Paeonol Ameliorates Chronic Itch and Spinal Astrocytic Activation via CXCR3 in an Experimental Dry Skin Model in Mice

Paeonol is a bioactive phenol presents mainly in Paeonia suffruticosa Andr. (Paeoniaceae), Paeonia lactiflora Pall., and Dioscorea japonica Thunb. (Dioscoreaceae), harboring various pharmacological activities including anti-inflammatory, antioxidant, immune regulatory activity and reverse chemoresistance. Recent reports revealed paeonol exhibited good effects on chronic dermatitis, such as atopic dermatitis (AD) and psoriasis. However, whether paeonol is effective for dry skin disease and its mechanism of action still remain unclear. In this study, we analysed the effects of paeonol on a mouse model of dry skin treated with acetone-ether-water (AEW), which showed impressive activities in reducing scratching behavior and skin inflammation. To elucidate the underlying molecular targets for the anti-pruritic ability of paeonol, we screened the expression of possible chemokine pathways in the spinal cord. The expression of CXCR3 was significantly alleviated by paeonol, which increased greatly in the spinal neurons of AEW mice. In addition, treatment of paeonol significantly inhibited AEW-induced expression of astrocyte activity-dependent genes including Tlr4, Lcn2 and Hspb1 et al. The inhibitory effects of paeonol on scratching behavior and astrocytic activation in the spinal cord induced by AEW were abolished when CXCR3 was antagonized or genetically ablated. Taken together, our results indicated that paeonol can ameliorate AEW-induced inflammatory response and itching behavior, and reduce the expression of spinal astrocyte activity-dependent genes induced by AEW, which are driven by CXCR3.

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Presynaptic and Interactive Peptidergic Modulation of Reticulospinal Synaptic Inputs in the Lamprey

Journal of Neurophysiology ◽

10.1152/jn.2000.83.5.2497 ◽

2000 ◽

Vol 83 (5) ◽

pp. 2497-2507 ◽

Cited By ~ 20

Author(s):

David Parker

Keyword(s):

Spinal Cord ◽

Brain Stem ◽

Peptide Yy ◽

Input Resistance ◽

Ventral Root ◽

Interactive Effects ◽

Inhibitory Effects ◽

Spinal Neurons ◽

Root Responses ◽

The Brain

The modulatory effects of neuropeptides on descending inputs to the spinal cord have been examined by making paired recordings from reticulospinal axons and spinal neurons in the lamprey. Four peptides were examined; peptide YY (PYY) and cholecystokinin (CCK), which are contained in brain stem reticulospinal neurons, and calcitonin-gene–related peptide (CGRP) and neuropeptide Y (NPY), which are contained in primary afferents and sensory interneurons, respectively. Each of the peptides reduced the amplitude of monosynaptic reticulospinal-evoked excitatory postsynaptic potentials (EPSPs). The modulation appeared to be presynaptic, because postsynaptic input resistance and membrane potential, the amplitude of the electrical component of the EPSP, postsynaptic responses to glutamate, and spontaneous miniature EPSP amplitudes were unaffected. In addition, none of the peptides affected the pattern of N-methyl-d-aspartate (NMDA)–evoked locomotor activity in the isolated spinal cord. Potential interactions between the peptides were also examined. The “brain stem peptides” CCK and PYY had additive inhibitory effects on reticulospinal inputs, as did the “sensory peptides” CGRP and NPY. Brain stem peptides also had additive inhibitory effects when applied with sensory peptides. However, sensory peptides increased or failed to affect the amplitude of reticulospinal inputs in the presence of the brain stem peptides. These interactive effects also appear to be mediated presynaptically. The functional consequence of the peptidergic modulation was investigated by examining spinal ventral root responses elicited by brain stem stimulation. CCK and CGRP both reduced ventral root responses, although in interaction both increased the response. These results thus suggest that neuropeptides presynaptically influence the descending activation of spinal locomotor networks, and that they can have additive or novel interactive effects depending on the peptides examined and the order of their application.

