| 1. |
- Carlsson-Jonsson, Anna, et al.
(författare)
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N-terminal truncations of substance P1-7 amide affect its action on spinal cord injury-induced mechanical allodynia in rats
- 2014
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 738, s. 319-325
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Tidskriftsartikel (refereegranskat)abstract
- Central neuropathic pain can arise from injury of the spinal cord and can become chronic. Treatment is difficult and, because complete pain relief is currently very hard to achieve, there is a need for new, more effective treatment options. In this study we used an animal model of spinal cord injury to evaluate the potency of a bioactive fragment of substance P (SP), i.e. SP1-7, in alleviating signs of allodynia and acute pain. SP1-7 is known from earlier studies to possess antinociceptive properties. We also studied the effects of intraperitoneal injection of an amidated analog of this heptapeptide and of its truncated analogs, all of which had high affinity to the SP1-7 binding site, to evaluate the importance of the removed amino acids for the bioclistribution and stability of the peptides. Most of the examined compounds alleviated mechanical alloclynia without any signs of sedation or motor impairment in the rats. In contrast, the response threshold to acute nociceptive stimulation was not affected by arty of the compounds tested. Most of the amino acids in the heptapepticle structure were essential for retaining the biological effect after peripheral injection. These observations suggest that the heptapepticle and its N-Lerminal truncated hexa- and pentapeptide analogs could be of interest for further development of analgesics in the management of mechanical allodynia.
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| 2. |
- Dondalska, Aleksandra, et al.
(författare)
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Amelioration of Compound 48/80-Mediated Itch and LL-37-Induced Inflammation by a Single-Stranded Oligonucleotide
- 2020
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Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Numerous inflammatory skin disorders display a high prevalence of itch. The Mas-related G protein coupled receptor X2 (MRGPRX2) has been shown to modulate itch by inducing non-IgE-mediated mast cell degranulation and the release of endogenous inducers of pruritus. Various substances collectively known as basic secretagogues, which include inflammatory peptides and certain drugs, can trigger MRGPRX2 and thereby induce pseudo-allergic reactions characterized by histamine and protease release as well as inflammation. Here, we investigated the capacity of an immunomodulatory single-stranded oligonucleotide (ssON) to modulate IgE-independent mast cell degranulation and, more specifically, its ability to inhibit the basic secretagogues compound 48/80 (C48/80)-and LL-37in vitroandin vivo. We examined the effect of ssON on MRGPRX2 activationin vitroby measuring degranulation in a human mast cell line (LAD2) and calcium influx in MRGPRX2-transfected HEK293 cells. To determine the effect of ssON on itch, we performed behavioral studies in established mouse models and collected skin biopsies for histological analysis. Additionally, with the use of a rosacea mouse model and RT-qPCR, we investigated the effect on ssON on LL-37-induced inflammation. We reveal that both mast cell degranulation and calcium influx in MRGPRX2 transfected HEK293 cells, induced by the antimicrobial peptide LL-37 and the basic secretagogue C48/80, are effectively inhibited by ssON in a dose-dependent manner. Further, ssON demonstrates a capability to inhibit LL-37 and C48/80 activationin vivoin two mouse models. We show that intradermal injection of ssON in mice is able to block itch induced via C48/80 in a dose-dependent manner. Histological staining revealed that ssON inhibits acute mast cell degranulation in murine skin treated with C48/80. Lastly, we show that ssON treatment ameliorates LL-37-induced inflammation in a rosacea mouse model. Since there is a need for new therapeutics targeting non-IgE-mediated activation of mast cells, ssON could be used as a prospective drug candidate to resolve itch and inflammation in certain dermatoses.
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| 3. |
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| 4. |
- Gao, Tianle
(författare)
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Experimental studies on the mechanisms and treatments of chronic pain
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic pain is a major concern for physical and mental health of a large patient population today while casting a significant economical burden on society. Work presented in this thesis deal with aspects of mechanisms and treatments of chronic pain using experimental models. A common characteristic for many chronic pain conditions, particularly those after nerve injury, is hypersensitivity to cold stimulation. In the first part of the thesis, I presented a new method using a Peltier thermode to examine the responses of rats to quantitative thermal stimulation (heating and cooling). Using this method with temperature as end points, I showed that we can reliably detect cold hypersensitivity in spinally injured rats as well as study quantitatively the effects of analgesics again cold pain. Sinomenine is a morphinan derivative alkaloid originally isolated from the root of the climbing plant Sinomenium Acutum that is native to Japan and China. The root of Sinomenium Acutum has long been used in East Asia as a remedy for disease conditions similar to rheumatism and sinomenine is currently used in China as an anti-rheumatic agent. In the second part of the thesis, we characterized the analgesic effect of sinomenine in a variety of experimental pain models. We showed that while sinomenine has modest effects on acute pain in normal rats, it produces marked analgesic effects in a wide-spectrum of models, including neuropathic pain in rats and mice after injury to the peripheral and central nervous system, acute inflammatory pain by carrageenan in mice as well as arthritic pain in mice using the collagen antibody-induced arthritis model (CAIA). We further showed that under chronic administration, sinomenine maintained its analgesic effect in neuropathic and arthritic pain models without producing tolerance or dependence. Our results thus suggested that sinomenine may be considered as a novel analgesic in treating neuropathic and arthritic pain. One of the main clinical features of rheumatoid arthritis (RA) is sex difference in its prevalence and symptoms, including pain. The underlying mechanisms of sex differences in RA are still largely unknown. In the last part of the thesis, we studied sex differences in the development arthritis and pain-like behaviors in mice using the CAIA model. We observed a significant sex difference (females > males) in the development of joint inflammation and localized mechanical allodynia in the paws after CAIA in CBA strain of mice. Similarly, female CAIA mice also developed more persistent spread mechanical allodynia in their neck and flank areas. Following CAIA, the greater mechanical hypersensitivity in females was correlated to a higher expression of ionized calcium-binding adapter molecule 1, but lower expressions of activating transcription factor 3 and galanin, in dorsal root ganglion (DRG) compared with males. We conclude that sex differences in the CAIA model in CBA mice are similar to the clinical condition and sex dependent phenotypic changes in the DRG may be keys for the sex differences in RA and pain.
