Persistent Catechol-O-methyltransferase-dependent Pain Is Initiated by Peripheral β-Adrenergic Receptors.
Persistent Catechol-O-methyltransferase-dependent Pain Is Initiated by Peripheral β-Adrenergic Receptors.
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DOI：
10.1097/aln.0000000000001070
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发表时间：
2016-05
期刊：
影响因子：
8.8
通讯作者：
Nackley AG
中科院分区：
文献类型：
--
作者：
Ciszek BP;O'Buckley SC;Nackley AG
肾上腺切除的大鼠或接受β受体拮抗剂外周注射的完整大鼠在持续的COMT抑制后没有出现疼痛，这表明外周肾上腺素能对COMT依赖的疼痛起作用。慢性疼痛障碍患者的儿茶酚胺水平升高，而代谢儿茶酚胺的酶-儿茶酚-O-甲基转移酶(COMT)活性降低。与临床观察一致，我们的实验室发现，在啮齿类动物中，COMT的急性药物抑制会产生疼痛。此外，我们还发现β2-和β3-肾上腺素能受体(ARs)介导了急性COMT依赖性疼痛的发生。然而，β2-和β3AR的不同群体在与儿茶酚胺信号异常相关的持续性疼痛的发生中的作用还需要进一步的研究。在这里，我们试图确定外周、脊髓和中枢β-2和β3AR在持续性COMT依赖性疼痛中的作用。具体地说，我们植入了渗透泵，以实现COMT抑制剂OR486在2周内的持续全身给药。在植入泵之前和之后每隔一天评估一次对机械和热刺激的行为反应。作用部位在接受持续OR486的肾上腺切除大鼠或接受持续βAR拮抗剂的完整大鼠的周围、脊髓或中央与持续OR486一起评估。我们发现，接受持续OR486的雄性和雌性大鼠在整个2周的时间里都表现出机械性痛觉过敏、机械性痛觉过敏和热痛觉过敏。相比之下，肾上腺切除的大鼠没有出现COMT依赖的疼痛。此外，非选择性β-AR拮抗剂心得安、β-2AR拮抗剂ICI118,511或β-3AR拮抗剂SR59230A的外周给药(而不是脊髓或中枢)可阻断COMT依赖性疼痛的发展。这些结果表明，外周肾上腺素能输入对于持续性COMT依赖型疼痛的发展是必要的，外周作用的βAR拮抗剂可能使慢性疼痛障碍患者受益。
Adrenalectomized rats or intact rats receiving peripheral administration of β-adrenergic receptor antagonists do not develop pain following sustained COMT inhibition, suggesting a peripheral adrenergic site of action for COMT-dependent pain. Patients with chronic pain disorders exhibit increased levels of catecholamines alongside diminished activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. Consistent with clinical observations, our lab found that acute pharmacologic inhibition of COMT in rodents produces pain. Furthermore, we found that the development of acute COMT-dependent pain is mediated by β2-and β3-adrenergic receptors (ARs). However, the contribution of distinct populations of β2- and β3ARs to the development of persistent pain linked to abnormalities in catecholamine signaling requires further investigation. Here, we sought to determine the contribution of peripheral, spinal, and central β2- and β3ARs to persistent COMT-dependent pain. Specifically, we implanted osmotic pumps to achieve sustained systemic delivery of the COMT inhibitor OR486 over 2-weeks. Behavioral responses to mechanical and thermal stimuli were evaluated prior to and every other day following pump implantation. Site of action was evaluated in adrenalectomized rats receiving sustained OR486 or in intact rats receiving sustained βAR antagonists peripherally, spinally or centrally alongside sustained OR486. We found that male and female rats receiving sustained OR486 exhibited mechanical allodynia, mechanical hyperalgesia and thermal hyperalgesia that lasted throughout the 2-week period. In contrast, adrenalectomized rats failed to develop COMT-dependent pain. Furthermore, peripheral, but not spinal or central, administration of the non-selective βAR antagonist propranolol, β2AR antagonist ICI-118,511 or β3AR antagonist SR59230A blocked the development of COMT-dependent pain. These results demonstrate that peripheral adrenergic input is necessary for the development of persistent COMT-dependent pain, and that peripherally-acting βAR antagonists may benefit patients with chronic pain disorders.