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Counter-stimuli Inhibit GRPR Neurons via GABAergic Signaling in the Spinal Cord

10.1101/489831 ◽

2018 ◽

Cited By ~ 2

Author(s):

Rita Bardoni ◽

Devin M. Barry ◽

Hui Li ◽

Kai-Feng Shen ◽

Joseph Jeffry ◽

...

Keyword(s):

Neural Mechanisms ◽

Projection Neurons ◽

List Type ◽

Inhibitory Effects ◽

Spinal Neurons ◽

Chronic Itch ◽

Spinal Mechanism ◽

Itch Sensation ◽

Neurokinin 1

AbstractA myriad of counter-stimuli, including algogens and cooling, could inhibit itch sensation; however, the underlying molecular and neural mechanisms remain poorly understood. Here, we show that the spinal neurons expressing gastrin releasing peptide receptor (GRPR) primarily comprise excitatory interneurons that receive direct and indirect inputs from C and Aδ fibers and form contacts with projection neurons expressing the neurokinin 1 receptor (NK1R). Optical or chemogenetic activation of GRPR neurons evokes itch behavior that is partly dependent on NK1R activation. Importantly, we show that noxious or cooling counter-stimuli inhibit the activity of GRPR neurons via GABAergic signaling. By contrast, capsaicin, which could evoke a mix of itch and pain sensations, could exert both excitatory and inhibitory effects on GRPR neurons. These data strengthen the role of GRPR neurons as a key circuit for itch transmission and illustrate a spinal mechanism whereby counter-stimuli inhibit itch by suppressing the function of GRPR neurons.HighlightsActivation of GRPR neurons evokes itch and is dependent upon NK1R activationGRPR neurons receive both direct and indirect inputs from C/Aδ fibersCounter-stimuli inhibit GRPR neurons via GABAergic signalingIncreased excitability of GRPR neurons in chronic itch condition

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Spinal cord NLRP1 inflammasome contributes to dry skin induced chronic itch in mice

Journal of Neuroinflammation ◽

10.1186/s12974-020-01807-3 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Jun-Juan Fan ◽

Bo Gao ◽

Ao-Qi Song ◽

Ya-Jing Zhu ◽

Jun Zhou ◽

...

Keyword(s):

Spinal Cord ◽

Dry Skin ◽

Nlrp1 Inflammasome ◽

Chronic Itch

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Development and Evaluation of a Topical Anti-Inflammatory Preparation Containing Dodonaea polyandra Extract

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j38p57 ◽

2015 ◽

Vol 18 (4) ◽

pp. 578 ◽

Cited By ~ 4

Author(s):

Bradley S Simpson ◽

Xianling Luo ◽

Jiping Wang ◽

Yunmei Song ◽

David Claudie ◽

...

Keyword(s):

Phase Separation ◽

Human Skin ◽

Dosage Form ◽

Interleukin 1 ◽

In Vitro Release ◽

Skin Inflammation ◽

Skin Model ◽

Inflammation Model ◽

Anti Inflammatory

Purpose: We have previously reported that the Australian Northern Kaanju (Kuuku I’yu) medicinal plant Dodonaea polyandra has anti-inflammatory activity. This is attributed largely to the presence of clerodane diterpenoids contained within the leaf resin. We envisaged developing a topical preparation to treat indications relating to skin inflammation. However, it was unknown whether the resin could be incorporated into a suitable dosage form while retaining the therapeutic value demonstrated in previous work. Therefore, the following study was undertaken to assess parameters of safety and efficacy for a prototype formulation containing the leaf resin extracted from D. polyandra. Methods: Using the assessment criteria of optimum appearance, tactile feeling, spreadability and odour, 78 different formulations were developed. Formulation stability was assessed using a centrifugal test with preparations displaying phase separation further modified or re-formulated. A prototype formulation containing 5% w/w plant resin was selected and subjected to in vitro release studies. This was quantified through HPLC analysis using two major bioactive diterpenoids as reference. The prototype formulation was tested for efficacy in a TPA-induced acute murine skin inflammation model as well as a 3D human skin model for irritancy/toxicity (Epiderm™). Results: The prototype resin cream was a chartreuse-coloured homogenous semisolid preparation that was readily spreadable upon contact with skin with no sensation of tackiness, residual greasiness, or irritation. The optimized cream showed no phase separation after 30 min centrifugation at 825 g. In the TPA-induced inflammation model, the resin formulation significantly reduced ear thickness and interleukin-1 beta levels in mouse ear tissue. The 5% w/w resin cream formulation showed no irritancy in a 3D human skin model. Conclusions: Our results demonstrate that bioactive resin from D. polyandra can be formulated into a stable and non-irritant semi-solid dosage form and reduce parameters of acute skin inflammation in vivo. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Changes in serotonin-induced potentials during spinal cord development

