Mycobacteria attenuate nociceptive responses by formyl peptide receptor triggered opioid peptide release from neutrophils.
Mycobacteria attenuate nociceptive responses by formyl peptide receptor triggered opioid peptide release from neutrophils.
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DOI：
10.1371/journal.ppat.1000362
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发表时间：
2009-04
期刊：
影响因子：
6.7
通讯作者：
Brack A
中科院分区：
文献类型：
--
作者：
Rittner HL;Hackel D;Voigt P;Mousa S;Stolz A;Labuz D;Schäfer M;Schaefer M;Stein C;Brack A
在炎症中，疼痛由促痛介质和镇痛介质的平衡调节。镇痛介质包括阿片肽，由炎症部位的中性粒细胞分泌，导致外周感觉神经元上的阿片受体激活。在人类中，局部阿片类药物和阿片肽可显着下调术后疼痛和关节炎疼痛。在大鼠中，通过足底内注射热灭活的丁酸分枝杆菌（完全弗氏佐剂的成分）来诱导炎性疼痛。我们假设分枝杆菌衍生的甲酰肽受体（FPR）和/或Toll样受体（TLR）激动剂可以激活中性粒细胞，导致阿片肽释放并抑制炎性疼痛。在完全弗氏佐剂诱导的炎症中，对爪子的热和机械伤害感受阈值进行了量化（分别为 Hargreaves 和 Randall-Selitto 方法）。全身中性粒细胞耗竭以及局部注射阿片受体拮抗剂或抗阿片肽（即甲硫氨酸脑啡肽、β-内啡肽）抗体后，停药时间缩短，表明疼痛增加。在体外，通过放射免疫测定法测量人和大鼠中性粒细胞中阿片肽的释放。甲硫氨酸脑啡肽的释放是由丁酸分枝杆菌和甲酰肽触发的，但不是由 TLR-2 或 TLR-4 激动剂触发的。通过 FURA 负载和钙成像测定，丁酸分枝杆菌诱导细胞内钙升高。阿片肽的释放被细胞内钙螯合以及磷酸肌醇-3-激酶抑制所阻断。 FPR 拮抗剂 Boc-FLFLF 和环孢菌素 H 在体外减少阿片肽释放，在体内增加炎症疼痛，而 TLR 2/4 似乎不参与其中。总之，分枝杆菌激活中性粒细胞上的 FPR，导致中性粒细胞强效分泌阿片肽并减少炎性疼痛。未来的治疗策略可能旨在选择性 FPR 激动剂以增强内源性镇痛。周围组织的炎症可由细菌引起，并且常常伴有疼痛。疼痛的严重程度取决于增强（促痛）介质和减少（镇痛）介质的平衡。局部内源性疼痛控制涉及炎症部位免疫细胞释放阿片肽。这些阿片肽与周围神经上的阿片受体结合并抑制伤害性冲动的传递。我们假设细菌可以直接刺激免疫细胞释放阿片肽，从而减轻疼痛。在大鼠模型中，给爪子接种热灭活的丁酸分枝杆菌会导致局部炎症和疼痛反应。免疫细胞（即中性粒细胞）耗竭、局部注射抗阿片肽抗体或阿片受体拮抗剂后，伤害感受阈值进一步降低（即疼痛增强）。免疫细胞通过 Toll 样和/或甲酰基肽受体识别细菌。先前的研究表明，分枝杆菌通过 toll 样受体 2 和 -4 增强伤害性反应。我们现在证明分枝杆菌还能激活中性粒细胞上的甲酰肽受体，导致阿片肽释放并抑制此类反应。由于细菌可以同时诱导促痛介质和镇痛介质的产生，因此我们的结果可能进一步解释了细菌感染后个体患者之间疼痛的差异。
In inflammation, pain is regulated by a balance of pro- and analgesic mediators. Analgesic mediators include opioid peptides which are secreted by neutrophils at the site of inflammation, leading to activation of opioid receptors on peripheral sensory neurons. In humans, local opioids and opioid peptides significantly downregulate postoperative as well as arthritic pain. In rats, inflammatory pain is induced by intraplantar injection of heat inactivated Mycobacterium butyricum, a component of complete Freund's adjuvant. We hypothesized that mycobacterially derived formyl peptide receptor (FPR) and/or toll like receptor (TLR) agonists could activate neutrophils, leading to opioid peptide release and inhibition of inflammatory pain. In complete Freund's adjuvant-induced inflammation, thermal and mechanical nociceptive thresholds of the paw were quantified (Hargreaves and Randall-Selitto methods, respectively). Withdrawal time to heat was decreased following systemic neutrophil depletion as well as local injection of opioid receptor antagonists or anti-opioid peptide (i.e. Met-enkephalin, β-endorphin) antibodies indicating an increase in pain. In vitro, opioid peptide release from human and rat neutrophils was measured by radioimmunoassay. Met-enkephalin