Vortioxetine as an analgesic in preclinical inflammatory pain models: Mechanism of action

Abstract

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...

Catecholaminergic and Cholinergic Systems Mediate Beneficial Effect of Vortioxetine on Diabetes-Induced Neuropathic Pain

“…These findings pointed out that muscarinic receptors, as well as the α 2 -, β 2 - and D 2 /D 3 -catecholaminergic receptors, participate in the aforementioned effect of vortioxetine. The results of a previous study by Todorović and co-workers suggesting that the analgesic activity of vortioxetine against trigeminal, visceral and somatic inflammatory pain is at least partially mediated by the α 2 /β 1 -adrenergic and muscarinic cholinergic receptors support the findings of our mechanistic studies [ 11 ].…”

“…In this study, based on previous reports presenting the therapeutic potential of vortioxetine for acute [ 12 , 13 ], inflammatory [ 11 ] and neuropathic pain [ 7 , 14 ], the potential efficacy of this drug against diabetes-induced hyperalgesia and allodynia responses was investigated in rats. Further mechanistic studies were conducted in order to elucidate the promising contributions of the catecholaminergic and cholinergic systems to the antihyperalgesic and antiallodynic activities of vortioxetine.…”

“…Considering that the pharmacological action of vortioxetine is mediated by multiple neurotransmitter systems, it can be thought that this drug may have various therapeutic effects on the central nervous system. For example, a number of studies in the literature suggest that this drug may also be effective for treating both acute and chronic pain [ 7 , 11 , 12 , 13 , 14 ]. The beneficial effects of this drug have been shown in some neuropathic pain models, including reserpine-induced fibromyalgia [ 15 ], chronic constriction injury [ 16 ], chronic neuropathic orofacial pain [ 7 , 17 ] and oxaliplatin-induced neuropathy [ 18 ].…”

The Analgezic Effect of Vortioxetine on somatic and visceral Pain using the mouse models

“…Some researches proved the antinociceptive effects of carrageenan-induced paw inflammation in mice [42], but others noted the lack of influence of this antidepressant in the inflammatory neuropathic pain [39]. The antinociceptive properties of VRT in neuropathic pain may be due to the antagonism of 5-HT3 receptors and the modulation of the 5-HT7 receptors, as well as due to its anti-inflammatory activity with favorable effects on the decreasing in neuro-inflammation associated with these types of chronic hyperalgesia [39,43].…”

The N‐methyl‐D‐aspartate receptor antagonist ketamin exerts analgesic effects via modulation of the nitric oxide pathway

“…We hypothesized that ketamine-blockade of NMDA receptors exerts its analgesic effects via modulation of NO synthesis. We have hence used inhibitors of NOS, including L-Nitro-Arginine Methyl Ester (L-NAME) as the non-specific NOS inhibitor, aminoguanidine (AG) as inducible NOS (iNOS) inhibitor, and 7-Nitroinidazole (7-Ni) as the selective inhibitor of neuronal NOS (nNOS) in the current study to determine the role of nitric oxide pathway associated with NMDA blockade by ketamine, using routine pain assessment behavioral tests as well as western blot [15]; the latter owing to the fact that L-NAME [16] and aminoguanidine [17] cause reduction in the NOS mRNA as well. Furthermore, we have tested the effect of chronic ketamine administration, since it is previously demonstrated that some effects may appear in chronic doses, which were acutely inactive [18].…”