Journal of Neurophysiology ◽

10.1152/jn.1993.69.4.1338 ◽

1993 ◽

Vol 69 (4) ◽

pp. 1338-1349 ◽

Cited By ~ 55

Author(s):

L. Ziskind-Conhaim ◽

B. S. Seebach ◽

B. X. Gao

Keyword(s):

Spinal Cord ◽

Direct Action ◽

Membrane Resistance ◽

Ventral Horn ◽

Repetitive Firing ◽

Lumbar Spinal Cord ◽

Receptor Subtypes ◽

Gamma Aminobutyric Acid ◽

Spinal Neurons ◽

Lumbar Spinal

1. Motoneuron responses to serotonin (5-hydroxytryptamine, 5-HT), and the growth pattern of 5-HT projections into the ventral horn were studied in the isolated spinal cord of embryonic and neonatal rats. 2. 5-HT projections first appeared in lumbar spinal cord at days 16-17 of gestation (E16-E17) and were localized in the lateral and ventral funiculi. By E18, the projections had grown into the ventral horn, and at 1-2 days after birth they were in close apposition to motoneuron somata. 3. At E16-E17, slow-rising depolarizing potentials of 1-4 mV were recorded intracellularly in lumbar motoneurons in response to bath application of 5-HT. These potentials were not apparent after E18; at that time 5-HT generated long-lasting depolarizations with an average amplitude of 6 mV, and an increase of 11% in membrane resistance. Starting at E18, 5-HT also induced high-frequency fast-rising potentials that were blocked by antagonists of glutamate, gamma-aminobutyric acid, and glycine. 4. Motoneuron responses to 5-HT increased significantly after birth, when 5-HT produced an average depolarization of 19 mV and repetitive firing of action potentials. 5. Tetrodotoxin and high Mg2+ did not reduce the amplitude of the long-lasting depolarizations, which suggested that they were produced by direct action of 5-HT on motoneuron membrane. 6. At all developmental ages, 5-HT reduced the amplitude of dorsal root-evoked potentials. The suppressed responses were neither due to 5-HT-induced depolarization nor the result of a decrease in motoneuron excitability. 7. The pharmacological profile of 5-HT-induced potentials was studied with the use of various agonists and antagonists of 5-HT. The findings indicated that the actions of 5-HT on spinal neurons were mediated via multiple 5-HT receptor subtypes. 8. Our results suggested that 5-HT excited spinal neurons before 5-HT projections grew into the ventral horn. The characteristics of 5-HT-induced potentials changed, however, at the time when the density of 5-HT projections increased in the motor nuclei.

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Spinal Motor and Sensory Neurons Are Androgen Targets in an Acrobatic Bird

Endocrinology ◽

10.1210/en.2012-1313 ◽

2012 ◽

Vol 153 (8) ◽

pp. 3780-3791 ◽

Cited By ~ 26

Author(s):

Matthew J. Fuxjager ◽

J. Douglas Schultz ◽

Julia Barske ◽

Ni Y. Feng ◽

Leonida Fusani ◽

...

