β2- and β3-adrenergic receptors drive COMT-dependent pain by increasing production of nitric oxide and cytokines.
β2- and β3-adrenergic receptors drive COMT-dependent pain by increasing production of nitric oxide and cytokines.
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DOI：
10.1016/j.pain.2014.04.011
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发表时间：
2014-07
期刊：
影响因子：
7.4
通讯作者：
Nackley AG
中科院分区：
文献类型：
--
作者：
Hartung JE;Ciszek BP;Nackley AG
儿茶酚-O-甲基转移酶(COMT)是一种代谢儿茶酚胺的酶，其活性降低会导致人类和动物的疼痛。在此之前，我们已经证明β2-和β3-肾上腺素能受体(β2-和β3AR)共同介导了COMT依赖性疼痛的发生。在这里，我们研究了β2-和β3ARs下游分子在COMT活性降低的动物中驱动疼痛的作用。基于将它们在疼痛和β2和β3AR刺激下游合成中的作用联系起来的证据，我们假设一氧化氮(NO)和促炎细胞因子推动COMT依赖的疼痛。为了验证这一点，我们测定了接受COMT抑制剂OR486的大鼠在存在或不存在β2AR拮抗剂ICI118,551+β3AR拮抗剂SR59320A的情况下的血浆NO衍生物和细胞因子。我们还评估了一氧化氮合酶抑制剂L-NG-硝基精氨酸甲酯(L-NAME)和细胞因子中和抗体是否能阻断COMT依赖性疼痛的发展。结果表明，接受OR486的小鼠血清中NO衍生物、肿瘤坏死因子α、白介素1α、白介素6和趋化因子(C-C基序)配体2(CCL2)水平升高，且呈β2和β3AR依赖关系。此外，抑制一氧化氮合酶和中和天然免疫细胞因子肿瘤坏死因子α、白介素1β和白介素6可阻止依赖辅酶原的疼痛的发展。结果发现，NO对肿瘤坏死因子α、IL-1β、IL-6和CCL_2水平有影响，而对NO水平有影响。总之，这些结果表明，β-2和β3AR至少部分地通过增加NO和细胞因子参与了COMT依赖的疼痛。此外，他们确定β-2和β3ARs、NO和促炎细胞因子是治疗COMT生理异常的疼痛患者的潜在靶点。
Decreased activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, contributes to pain in humans and animals. Previously, we demonstrated that development of COMT-dependent pain is mediated by both β2- and β3-adrenergic receptors (β2-and β3ARs). Here, we investigated molecules downstream of β2-and β3ARs driving pain in animals with decreased COMT activity. Based on evidence linking their role in pain and synthesis downstream of β2- and β3AR stimulation, we hypothesized that nitric oxide (NO) and pro-inflammatory cytokines drive COMT-dependent pain. To test this, we measured plasma NO derivatives and cytokines in rats receiving the COMT inhibitor OR486 in the presence or absence of the β2AR antagonist ICI118,551 + β3AR antagonist SR59320A. We also assessed if the NO synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME) and cytokine neutralizing antibodies block the development of COMT-dependent pain. Results showed that animals receiving OR486 exhibited higher levels of NO derivatives, tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), interleukin-6 (IL-6), and chemokine (C-C motif) ligand 2 (CCL2) in a β2-and β3AR-dependent manner. Additionally, inhibition of NO synthases and neutralization of the innate immunity cytokines TNFα, IL-1β, and IL-6 blocked the development of COMT-dependent pain. Finally, we found that NO influences TNFα, IL-1β, IL-6 and CCL2 levels, while TNFα and IL-6 influence NO levels. Altogether, these results demonstrate that β2- and β3ARs contribute to COMT-dependent pain, at least partly, by increasing NO and cytokines. Furthermore, they identify β2- and β3ARs, NO, and pro-inflammatory cytokines as potential therapeutic targets for pain patients with abnormalities in COMT physiology.
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影响因子：
3.5
作者：
Diatchenko, L;Slade, GD;Maixner, W
通讯作者：
Maixner, W
DOI：
10.1523/jneurosci.3795-08.2008
发表时间：
2008-12-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Binshtok AM;Wang H;Zimmermann K;Amaya F;Vardeh D;Shi L;Brenner GJ;Ji RR;Bean BP;Woolf CJ;Samad TA
通讯作者：
Samad TA
DOI：
10.1073/pnas.0409225102
发表时间：
2005-02-01
影响因子：
11.1
作者：
Cunha, TM;Verri, WA;Ferreira, SH
通讯作者：
Ferreira, SH
影响因子：
4.8
作者：
Flach, Rachel J. Roth;Matevossian, Anouch;Czech, Michael P.
通讯作者：
Czech, Michael P.
影响因子：
3.3
作者：
Hodges, Gary J.;Kosiba, Wojciech A.;Johnson, John M.
通讯作者：
Johnson, John M.