropeptides, and non-peptidergic fibers that bind the lectin IB4. However, many small diameter primary afferent neurons ... ...

    Abstract Background: Unmyelinated primary afferent nociceptors are commonly classified into two main functional types: those expressing neuropeptides, and non-peptidergic fibers that bind the lectin IB4. However, many small diameter primary afferent neurons neither contain any known neuropeptides nor bind IB4. Most express high levels of vesicular glutamate transporter 2 (VGluT2) and are assumed to be glutamatergic nociceptors but their terminations within the spinal cord are unknown. We used in vitro anterograde axonal tracing with Neurobiotin to identify the central projections of these putative glutamatergic nociceptors. We also quantitatively characterised the spatial arrangement of these terminals with respect to those that expressed the neuropeptide, calcitonin gene-related peptide (CGRP).
    Results: Neurobiotin-labeled VGluT2-immunoreactive (IR) terminals were restricted to lamina I, with a medial-to-lateral distribution similar to CGRP-IR terminals. Most VGluT2-IR terminals in lateral lamina I were not labeled by Neurobiotin implying that they arose mainly from central neurons. 38 ± 4% of Neurobiotin-labeled VGluT2-IR terminals contained CGRP-IR. Conversely, only 17 ± 4% of Neurobiotin-labeled CGRP-IR terminals expressed detectable VGluT2-IR. Neurobiotin-labeled VGluT2-IR or CGRP-IR terminals often aggregated into small clusters or microdomains partially surrounding intrinsic lamina I neurons.
    Conclusions: The central terminals of primary afferents which express high levels of VGluT2-IR but not CGRP-IR terminate mainly in lamina I. The spatial arrangement of VGluT2-IR and CGRP-IR terminals suggest that lamina I neurons receive convergent inputs from presumptive nociceptors that are primarily glutamatergic or peptidergic. This reveals a previously unrecognized level of organization in lamina I consistent with the presence of multiple nociceptive processing pathways.
    MeSH term(s) Animals ; Immunohistochemistry ; Mice ; Mice, Inbred C57BL ; Neurons, Afferent/metabolism ; Nociceptors/metabolism ; Posterior Horn Cells/metabolism ; Presynaptic Terminals/metabolism ; Receptors, Calcitonin Gene-Related Peptide/metabolism ; Spinal Cord/metabolism ; Vesicular Glutamate Transport Protein 2/metabolism
    Chemical Substances Receptors, Calcitonin Gene-Related Peptide ; Slc17a6 protein, mouse ; Vesicular Glutamate Transport Protein 2
    Language English
    Publishing date 2011-12-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2174252-2
    ISSN 1744-8069 ; 1744-8069
    ISSN (online) 1744-8069
    ISSN 1744-8069
    DOI 10.1186/1744-8069-7-95
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  10. Article ; Online: Antibodies interfering with the type 3 muscarinic receptor pathway inhibit gastrointestinal motility and cholinergic neurotransmission in Sjögren's syndrome.

    Park, Kyungpyo / Haberberger, Rainer V / Gordon, Tom P / Jackson, Michael W

    Arthritis and rheumatism

    2011  Volume 63, Issue 5, Page(s) 1426–1434

    Abstract: Objective: In primary Sjögren's syndrome (SS), impairment of the gastrointestinal (GI) tract is common, and includes reduced esophageal motor function, delayed gastric emptying, and abnormalities in colonic motility; the pathogenesis is as yet unknown. ... ...

    Abstract Objective: In primary Sjögren's syndrome (SS), impairment of the gastrointestinal (GI) tract is common, and includes reduced esophageal motor function, delayed gastric emptying, and abnormalities in colonic motility; the pathogenesis is as yet unknown. We undertook this study to investigate the role of functional antibodies to the type 3 muscarinic receptor (M3R) in GI dysfunction associated with primary SS.
    Methods: Muscle strip and whole-organ functional assays were used to determine whether IgG with anti-M3R activity from patients with primary SS disrupted neurotransmission in tissue from throughout the mouse GI tract. Specificity of the autoantibody for the M3R was determined using knockout mice that were deficient in the expression of muscarinic receptor subtypes.
    Results: Functional antibodies to the M3R inhibited neuronally mediated contraction of smooth muscle from throughout the GI tract and disrupted complex contractile motility patterns in the colon. The autoantibodies were not active on tissue from mice that lacked the M3R, providing compelling evidence of the direct interaction of patient autoantibodies with the M3R.
    Conclusion: Our results indicate that anti-M3R autoantibodies have the potential to mediate multiple dysfunctions of the GI tract in primary SS, ranging from reduced esophageal motor activity to altered colonic motility. We hypothesize that altered GI motility forms part of a broader autonomic dysfunction mediated by pathogenic anti-M3R autoantibodies in primary SS.
    MeSH term(s) Acetylcholine/metabolism ; Analysis of Variance ; Animals ; Antineoplastic Combined Chemotherapy Protocols ; Autoantibodies/immunology ; Carbachol/pharmacology ; Cholinergic Agonists/pharmacology ; Cisplatin ; Gastrointestinal Motility/drug effects ; Gastrointestinal Motility/immunology ; Humans ; Ifosfamide ; Male ; Mice ; Mice, Knockout ; Mitomycin ; Muscle Contraction/drug effects ; Muscle Contraction/immunology ; Muscle, Smooth/drug effects ; Muscle, Smooth/immunology ; Receptor, Muscarinic M3/immunology ; Receptor, Muscarinic M3/metabolism ; Sjogren's Syndrome/immunology ; Sjogren's Syndrome/metabolism ; Sjogren's Syndrome/physiopathology ; Synaptic Transmission/drug effects ; Synaptic Transmission/immunology
    Chemical Substances Autoantibodies ; Cholinergic Agonists ; Receptor, Muscarinic M3 ; Mitomycin (50SG953SK6) ; Carbachol (8Y164V895Y) ; Acetylcholine (N9YNS0M02X) ; Cisplatin (Q20Q21Q62J) ; Ifosfamide (UM20QQM95Y)
    Language English
    Publishing date 2011-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 127294-9
    ISSN 1529-0131 ; 0004-3591 ; 2326-5191
    ISSN (online) 1529-0131
    ISSN 0004-3591 ; 2326-5191
    DOI 10.1002/art.30282
    Database MEDical Literature Analysis and Retrieval System OnLINE

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