Keyword(s):

Spinal Cord ◽

Sensory Neurons ◽

Courtship Behavior ◽

Estrogen Receptor Α ◽

Tropical Species ◽

Spinal Neurons ◽

Male And Female ◽

Leg Muscles ◽

Courtship Activity ◽

Peripheral Motor

Sex steroids affect the motivation to court mates, but less is known about how they influence motor movements associated with courtship behavior. Steroidal control of motor function may be especially important for species in which courtship requires superior strength, stamina, and neuromuscular coordination. Here we use the golden-collared manakin (Manacus vitellinus) to examine whether the neuromuscular circuitry that controls motoric aspects of courtship activity is sensitive to androgens. Males of this tropical species attract mates by rapidly jumping among branches in a courtship arena and using their wings to produce loud wing snaps. Testosterone activates this display via the androgen receptor (AR), and past work reveals that manakins injected with radio-labeled T (3H-T) accumulate radioactivity in the spinal cord. Thus, we used quantitative PCR to measure AR, estrogen receptor-α (ER-α) subtype, and aromatase (AROM) mRNA in spinal cords of male and female manakins and zebra finches. Expression of AR, but not ER-α or aromatase, was higher throughout the manakin spinal cord compared with the zebra finch. Next, we tested whether AR-expressing skeletal muscles are innervated by motor and sensory neurons that also express AR. To do this, we backfilled spinal neurons by injecting fluorescent tracers into select AR-sensitive wing and leg muscles of wild caught male and female manakins. We then removed these spinal cords and measured AR expression with in situ hybridization. Both sexes showed abundant AR mRNA in the cervical and lumbosacral spinal enlargements as well as in dorsal root ganglia attached to these enlargements. Together our findings suggest that androgens act widely on peripheral motor and sensory circuits in golden-collared manakins to influence wing snapping displays.

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Central opioid receptors mediate morphine-induced itch and chronic itch

10.1101/2020.05.31.126805 ◽

2020 ◽

Author(s):

Zilong Wang ◽

Changyu Jiang ◽

Hongyu Yao ◽

Ouyang Chen ◽

Sreya Rahman ◽

...

Keyword(s):

Spinal Cord ◽

Sensory Neurons ◽

Common Side Effect ◽

Cellular Mechanisms ◽

Conditional Deletion ◽

Outward Currents ◽

Clinical Pain ◽

Chronic Itch ◽

Allergic Contact

AbstractOpioids, such as morphine are mainstay treatments for clinical pain conditions. Itch is a common side effect of opioids, particularly as a result of epidural or intrathecal (i.t.) administration. Recent progress has advanced our understanding of itch circuits in the spinal cord. However, the mechanisms underlying opioid-induced itch are not fully understood, although an interaction between µ-opioid receptor (MOR) and gastrin-releasing peptide receptor (GRPR) in spinal GRPR-expressing neurons has been implicated. In this study we investigated the cellular mechanisms of intrathecal (i.t.) opioid-induced itch by conditional deletion of MOR-encoding Oprm1 in distinct populations of interneurons and sensory neurons. We found that i.t. injection of the MOR agonists morphine or DAMGO elicited dose-dependent scratching, but this pruritus was totally abolished in mice with a specific Oprm1 deletion in Vgat+ neurons (Oprm1-Vgat). Loss of MOR in somatostatin+ interneurons and TRPV1+ sensory neurons did not affect morphine-induced itch but impaired morphine-induced antinociception. In situ hybridization revealed Oprm1 expression in 30% of inhibitory and 20% of excitatory interneurons in the spinal dorsal horn. Whole-cell recordings from spinal cord slices showed that DAMGO induced outward currents in 9 out of 19 Vgat+ interneurons examined. Morphine also inhibited action potentials in Vgat+ interneurons and suppressed evoked IPSCs in postsynaptic Vgat- excitatory neurons, suggesting a mechanism of disinhibition by MOR agonists. Notably, morphine-elicited itch was suppressed by i.t. administration of NPY and abolished by spinal ablation of GRPR+ neurons, whereas i.t. GRP-induced itch response remained intact in mice lacking Oprm1-Vgat. Additionally, chronic itch from DNFB-induced allergic contact dermatitis was decreased by Oprm1-Vgat deletion. Finally, naloxone, but not peripherally restricted naloxone methiodide, inhibited chronic itch in the DNFB model and the cutaneous T-cell lymphoma (CTCL) model, indicating a contribution of central MOR signaling to chronic itch. Our findings demonstrate that i.t. morphine elicits itch via acting on MOR on spinal inhibitory interneurons, leading to disinhibition of the spinal itch circuit. Our data also suggest that chronic itch could be effectively treated with CNS-targeted naloxone.

