Reduced antinociception and plasma extravasation in mice lacking a neuropeptide Y receptor

Naveilhan, Philippe; Hassani, Hessameh; Lucas, Guilherme; Blakeman, Karin Hygge; Hao, Jing‐Xia; Xu, Xiao‐Jun; Wiesenfeld‐Hallin, Zsuzsanna; Thorén, Peter; Ernfors, Patrik

doi:10.1038/35054063

Cited by 173 publications

(123 citation statements)

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“…amacrine cells; choline acetyltransferase; calcium binding protein; horizontal cells; neuropeptides Neuropeptide Y (NPY) has multiple physiologic actions in both the central and peripheral nervous system, including effects on blood flow, memory retention, food intake, epilepsy, and pain (Lundberg et al, 1996;Munglani et al, 1996;Balasubramaniam, 1997;Blomqvist and Herzog, 1997;Thorsell et al, 2000;Furtinger et al, 2001;Naveilhan et al, 2001). These …”

Section: Indexing Termsmentioning

confidence: 99%

Localization of neuropeptide Y1 receptor immunoreactivity in the rat retina and the synaptic connectivity of Y1 immunoreactive cells

D'Angelo¹,

Oh²,

Chun³

et al. 2002

J of Comparative Neurology

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Neuropeptide Y (NPY), an inhibitory neuropeptide expressed by a moderately dense population of wide-field amacrine cells in the rat retina, acts through multiple (Y1-y6) G-protein-coupled receptors. This study determined the cellular localization of Y1 receptors and the synaptic connectivity of Y1 processes in the inner plexiform layer (IPL) of the rat retina. Specific Y1 immunoreactivity was localized to horizontal cell bodies in the distal inner nuclear layer and their processes in the outer plexiform layer. Immunoreactivity was also prominent in cell processes located in strata 2 and 4, and puncta in strata 4 and 5 of the IPL. Double-label immunohistochemical experiments with calbindin, a horizontal cell marker, confirmed Y1 immunostaining in all horizontal cells. Double-label immunohistochemical experiments, using antibodies to choline acetyltransferase and vesicular acetylcholine transporter to label cholinergic amacrine cell processes, demonstrated that Y1 immunoreactivity in strata 2 and 4 of the IPL was localized to cholinergic amacrine cell processes. Electron microscopic studies of the inner retina showed that Y1-immunostained amacrine cell processes and puncta received synaptic inputs from unlabeled amacrine cell processes (65.2%) and bipolar cell axon terminals (34.8%). Y1-immunoreactive amacrine cell processes most frequently formed synaptic outputs onto unlabeled amacrine cell processes (34.0%) and ganglion cell dendrites (54.1%). NPY immunoreactivity in the rat retina is distributed primarily to strata 1 and 5 of the IPL, and the present findings, thus, suggest that NPY acts in a paracrine manner on Y1 receptors to influence both horizontal and amacrine cells. Indexing termsamacrine cells; choline acetyltransferase; calcium binding protein; horizontal cells; neuropeptides Neuropeptide Y (NPY) has multiple physiologic actions in both the central and peripheral nervous system, including effects on blood flow, memory retention, food intake, epilepsy, and pain (Lundberg et al., 1996;Munglani et al., 1996;Balasubramaniam, 1997;Blomqvist and Herzog, 1997;Thorsell et al., 2000;Furtinger et al., 2001;Naveilhan et al., 2001). These NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript effects are mediated by means of at least five G-protein-coupled receptors, designated as Y1, Y2, Y4, Y5, and y6, which are coupled to pertussis toxin-sensitive inhibitory Gproteins (Lundberg et al., 1996;Munglani et al., 1996;Balasubramaniam, 1997;Blomqvist and Herzog, 1997;Michel et al., 1998). Y-receptors have been localized to specific regions of the central and peripheral nervous system by receptor binding autoradiography, immunohistochemistry, and in situ hybridization (Zhang et al., 1994;Bao et al., 1997;Jacques et al., 1997;Dumont et al., 1998;Hökfelt et al., 1998;Gackenheimer et al., 2001). Y1 receptor is the most studied Y-receptor and it plays key roles in many of the central and peripheral effects of NPY (Lundberg et al., 1996;Munglani et al., 1996;Balasubramaniam, 1997;Blomqvist and H...

