Toll like Receptor (TLR)-4 as a Regulator of Peripheral Endogenous Opioid-Mediated Analgesia in Inflammation

Sauer, Reine-Solange; Hackel, Dagmar; Morschel, Laura; Sahlbach, Henrike; Wang, Ying; Mousa, Shaaban A.; Roewer, Norbert; Brack, Alexander; Rittner, Heike L.

doi:10.1186/1744-8069-10-10

Cited by 55 publications

(47 citation statements)

References 57 publications

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“…There are, however, relatively few studies examining the effect of myeloid cell depletion in inflammatory pain, and these show contradictory results. One study showed that local depletion of Mø using clodronate liposomes did not alter pain behavior after intraplantar injection of CFA (56), whereas others have reported that systemic depletion of these cells using clodronate liposomes or an α-CCR2 antibody results in an unexpected increase in mechanical and thermal hypersensitivity after intraplantar injection of carrageenan (70) or CFA (71). The mechanisms suggested for the inferred antinociceptive effects for these cells was that they either secrete β-endorphins (71) or act in the dorsal root ganglia and spinal cord to produce antiinflammatory cytokines like IL-10 (70).…”

Section: Discussionmentioning

confidence: 99%

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

Ghasemlou

Chiu

Julien

et al. 2015

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

147

135

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Pain hypersensitivity at the site of inflammation as a result of chronic immune diseases, pathogenic infection, and tissue injury is a common medical condition. However, the specific contributions of the innate and adaptive immune system to the generation of pain during inflammation have not been systematically elucidated. We therefore set out to characterize the cellular and molecular immune response in two widely used preclinical models of inflammatory pain: (i) intraplantar injection of complete Freund's adjuvant (CFA) as a model of adjuvant-and pathogen-based inflammation and (ii) a plantar incisional wound as a model of tissue injury-based inflammation. Our findings reveal differences in temporal patterns of immune cell recruitment and activation states, cytokine production, and pain in these two models, with CFA causing a nonresolving granulomatous inflammatory response whereas tissue incision induced resolving immune and pain responses. These findings highlight the significant differences and potential clinical relevance of the incisional wound model compared with the CFA model. By using various cell-depletion strategies, we find that, whereas lymphocyte antigen 6 complex locus G (Ly)6G + CD11b + neutrophils and T-cell receptor (TCR) β + T cells do not contribute to the development of thermal or mechanical pain hypersensitivity in either model, proliferating CD11b + Ly6G − myeloid cells were necessary for mechanical hypersensitivity during incisional pain, and, to a lesser extent, CFA-induced inflammation. However, inflammatory (CCR2 + Ly6C hi ) monocytes were not responsible for these effects. The finding that a population of proliferating CD11b + Ly6G − myeloid cells contribute to mechanical inflammatory pain provides a potential cellular target for its treatment in wound inflammation.pain | inflammation | cytokines | monocytes | macrophages

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Section: Discussionmentioning

confidence: 99%

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

Ghasemlou

Chiu

Julien

et al. 2015

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

147

135

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“…Наприклад, ІЛ-1β може викликати експресію ФНП-α і ІЛ-6, тоді як ІЛ-18 стимулює про-дукцію ІЛ-17 [2]. Прозапальні цитокіни пригнічують функції гематоенцефалічного бар'єру, опосередкову-ють залучення гематогенних лейкоцитів у мозок та є причиною виникнення болю запального ґенезу [3][4][5][6].…”

Section: вступunclassified

“…Локально впливати на біль, зокрема запального характеру, здатні клітини моноцитар-но-макрофагальної системи завдяки наявності в них опіоїдних пептидів. При активації TLR4 моноцитів/ макрофагів, окрім прозапальних цитокінів, виникає вихід опіоїдних пептидів з останніх, що є одним із важливих механізмів антиноцицептивної системи [5]. Саме тому доцільно вивчити експресію TLR4 в плазмі як маркеру розвитку гіпералгезії в післяопе-раційному періоді.…”

Section: обґрунтування дослідженняunclassified

“…Вони продукуються клітинами мікроглії цен-тальної нервової системи та мають важливу роль в ґенезі патологічного болю і, можливо, гіпералгезії, особливо, як що причиною цього є пошкодження нервів, запалення тканин, що характерно для ран-нього післяопераційного періоду. Активація TLR-4 спричинює синаптичну пластичність, підтримує нейрозапалення, викликає аномальну нейронну ді-яльність, що є характерним для такого патологічного стану як гіпералгезія [1,2,5,7].…”

Section: обговорення результатів дослідженняunclassified

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Level of TOLL-like receptors (TLR-4) in plasma – marker of hyperalgesia in the early postoperative period