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Spinal cord representation of motor cortex plasticity reflects corticospinal tract LTP

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2113192118 ◽

2021 ◽

Vol 118 (52) ◽

pp. e2113192118

Author(s):

Alzahraa Amer ◽

Jianxun Xia ◽

Michael Smith ◽

John H. Martin

Keyword(s):

Spinal Cord ◽

Motor Cortex ◽

Corticospinal Tract ◽

Cervical Spinal Cord ◽

Long Term Potentiation ◽

Dependent Manner ◽

Term Potentiation ◽

Spinal Cord Segment ◽

Spinal Interneuron ◽

Activity Dependent

Although it is well known that activity-dependent motor cortex (MCX) plasticity produces long-term potentiation (LTP) of local cortical circuits, leading to enhanced muscle function, the effects on the corticospinal projection to spinal neurons has not yet been thoroughly studied. Here, we investigate a spinal locus for corticospinal tract (CST) plasticity in anesthetized rats using multichannel recording of motor-evoked, intraspinal local field potentials (LFPs) at the sixth cervical spinal cord segment. We produced LTP by intermittent theta burst electrical stimulation (iTBS) of the wrist area of MCX. Approximately 3 min of MCX iTBS potentiated the monosynaptic excitatory LFP recorded within the CST termination field in the dorsal horn and intermediate zone for at least 15 min after stimulation. Ventrolaterally, in the spinal cord gray matter, which is outside the CST termination field in rats, iTBS potentiated an oligosynaptic negative LFP that was localized to the wrist muscle motor pool. Spinal LTP remained robust, despite pharmacological blockade of iTBS-induced LTP within MCX using MK801, showing that activity-dependent spinal plasticity can be induced without concurrent MCX LTP. Pyramidal tract iTBS, which preferentially activates the CST, also produced significant spinal LTP, indicating the capacity for plasticity at the CST–spinal interneuron synapse. Our findings show CST monosynaptic LTP in spinal interneurons and demonstrate that spinal premotor circuits are capable of further modifying descending MCX control signals in an activity-dependent manner.

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Animal models of damage, repair, and plasticity in the spinal cord

Oxford Textbook of Neurorehabilitation ◽

10.1093/med/9780198824954.003.0013 ◽

2020 ◽

pp. 155-168

Author(s):

Patrick Freund ◽

V. Reggie Edgerton ◽

Roland R. Roy ◽

Daniel C. Lu ◽

Yury Gerasimenko

Keyword(s):

Neural Networks ◽

Spinal Cord ◽

Sensory Input ◽

Sensorimotor Function ◽

Post Injury ◽

Spinal Circuitry ◽

Damage Repair ◽

Cord Injury ◽

Activity Dependent ◽

Physiological Systems

Sensorimotor function can improve for years, even after a spinal cord injury (SCI). We also know that an effective intervention that can improve motor function is re-engagement of the spinal neural networks through supraspinal control and that this regularity in re-engagement is fundamental to learning within the activated sensorimotor circuits. Several interventions, ranging from monoclonal antibodies against neurit outgrowth inhibitors to epidural electrical stimulation, have been developed allowing individuals with a SCI to re-engage sensorimotor circuits. These interventions enable spinal neural circuits to neuromodulate the level of excitability closer to a near motor threshold state. This is because of the built-in level of automaticity within the spinal circuits that then is translated into motor commands specified by the sensory input. Another increasingly apparent feature of the spinal circuitry is the highly integrated nature of multiple physiological systems linked to load bearing sensory input. Thus, it is clear that multiple physiological systems are highly responsive to activity-dependent interventions after a severe SCI and that this responsiveness can persist for years post-injury and be therapeutically modulated.

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