Abstract
Metformin, a well-known antidiabetic drug, has been shown to possess analgesic properties in inflammatory pain models, but the mechanisms of its antinociceptive effects are not completely understood. We aimed to examine the involvement of serotonergic mechanisms in metformin-induced antinociception in a model of inflammatory pain, using the formalin test in mice. Firstly, we examined the antinociceptive effects of intraperitoneally administered metformin in the first and second phase of the test. Then, the involvement of serotonergic receptors was evaluated by intraperitoneally pretreating mice with a 5-HT1B/1D (GR127935) or 5-HT1A receptor antagonist (WAY100635). Further, we examined the effect of metformin after depletion of endogenous serotonin with a tryptophan-hydroxylase inhibitor (PCPA; applied intraperitoneally for 4 days). Additionally, to avoid misinterpretation of motor incoordination, we performed the rotarod test with the highest tested metformin dose. Metformin (50-200 mg/kg) produced significant and dose-dependent antinociceptive effects (17-81%) in the second (inflammatory) phase of the test. Pretreatment with antagonists significantly reduced the antinociceptive effect of metformin (150 mg/kg). GR127935 inhibited the effects of metformin by 67% (1 mg/kg) and 100% (3 mg/kg), whereas the inhibitory effects for WAY100635 were 19% (1 mg/kg) and 68% (3 mg/kg). Depletion of serotonin with PCPA (100 mg/kg/day) significantly reduced the antinociceptive effects of higher metformin doses (150 and 200 mg/kg). Metformin (200 mg/kg) had no influence on rotarod performance. This study demonstrates that 5-HT1B/1D and 5-HT1A receptors are involved in metformin’s antinociceptive effects and that metformin’s action on these receptors seems to be indirect (mediated by endogenous serotonin released by metformin).
References
Pecikoza UB, Tomić MA, Micov AM, Stepanović-Petrović RM. Metformin Synergizes With Conventional and Adjuvant Analgesic Drugs to Reduce Inflammatory Hyperalgesia in Rats. Anesth Analg. 2017;124(4):1317-1329.
Russe OQ, Möser CV, Kynast KL, King TS, Stephan H, Geisslinger G, Niederberger E. Activation of the AMP-activated protein kinase reduces inflammatory nociception. J Pain. 2013;14(11):1330-40.
- Autori zadržavaju autorska prava i pružaju časopisu pravo prvog objavljivanja rada i licenciraju ga "Creative Commons Attribution licencom" koja omogućava drugima da dele rad, uz uslov navođenja autorstva i izvornog objavljivanja u ovom časopisu.
- Autori mogu izraditi zasebne, ugovorne aranžmane za neekskluzivnu distribuciju članka objavljenog u časopisu (npr. postavljanje u institucionalni repozitorijum ili objavljivanje u knjizi), uz navođenje da je članak izvorno objavljen u ovom časopisu.
- Autorima je dozvoljeno i podstiču se da postave objavljeni članak onlajn (npr. u institucionalni repozitorijum ili na svoju internet stranicu) pre ili tokom postupka prijave rukopisa, s obzirom da takav postupak može voditi produktivnoj razmeni ideja i ranijoj i većoj citiranosti objavljenog članka (Vidi Efekti otvorenog pristupa).