Department of Pharmacology, University of Belgrade - Faculty of Pharmacy, Belgrade, Serbia.
Fundam Clin Pharmacol. 2022 Apr;36(2):237-249. doi: 10.1111/fcp.12737. Epub 2021 Dec 9.
Vortioxetine is a novel atypical antidepressant with multimodal activity that has recently demonstrated efficacy against neuropathic pain. There is no published data about its analgesic properties in models characterized by peripheral inflammation and consequent pain pathway sensitization, nor data on its mechanism of antinociceptive action. This study aimed to investigate vortioxetine's antinociceptive/antihyperalgesic effects in trigeminal, visceral, and somatic inflammatory pain models, and provide evidence on its mechanism of action in the modulation of trigeminal nociception. Vortioxetine's effects on the nociceptive behavior in orofacial formalin test (OFT) and acetic acid-writhing test in mice and on mechanical hyperalgesia in carrageenan-induced paw inflammation in rats were examined following peroral single administration. The involvement of serotonergic/adrenergic/cholinergic/cannabinoid/adenosine receptors was evaluated in OFT by intraperitoneally treating mice with an appropriate antagonist immediately after vortioxetine application. We used antagonists of 5-HT serotonergic (GR 127935), α -adrenergic (prazosin), α -adrenergic (yohimbine), β -adrenergic (metoprolol), muscarinic (atropine), α nicotinic (methyllycaconitine), CB /CB cannabinoid (AM251 and AM630), and adenosine A (DPCPX) receptors. Vortioxetine dose-dependently reduced pain behavior in OFT and acetic acid writhing test, as well as inflammatory hyperalgesia in paw pressure test. All examined antagonists except prazosin dose-dependently inhibited vortioxetine's antinociceptive effects. In conclusion, vortioxetine exerted analgesic efficacy in trigeminal, visceral, and somatic inflammatory pain. The effect is at least in part mediated by 5-HT serotonergic, α /β -adrenergic, muscarinic and nicotinic cholinergic, CB /CB cannabinoid, and adenosine A receptors. These findings contribute to better understanding of the analgesic effect of vortioxetine and suggest its potential usefulness for inflammatory pain treatment.
文拉法辛是一种新型的具有多模式活性的非典型抗抑郁药，最近已证明其对神经性疼痛有效。目前还没有关于其在以周围炎症和随之而来的疼痛通路敏化为特征的模型中的镇痛特性的发表数据，也没有关于其镇痛作用机制的数据。本研究旨在研究文拉法辛在三叉神经、内脏和躯体炎症性疼痛模型中的镇痛/抗痛觉过敏作用，并提供其在调节三叉神经痛觉中的作用机制的证据。文拉法辛经口单次给药后，观察其对小鼠口腔福尔马林试验（OFT）和醋酸扭体试验以及大鼠角叉菜胶诱导的爪炎症性机械性痛觉过敏的镇痛/抗痛觉过敏作用。通过在文拉法辛应用后立即腹膜内给予适当的拮抗剂，评估 OFT 中文拉法辛对 5-羟色胺能/肾上腺素能/胆碱能/大麻素/腺苷能受体的影响。我们使用 5-羟色胺能（GR 127935）、α -肾上腺素能（普萘洛尔）、α -肾上腺素能（育亨宾）、β -肾上腺素能（美托洛尔）、毒蕈碱（阿托品）、α 烟碱（甲基藜芦碱）、CB / CB 大麻素（AM251 和 AM630）和腺苷 A（DPCPX）受体的拮抗剂。文拉法辛呈剂量依赖性地减少 OFT 和醋酸扭体试验中的疼痛行为以及爪压力试验中的炎症性痛觉过敏。除普萘洛尔外，所有研究的拮抗剂均呈剂量依赖性地抑制文拉法辛的镇痛作用。总之，文拉法辛在三叉神经、内脏和躯体炎症性疼痛中表现出镇痛作用。这种作用至少部分是由 5-羟色胺能、α /β -肾上腺素能、毒蕈碱和烟碱胆碱能、CB / CB 大麻素和腺苷 A 受体介导的。这些发现有助于更好地理解文拉法辛的镇痛作用，并表明其对炎症性疼痛治疗的潜在用途。