Дмитрієв¹,

Кобеляцький²

2015

ScienceRise

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“…This study has demonstrated that DYN 3-14 blocks LPS-induced TLR4 signalling in HEK-Blue™- This study highlights that TLR4 potentially regulates peripheral endogenous opioid-mediated analgesia in inflammation (56). Opioid agents such as morphine and fentanyl have been shown to inhibit TLR4 signalling through non-competitive binding with LPS (54).…”

Section: Dyn 3-14 Inhibits Lps-induced Tlr4 Activation In Hek-blue™-hmentioning

confidence: 69%

The immunomodulation of dynorphin 1-17 and its biotransformation fragments on inflammatory signalling pathways

Rahiman¹,

Sarah²

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Inflammation is a complex physiological process that involves host defense mechanisms in response to the intrusion of harmful external stimuli. Uncoordinated inflammatory responses, however, are the underlying pathophysiological cause of many chronic diseases. Inflammation is characterised by the burgeoning migration of leukocytes to the point of injury and subsequent release of pro-nociceptive mediators, generating inflammatory pain. Dynorphin 1-17 (DYN 1-17) is endogenously produced and released from leukocytes upon stimulation by local inflammatory factors in the inflamed area. This opioid peptide primarily binds to kappa-opioid receptor (KOR) to produce analgesia. Under inflammatory milieu, DYN 1-17 undergoes spontaneous degradation, yielding a variety of opioid and non-opioid fragments that may have significant implications in inflammation. The underlying cellular effects of these fragments remain unclear. This thesis seeks to explore potential mechanistic insights into selected major DYN 1-17 fragments, identified from a previous biotransformation study of DYN 1-17 in rodent inflamed tissue. This thesis examines the DYN 1-17 fragments modulation of intracellular signals associated with inflammation and thereby, gain an insight into novel therapeutic targets through exploring these endogenous mechanisms.Utilising THP-1 macrophages as an in vitro model of inflammation, this thesis begins with a semiquantitative assessment of nuclear factor-kappa B/p65 (NF-κB/p65) translocation, a major transcription factor that regulates genes responsible for immune and inflammatory responses. The findings presented in Chapter Three of this thesis demonstrated that DYN 1-17 and selected major fragments (DYN 1-6, 1-7, 1-9, 1-10, 1-11, 3-14, 6-12, 2-17 and 7-17) significantly attenuated NF-κB/p65 nuclear translocation induced by lipopolysaccharide (LPS), with the greatest reduction observed with DYN 1-7 at 10 nM. A selective KOR antagonist, ML-190, was used to examine KOR involvement in this inhibitory action. ML-190 significantly reversed the inhibition of NF-κB/p65 translocation produced by DYN 1-17, DYN 1-6, DYN 1-7 and DYN 1-9, but not DYN 1-10 and DYN 1-11.Cytokine production is linked as a downstream process to NF-κB activation; hence it is necessary to evaluate the ability of DYN 1-17 and selected biotransformation fragments in the modulation of IL-1β and TNF-α release in differentiated THP-1 cells, as presented in Chapter Four, to gain an insight into the effects on major pro-inflammatory cytokines. DYN 1-17 and the fragments, demonstrated differential modulatory effects on LPS-induced release of IL-1β and TNF-α. DYN 1-7 and DYN 1-6, inhibited and elevated the secretion of both cytokines, respectively, in a concentration-dependent manner (10 -11 to 10 -7 M). DYN 1-17, however, only inhibited IL-1β release from differentiated iii THP-1 cells and had no effect on TNF-α secretion. Intriguingly, DYN 3-14 at 10 -17 to 10 -11 M demonstrated significant inhibition on IL-1β release and paradoxically increased TNF-α lev...

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Toll like Receptor (TLR)-4 as a Regulator of Peripheral Endogenous Opioid-Mediated Analgesia in Inflammation

Cited by 55 publications

References 57 publications

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

Level of TOLL-like receptors (TLR-4) in plasma – marker of hyperalgesia in the early postoperative period

The immunomodulation of dynorphin 1-17 and its biotransformation fragments on inflammatory signalling pathways

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Toll like Receptor (TLR)-4 as a Regulator of Peripheral Endogenous Opioid-Mediated Analgesia in Inflammation

Cited by 55 publications

References 57 publications

CD11b+Ly6G−myeloid cells mediate mechanical inflammatory pain hypersensitivity

CD11b+Ly6G−myeloid cells mediate mechanical inflammatory pain hypersensitivity

Level of TOLL-like receptors (TLR-4) in plasma – marker of hyperalgesia in the early postoperative period

The immunomodulation of dynorphin 1-17 and its biotransformation fragments on inflammatory signalling pathways

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CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity