Small-molecule nociceptin receptor agonist ameliorates mast cell activation and pain in sickle mice

Vang, Derek; Paul, Jinny; Nguyen, Julia; Tran, Huy; Vincent, Lucile; Yasuda, Dennis; Zaveri, Nurulain T.; Gupta, Kalpna

doi:10.3324/haematol.2015.128736

Cited by 42 publications

(37 citation statements)

References 41 publications

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“…While we did not observe a difference between male and female control mice, the MGS score demonstrates a difference between male and female sickle mice upon cold exposure, which suggests that sensitivity to cold is gender biased. These results corroborate previous findings that mice and individuals with SCD show increased cold sensitivity [2, 5, 8, 9, 14, 16] Therefore, image analysis of body parameters along with facial expressions can be quantified for evaluating pain in mice.…”

Section: Disscussionsupporting

confidence: 90%

“…[5, 13] Control HbAA-BERK mice, Called “control” mice henceforth, express normal human hemoglobin A and are a progeny of the same breeders as sickle mice. Mice were phenotyped for the presence of human sickle hemoglobin (HbS) and normal human hemoglobin A, by isoelectric focusing as described and genotyped using Transnetyx services [14]. All animal procedures were performed in compliance with the University of Minnesota Institutional Animal Care and Use Committee.…”

Section: Methodsmentioning

confidence: 99%

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Quantification of pain in sickle mice using facial expressions and body measurements

Mittal

Gupta

Lamarre

et al. 2016

Blood Cells, Molecules, and Diseases

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Pain is a hallmark feature of sickle cell disease (SCD). Subjects typically quantify pain by themselves, which can be biased by other factors leading to overtreatment or under-treatment. Reliable and accurate quantification of pain, in real time, might enable to provide appropriate levels of analgesic treatment. The mouse grimace scale (MGS), a standardized behavioral coding system with high accuracy and reliability has been used to quantify varied types of pain. We hypothesized that addition of the objective parameters of body length and back curvature will strengthen the reproducibility of MGS. We examined MGS scores and body length and back curvature of transgenic BERK sickle and control mice following cold treatment or following treatment with analgesic cannabinoid CP55,940. We observed that sickle mice demonstrated decreased length and increased back curvature in response to cold. These observations correlate with changes in facial expression for the MGS score. CP55,940 treatment of sickle mice showed an increase in body length and a decrease in back curvature concordant with MGS scores indicative of an analgesic effect. Thus, body parameters combined with facial expressions may provide a quantifiable unbiased method for objective measure of pain in SCD.

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Section: Disscussionsupporting

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Quantification of pain in sickle mice using facial expressions and body measurements

Mittal

Gupta

Lamarre

et al. 2016

Blood Cells, Molecules, and Diseases

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show abstract

“…The endogenous ligand of NOP/OR is nociceptin/ orphanin FQ N/OFQ , and it is known to atenuate secretion of neuropeptides SP and CGRP from peripheral nerve endings [64] and from mast cells [6 ]. Our recent indings demonstrate that a small molecule agonist of NOP/OR, "T200, is able to decrease hyperalgesia in sickle mice by reducing inlammation and mast cell activation [66]. Continuous treatment of sickle mice with "T200 did not produce any tolerance, suggestive of a feasible opioid drug devoid of tolerance.…”

Section: Treatable Targets For Ameliorating Sickle Pain Opioid mentioning

confidence: 99%

Mechanisms of Pain in Sickle Cell Disease

Aich¹,

Beitz²,

Gupta³

2016

Sickle Cell Disease - Pain and Common Chronic Complications

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Pain is one of the most common features of sickle cell disease SCD lacking efective therapy. Pain in SCD is relatively more complicated than other conditions associated with pain requiring understanding of the pathobiology of pain speciic to SCD. The characterization of pain to deine the diverse modalities of nociception in SCD is currently under progress via human studies accompanied by transgenic mouse models of SCD. Sickle pathobiology characterized by oxidative stress, inlammation and vascular dysfunction contributes to both peripheral and central nociceptive sensitization via mast cell activation in the periphery, and reactive oxygen species and glial activation and endoplasmic reticulum stress in the spinal cord among other efectors. These efects are mediated via several cellular receptors, which can be targeted to produce positive therapeutic outcomes. In this chapter, we will discuss the present understanding of molecular mechanisms of SCD pain and outline the mechanism-based translational potential of novel actionable targets to treat SCD pain.Keywords: pain, sickle cell disease, neurogenic inlammation, substance P, mast cell . IntroductionPain is a hallmark feature of sickle cell disease SCD , which can start in infancy, leading to hospitalization, reduced survival and poor quality of life. Pain in SCD is unique because of unpredictable and recurrent episodes of acute pain due to vaso-occlusive crises VOC , in addition to chronic pain experienced by a majority of adult patients on a daily basis [1]. Treatment choices remain limited to opioids, which impose liabilities of their own including constipation, mast cell activation, fear of addiction and respiratory depression [2]. Moreover, signiicantly larger doses of opioids are required to treat pain in SCD as compared to other acute and chronic pain conditions [1]. Pain can be lifelong in SCD and may therefore inluence © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.cognitive function and lead to depression and anxiety, which can in turn promote the perception of pain [1].Treatment of chronic pain remains unsatisfactory overall, perhaps due to the diverse pathobiology in diferent diseases. Therefore, it is critical to understand the mechanisms speciic to the genesis of sickle pain to develop targeted therapies. Vascular dysfunction, inlammation, ischemia/reperfusion injury and oxidative stress in the wake of VOC can each evoke activation of the nociceptive nerve ibers leading to acute pain. On the other hand, con...

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“…These SCD mice have elevated plasma SP levels. Further treatment of these animals with a high-affinity small molecule (AT200), a nociceptin opioid receptor agonist, ameliorates mast cell activation and pain in this murine SCD model (Vang et al 2015). …”

mentioning

confidence: 99%

Substance P and sickle cell disease—a marker for pain and novel therapeutic approaches

Douglas

2016

Br J Haematol

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Small-molecule nociceptin receptor agonist ameliorates mast cell activation and pain in sickle mice

Cited by 42 publications

References 41 publications

Quantification of pain in sickle mice using facial expressions and body measurements

Quantification of pain in sickle mice using facial expressions and body measurements

Mechanisms of Pain in Sickle Cell Disease

Substance P and sickle cell disease—a marker for pain and novel therapeutic approaches

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