CONTRIBUTION OF INTERLEUKIN-1-BETA TO THE INFLAMMATION-INDUCED INCREASE IN NERVE GROWTH-FACTOR LEVELS AND INFLAMMATORY HYPERALGESIA
CONTRIBUTION OF INTERLEUKIN-1-BETA TO THE INFLAMMATION-INDUCED INCREASE IN NERVE GROWTH-FACTOR LEVELS AND INFLAMMATORY HYPERALGESIA
复制标题
DOI：
10.1111/j.1476-5381.1995.tb15035.x
复制
发表时间：
1995-08-01
影响因子：
7.3
通讯作者：
WOOLF, CJ
中科院分区：
文献类型：
--
作者：
SAFIEHGARABEDIAN, B;POOLE, S;WOOLF, CJ
1外周炎症与神经活性炎性细胞因子和生长因子的局部产生有关。这些可能通过直接或间接改变反应性初级感觉神经元的功能或化学表型而导致炎性疼痛和痛觉过敏。2为了研究这一点，通过足底注射完全弗氏佐剂（CFA）在成年大鼠中产生炎症。这导致白细胞介素-lp显著升高（IL-1 β）和神经生长因子（NGF）水平，CFA注射后48 h LA背根神经节中的P物质和降钙素基因相关肽（CGRP）。（地塞米松）和非甾体类消炎药对炎症患者的NGF和IL-1 β水平的影响;组织进行了研究，并与行为痛觉过敏和感觉神经元中神经肽表达的变化进行了比较。4全身性地塞米松（从注射CFA前一天开始每天120 μ g/kg）对炎性痛觉过敏没有影响。当每天给药3次时，机械敏感性降低，热敏感性降低程度较小。吲哚美辛2 mg/kg（-1）每日（i. p.）对痛觉过敏没有影响，需要每天4 mg kg（-1）的剂量才能显著降低机械和热超敏性。5地塞米松和吲哚美辛都能阻止CFA炎症产生的NGF增加，但仅在较高剂量水平下。地塞米松在较低和较高剂量方案下减少了IL-1 β的上调，而吲哚美辛仅在较高剂量下具有效果。6由CFA炎症产生的SP和CGRP水平的增加被地塞米松和吲哚美辛在较低和较高剂量方案下阻止。7足底注射IL-1 β（0.01、0.1和1 ng）产生短暂（6 h）热痛觉过敏和皮肤NGF水平升高，这可通过用人重组IL-1受体拮抗剂（IL-1 ra）（0.625 μ g，i. v.）预处理来防止。热痛觉过敏，但不是由足底IL-1 β（1 ng）产生的神经生长因子的升高，预防了多克隆的中和抗神经生长因子血清的管理。8 IL-1 ra显着减少CFA产生的机械痛觉过敏6小时后，管理以及CFA诱导的神经生长因子水平的升高。抗NGF预处理显著降低CFA诱导的机械和热痛觉过敏，而不降低IL-1 β的升高。（0.02，0.2和2 μ g）注射产生短暂的热和机械痛觉过敏，但不改变后爪皮肤中的IL-1 β水平。1 β有助于炎症期间NGF的上调，并且NGF在炎症性疼痛超敏反应的产生中发挥重要作用。
1 Peripheral inflammation is associated with the local production of neuroactive inflammatory cytokines and growth factors. These may contribute to inflammatory pain and hyperalgesia by directly or indirectly altering the function or chemical phenotype of responsive primary sensory neurones.2 To investigate this, inflammation was produced by the intraplantar injection of complete Freund's adjuvant (CFA) in adult rats. This resulted in a significant elevation in interleukin-lp (IL-1 beta) and nerve growth factor (NGF) levels in the inflamed tissue and of the peptides, substance P and calcitonin gene-related peptide (CGRP) in the LA dorsal root ganglion 48 h post CFA injection.3 The effects of a steroidal (dexamethasone) and a non-steroidal (indomethacin) anti-inflammatory drug on the levels of NGF and IL-1 beta in inflamed; tissue were investigated and compared with alterations in behavioural hyperalgesia and neuropeptide expression in sensory neurones.4 Systemic dexamethasone (120 mu g kg(-1) per day starting the day before the CFA injection) had no effect on the inflammatory hyperalgesia. When the dose was administered 3 times daily, a reduction in mechanical and to a lesser extent thermal sensitivity occurred. Indomethacin at 2 mg kg(-1) daily (i.p.) had no effect on the hyperalgesia and a dose of 4 mg kg(-1) daily was required to reduce significantly mechanical and thermal hypersensitivity.5 The increase in NGF produced by the CFA inflammation was prevented by both dexamethasone and indomethacin, but only at the higher dose levels. Dexamethasone at the lower and higher dose regimes diminished the upregulation of IL-1 beta whereas indomethacin had an effect only at the higher dose.6 The increase in SP and CGRP levels produced by the CFA inflammation was prevented by dexamethasone and indomethacin at the lower and higher dose regimes.7 Intraplantar injections of IL-1 beta (0.01, 0.1 and 1 ng) produced a brief (6 h) thermal hyperalgesia and an elevation in cutaneous NGF levels which was prevented by pretreatment with human recombinant IL-1 receptor antagonist (IL-1 ra) (0.625 mu g, i.v.). The thermal hyperalgesia but not the NGF elevation produced by intraplantar IL-1 beta (1 ng) was prevented by administration of a polyclonal neutralizing anti-NGF serum.8 IL-1 ra significantly reduced the mechanical hyperalgesia produced by CFA for 6 h after administration as well as the CFA-induced elevation in NGF levels. Anti-NGF pretreatment substantially reduced CFA-induced mechanical and thermal hyperalgesia without reducing the elevation in IL-1 beta.9 Intraplantar NGF (0.02, 0.2 and 2 mu g) injections produced a short lasting thermal and mechanical hyperalgesia but did not change IL-1 beta levels in the hindpaw skin.10 Our results demonstrate that IL-1 beta contributes to the upregulation of NGF during inflammation and that NGF has a major role in the production of inflammatory pain hypersensitivity.