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 1B/1D serotonergic (GR 127935), α 1 -adrenergic (prazosin), α 2 -adrenergic (yohimbine), β 1adrenergic (metoprolol), muscarinic (atropine), α 7 nicotinic (methyllycaconitine), CB 1 /CB 2 cannabinoid (AM251 and AM630), and adenosine A 1 (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 1B/1D serotonergic, α 2 /β 1 -adrenergic, muscarinic and nicotinic cholinergic, CB 1 /CB 2 cannabinoid, and adenosine A 1 receptors. These findings contribute to better understanding of the analgesic effect of vortioxetine and suggest its potential usefulness for inflammatory pain treatment. K E Y W O R D Spain-modulating receptors, somatic pain, trigeminal pain, visceral pain, vortioxetine ABBREVIATIONS: 5-HT, 5-hydroxytryptamine; %AA, percentage of antihyperalgesic activity; %AN, percentage of antinociceptive activity; ACh, acetylcholine; AM251, 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide; AM630, 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone; ANOVA, analysis of variance; DPCPX, 1,3-dipropyl-8-cyclopentylxanthine; ED 50 , dose that produces an antinociceptive/ antihyperalgesic effect of 50%; GABA, gamma-aminobutyric acid; GR 127935, N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2 0 -methyl-4 0 -(5-methyl-1,2,4-oxadiazol-3-yl)-1,1 0 -biphenyl-4-carboxamide hydrochloride; i.p., intraperitoneally; i.pl., intraplantarly; NA, noradrenaline; p.o., perorally; RM ANOVA, repeated measures analysis of variance; s.c., subcutaneously; SEM, standard error of mean; SERT, serotonin transporter; VAC, ventral orbital...
Thromboembolic events are the leading cause of morbidity and mortality worldwide. From the second half of the 20th century, vitamin K antagonists (VKAs), warfarin and acenocoumarol, were the only anticoagulants taken orally. The major reform in anticoagulation therapy was made by the advent of direct oral anticoagulants (DOACs), about 10 years ago. Direct thrombin inhibitor (dabigatran) and direct inhibitors of factor Xa (rivaroxaban, apixaban, edoxaban, and betrixaban) have demonstrated favorable risk/benefit ratio. Compared to warfarin, DOACs are associated with a predictable pharmacokinetic profile, lower severe bleeding complications, particularly intracranial hemorrhages, and minimal drug interactions. Moreover, DOACs achieve a rapid onset of action and have shown comparable efficacy with warfarin and low molecular weight heparin (LMWH) in clinical trials. As a result, DOACs are now replacing VKAs and LMWH for many indications including stroke and systemic embolism prevention in nonvalvular atrial fibrillation, prevention, and treatment of venous thromboembolism and thromboprophylaxis following total knee/hip replacement surgery. In addition, rivaroxaban (in combination with aspirin alone or aspirin and clopidogrel) is used in the prevention of atherothrombotic events following acute coronary syndrome with elevated cardiac biomarkers. In case of severe bleeding complications under DOACs treatment, antidotes are available; idarucizumab for dabigatran reversal and andexanet alfa for rivaroxaban and apixaban.
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