release was triggered by Mycobacterium butyricum and formyl peptides but not by TLR-2 or TLR-4 agonists. Mycobacterium butyricum induced a rise in intracellular calcium as determined by FURA loading and calcium imaging. Opioid peptide release was blocked by intracellular calcium chelation as well as phosphoinositol-3-kinase inhibition. The FPR antagonists Boc-FLFLF and cyclosporine H reduced opioid peptide release in vitro and increased inflammatory pain in vivo while TLR 2/4 did not appear to be involved. In summary, mycobacteria activate FPR on neutrophils, resulting in tonic secretion of opioid peptides from neutrophils and in a decrease in inflammatory pain. Future therapeutic strategies may aim at selective FPR agonists to boost endogenous analgesia. Inflammation of peripheral tissue can be caused by bacteria and is frequently accompanied by pain. Pain severity depends on the balance of enhancing (proalgesic) and decreasing (analgesic) mediators. Local endogenous pain control involves the release of opioid peptides from immune cells at the site of inflammation. These opioid peptides bind to opioid receptors on peripheral nerves and inhibit transmission of nociceptive impulses. We hypothesized that bacteria can directly stimulate immune cells to release opioid peptides and thereby decrease pain. In a rat model, inoculation of the paw with heat-inactivated Mycobacterium butyricum led to local inflammation and pain responses. Nociceptive thresholds were further decreased (i.e. pain was enhanced) following immune cell (i.e. neutrophil) depletion, local injection of anti-opioid peptide antibodies or opioid receptor antagonists. Immune cells recognize bacteria by toll-like and/or formyl peptide receptors. Previous research indicated that mycobacteria enhance nociceptive responses via toll like receptors-2 and -4. We now demonstrate that mycobacteria also activate formyl peptide receptors on neutrophils leading to opioid peptide release and the inhibition of such responses. Since bacteria can simultaneously induce the generation of pro- and analgesic mediators, our results might be a further explanation for differences in pain between individual patients following bacterial infections.
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影响因子：
--
作者：
Itou, Takuya;Collins, L. Vincent;Karlsson, Anna
通讯作者：
Karlsson, Anna
影响因子：
4.4
作者：
He, R;Tan, L;Ye, RD
通讯作者：
Ye, RD
DOI：
10.1084/jem.193.10.1213
发表时间：
2001-05-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chun T;Serbina NV;Nolt D;Wang B;Chiu NM;Flynn JL;Wang CR
通讯作者：
Wang CR
DOI：
10.1073/pnas.0711891105
发表时间：
2008-02-12
影响因子：
11.1
作者：
Amaral, F. A.;Sachs, D.;Teixeira, M. M.
通讯作者：
Teixeira, M. M.
影响因子：
3.2
作者：
Gripentrog, Jeannie M.;Mills, John S.;Saari, George J.;Miettinen, Heini M.
通讯作者：
Miettinen, Heini M.