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Section: Indexing Termsmentioning

confidence: 99%

Localization of neuropeptide Y1 receptor immunoreactivity in the rat retina and the synaptic connectivity of Y1 immunoreactive cells

D'Angelo¹,

Oh²,

Chun³

et al. 2002

J of Comparative Neurology

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“…The intrathecal administration of NPY or its analogs produces both antinociception and antihyperalgesia (Hua et al, 1991;Taiwo and Taylor, 2002). Recent studies utilizing Y1-R knockout mice or specific NPY receptor antagonists indicate that the intrathecal effects of NPY are due primarily to activation of the Y1-R (Naveilhan et al, 2001;Taiwo and Taylor, 2002). However, the target neuronal populations mediating this effect have yet to be determined.…”

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confidence: 99%

Neuropeptide Y inhibits capsaicin-sensitive nociceptors via a Y1-receptor-mediated mechanism

2004

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Neuropeptide Y (NPY) is expressed in certain primary afferent fibers, is up-regulated in response to tissue injury and is capable of inhibiting nociceptive behavior at the spinal level. However, the spinal mechanism(s) for NPY-evoked antinociception is unknown. In this study, we evaluated the hypothesis that agonists at the NPY Y1 receptor subtype (Y1-R) inhibit exocytosis from the capsaicin-sensitive class of nociceptors. Using in vitro superfusion of rat dorsal spinal cord slices, pre-treatment with the Y1-R agonist [Leu 31 Pro 34 ]NPY significantly inhibited capsaicin-evoked release of immunoreactive calcitonin gene-related peptide with an EC 50 value of 10.6 nM. This inhibitory effect was concentration dependent, significantly attenuated by pre-treatment with the Y1 receptor antagonist BIBP3226 and reproduced by synthetic NPY. Examination of adult rat dorsal root ganglia using double immunofluorescent labeling revealed frequent co-localization of Y1 receptor immunoreactivity in vanilloid receptor type 1-immunoreactive neurons, indicating that Y1 agonists may directly modulate the capsaicin-sensitive class of nociceptors. Collectively, these results indicate that NPY is capable of inhibiting capsaicin-sensitive neurons via a Y1 receptor mechanism, suggesting the mechanisms for spinal NPY-induced antinociception is due, at least in part, to inhibition of central terminals of capsaicin-sensitive nociceptors. Keywords superfusion; pain; spinal cord; dorsal root ganglion; exocytosis Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is highly expressed throughout the central and peripheral nervous systems (Balasubramaniam, 1997;Larhammar, 1996;Malstrom, 1997). NPY has been proposed to mediate several physiologic systems including the processing of nociceptive signaling at the level of the spinal cord (Duggan et al., 1991;Mark et al., 1997;Balasubramaniam, 1997;Hokfelt et al., 1998). The NPY Y1 and Y2 receptors are expressed in the dorsal horn of the spinal cord as well as in dorsal root ganglia (DRG) (Kar and Quirion, 1992;Mantyh et al., 1994). The NPY Y1 receptor (Y1-R) is expressed primarily in small-and medium-sized neurons that express calcitonin gene related peptide (CGRP) in the DRG as well as in the dorsal spinal cord in inner lamina II . The NPY Y2 receptor is also expressed in DRG neurons, but primarily in large-* Corresponding author. Tel: +1-210-567-6668; fax: +1-210-567-3389. gibbs@uthscsa.edu (J. Gibbs). The intrathecal administration of NPY or its analogs produces both antinociception and antihyperalgesia (Hua et al., 1991;Taiwo and Taylor, 2002). Recent studies utilizing Y1-R knockout mice or specific NPY receptor antagonists indicate that the intrathecal effects of NPY are due primarily to activation of the Y1-R (Naveilhan et al., 2001;Taiwo and Taylor, 2002). However, the target neuronal populations mediating this effect have yet to be determined. HHS Public AccessNumerous studies have demonstrated that CGRP is involved in spinal nociception (see Vasko, 1995; van Rossum et al., 19...

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“…Several other genes with documented roles in chronic pain and antidepressant actions that are down-regulated by chronic DMI treatment in the Rgs9KO SNI group, including Neuropeptide Y1 receptor (Npy1R) (Fig. 6B, 60), were also altered (45). Neuropeptide systems constitute major drug development targets for the treatment of anxiety and depression, which are often comorbid with chronic pain (46,47).…”

Section: Discussionmentioning

confidence: 99%

RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states

Mitsi

Terzi

Purushothaman

et al. 2015

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

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The striatal protein Regulator of G-protein signaling 9-2 (RGS9-2) plays a key modulatory role in opioid, monoamine, and other G-protein-coupled receptor responses. Here, we use the murine spared-nerve injury model of neuropathic pain to investigate the mechanism by which RGS9-2 in the nucleus accumbens (NAc), a brain region involved in mood, reward, and motivation, modulates the actions of tricyclic antidepressants (TCAs). Prevention of RGS9-2 action in the NAc increases the efficacy of the TCA desipramine and dramatically accelerates its onset of action. By controlling the activation of effector molecules by G protein α and βγ subunits, RGS9-2 affects several protein interactions, phosphoprotein levels, and the function of the epigenetic modifier histone deacetylase 5, which are important for TCA responsiveness. Furthermore, information from RNA-sequencing analysis reveals that RGS9-2 in the NAc affects the expression of many genes known to be involved in nociception, analgesia, and antidepressant drug actions. Our findings provide novel information on NAc-specific cellular mechanisms that mediate the actions of TCAs in neuropathic pain states.desipramine | duloxetine | HDAC5 | spared nerve injury | gene expression R egulator of G-protein signaling 9-2 (RGS9-2) is an intracellular modulator of G-protein-coupled receptor (GPCR) function, which is expressed in medium spiny neurons and cholinergic interneurons of the striatum (1, 2). RGS9-2 influences the magnitude and time course of GPCR signaling by promoting GTPase activity of the Gα subunit and by preventing activation of Gα effectors (3). This modulation can also influence the duration of interactions between the Gβγ subunits and their effector molecules. In addition to Gα subunits, RGS9-2 interacts with several scaffolds and signal transduction proteins that affect its function, expression, and cellular localization. Interactions with the Gβ5 subunit and the adaptor protein R7BP determine the stability and cellular localization of RGS9-2, respectively (3, 4). Several recent studies have provided information on the regulation and function of RGS9-2 complexes in the striatum and how these complexes affect pharmacologic responses (2, 5, 6). In particular, RGS9-2 has been shown to modulate the actions of various psychotropic, antiparkinsonian, neuroleptic, and opiate analgesic drugs (1, 7). The nucleus accumbens (NAc) is a striatal brain region that is a major site of antidepressant drug action (8). Recent studies provided information on signal transduction events triggered by tricyclic antidepressants (TCAs) in NAc neurons and identified several second messengers, transcription factors, and epigenetic molecules involved in their therapeutic actions (9-11). TCAs, such as desipramine (DMI) and nortriptyline (NTL), and selective serotonin/norepinephrine reuptake inhibitors (SNRIs) have also been used to treat neuropathic pain, a complex chronic disorder that is highly comorbid with anxiety and depression (12, 13) and is characterized by thermal hyperalgesia, mech...

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Reduced antinociception and plasma extravasation in mice lacking a neuropeptide Y receptor

Cited by 173 publications

References 26 publications

Localization of neuropeptide Y1 receptor immunoreactivity in the rat retina and the synaptic connectivity of Y1 immunoreactive cells

Localization of neuropeptide Y1 receptor immunoreactivity in the rat retina and the synaptic connectivity of Y1 immunoreactive cells

Neuropeptide Y inhibits capsaicin-sensitive nociceptors via a Y1-receptor-mediated mechanism

RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states

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