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| 5. |
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| 6. |
- Gao, Tianle, et al.
(författare)
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The Neuropeptide Y System Regulates Both Mechanical and Histaminergic Itch
- 2018
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Ingår i: Journal of Investigative Dermatology. - : ELSEVIER SCIENCE INC. - 0022-202X .- 1523-1747. ; 138:11, s. 2405-2411
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Tidskriftsartikel (refereegranskat)abstract
- Itch is a somatosensory modality that serves to alert an organism to harmful elements removable by scratching, such as parasites and chemical irritants. Recently, ablation or silencing of neuropeptide Y (NPY)-expressing spinal interneurons was reported to selectively enhance mechanical itch, whereas chemical itch was unaffected. We examined the effect of activating the NPY/Y-1 receptor system on scratch behavior in mice. We found that intrathecal administration of the Y-1 agonist [Leu(31), Pro(34)]-NPY (LP-NPY) attenuated itch behavior induced by application of 0.07 g von Frey filament in the nape of the neck compared with saline treatment, indicating that activation of the spinal NPY/Y-1 system dampens mechanical itch. However, intrathecal administration of LP-NPY also attenuated chemically induced scratching provoked by intradermal application of histamine or the mast cell degranulator 48/80 (histaminergic itch), and the latter effect could be reversed by administration of the Y-1 antagonist BIBO3304. Intrathecal application of the native nonselective agonist NPY also attenuated histamine or 48/80-induced scratching. Our analyses emphasize the importance of including additional quantitative parameters to characterize the full spectrum of itch behavior and show that the NPY/Y-1 system dampens both mechanically and chemically induced scratching and hence is shared by the two submodalities of itch.
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| 7. |
- Li, Lili, et al.
(författare)
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Heparanase overexpression reduces carrageenan-induced mechanical and cold hypersensitivity in mice
- 2012
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 511:1, s. 4-7
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Tidskriftsartikel (refereegranskat)abstract
- Heparanase controls the structure and functions of extracellular matrix (ECM) by degrading heparan sulfate proteoglycans. Heparanase is involved in inflammatory process through modulating the functions of inflammatory cytokines. The present study aimed to find out whether overexpression of heparanase in mice affects carrageenan-induced localized inflammation and inflammatory hyperalgesia. Without challenge, the heparanase overexpression did not significantly affect the mice in response to mechanical, cold and heat stimulation. Unilateral subcutaneous administration of carrageenan produced hypersensitivity to mechanical and cold in both wildtype and the heparanase overexpression (Hpa-tg) mice 24h after treatment. In comparison to wildtype animals, the Hpa-tg mice showed significantly reduced mechanical and cold hypersensitivity. This may, at least partially, due to the reduced mast cell infiltration at the site of inflammation in Hpa-tg mice. These data support a role for heparanase that reduces localized inflammation and inflammatory hyperalgesia in mice.
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| 8. |
- Ma, Haisha, et al.
(författare)
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The Neuropeptide Y Y-2 Receptor Is Coexpressed with Nppb in Primary Afferent Neurons and Y-2 Activation Reduces Histaminergic and IL-31-Induced Itch
- 2020
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Ingår i: Journal of Pharmacology and Experimental Therapeutics. - : AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS. - 0022-3565 .- 1521-0103. ; 372:1, s. 73-82
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Tidskriftsartikel (refereegranskat)abstract
- Itch stimuli are detected by specialized primary afferents that convey the signal to the spinal cord, but how itch transmission is regulated is still not completely known. Here, we investigated the roles of the neuropeptide Y (NPY)/Y-2 receptor system on scratch behavior. The inhibitory Y-2 receptor is expressed on mouse primary afferents, and intrathecal administration of the Y-2 agonist peptide YY (PYY)(3-36) reduced scratch episode frequency and duration induced by compound 48/80, an effect that could be reversed by intrathecal preadministration of the Y-2 antagonist BIIE0246. Also, scratch episode duration induced by histamine could be reduced by PYY3-36. In contrast, scratch behavior induced by alpha-methyl-5HT, protease-activated receptor-2-activating peptide SLIGRL, chloroquine, topical dust mite extract, or mechanical itch induced by von Frey filaments was unaffected by stimulation of Y2. Primary afferent neurons expressing the Npy2r gene were found to coexpress itch-associated markers such as natriuretic peptide precursor b, oncostatin M receptor, and interleukin (IL) 31 receptor A. Accordingly, intrathecal PYY3-36 reduced the scratch behavior induced by IL-31. Our findings imply that the NPY/Y-2 system reduces histaminergic and IL-31-associated itch through presynaptic inhibition of a subpopulation of itch-associated primary afferents. SIGNIFICANCE STATEMENT The spinal neuropeptide Y system dampens scratching behavior induced by histaminergic compounds and interleukin 31, a cytokine involved in atopic dermatitis, through interactions with the Y-2 receptor. The Y-2 receptor is expressed by primary afferent neurons that are rich in itch-associated neurotransmitters and receptors such as somatostatin, natriuretic peptide precursor b, and interleukin 31 receptors.
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