The involvement of serotonergic mechanisms in the antinociceptive effect of metformin
Učešće serotonergičkih mehanizama u antinociceptivnom dejstvu metformina
Authors
Lasica, AnđelkaTomić, Maja

Nastić, Katarina

Pecikoza, Uroš

Micov, Ana

Stepanović-Petrović, Radica

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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 (1,2). 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. Met...formin (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).
Metformin je dobro poznat antidijabetik, za koji je pokazano da poseduje analgetička
svojstva u modelima inflamatornog bola. Međutim, mehanizmi njegovog antinociceptivnog
dejstva nisu u potpunosti rasvetljeni (1,2). Cilj ovog rada je bio ispitati učešće
serotonergičkih mehanizama u antinociceptivnom dejstvu metformina u inflamatornom
modelu bola – korišćenjem formalinskog testa kod miševa. Inicijalno su ispitani
antinociceptivni efekti metformina, nakon intraperitonealne primene, u prvoj i drugoj fazi
testa. Uključenost serotoninskih receptora je procenjena nakon intraperitonealne primene
antagonista 5-HT 1B/1D (GR127935) ili 5-HT1A (WAY100635) receptora. U nastavku
eksperimenata, efekat metformina je ispitan nakon deplecije endogenog serotonina,
primenom inhibitora triptofan-hidroksilaze (PCPA; primenjen intraperitonealno tokom 4
dana). Dodatno, efekat najveće testirane doze metformina je ispitan u rotarod testu, kako bi
se isključila mogućnost pogrešnog tumačenja motorne i...nkoordinacije. Metformin (50-200
mg/kg) je pokazao značajno i dozno-zavisno antinociceptivno dejstvo (17-81%) u drugoj
(inflamatornoj) fazi testa. Primena antagonista je značajno smanjila antinociceptivni efekat
metformina (150 mg/kg). GR127935 je inhibirao efekte metformina za 67% (1 mg/kg) i
100% (3 mg/kg), dok su inhibitorni efekti WAY100635 bili 19% (1 mg/kg) i 68% (3 mg/kg).
Deplecija serotonina korišćenjem PCPA (100 mg/kg/dan) je značajno smanjila
antinociceptivne efekte metformina primenjenog u većim dozama (150 i 200 mg/kg).
Metformin (200 mg/kg) nije imao značajan uticaj na performanse miševa u rotarod testu.
Ova studija je pokazala uključenost 5-HT1B/1D i 5-HT1A receptora u antinociceptivnom dejstvu
metformina, koje je verovatno posledica indirektnog uticaja leka na receptore (posredstvom
oslobađanja endogenog serotonina od strane metformina).
Source:
Arhiv za farmaciju, 2022, 72, 4 suplement, S448-S449Publisher:
- Savez farmaceutskih udruženja Srbije (SFUS)
Funding / projects:
Note:
- VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beograd
Collections
Institution/Community
PharmacyTY - CONF AU - Lasica, Anđelka AU - Tomić, Maja AU - Nastić, Katarina AU - Pecikoza, Uroš AU - Micov, Ana AU - Stepanović-Petrović, Radica PY - 2022 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4578 AB - 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 (1,2). 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). AB - Metformin je dobro poznat antidijabetik, za koji je pokazano da poseduje analgetička svojstva u modelima inflamatornog bola. Međutim, mehanizmi njegovog antinociceptivnog dejstva nisu u potpunosti rasvetljeni (1,2). Cilj ovog rada je bio ispitati učešće serotonergičkih mehanizama u antinociceptivnom dejstvu metformina u inflamatornom modelu bola – korišćenjem formalinskog testa kod miševa. Inicijalno su ispitani antinociceptivni efekti metformina, nakon intraperitonealne primene, u prvoj i drugoj fazi testa. Uključenost serotoninskih receptora je procenjena nakon intraperitonealne primene antagonista 5-HT 1B/1D (GR127935) ili 5-HT1A (WAY100635) receptora. U nastavku eksperimenata, efekat metformina je ispitan nakon deplecije endogenog serotonina, primenom inhibitora triptofan-hidroksilaze (PCPA; primenjen intraperitonealno tokom 4 dana). Dodatno, efekat najveće testirane doze metformina je ispitan u rotarod testu, kako bi se isključila mogućnost pogrešnog tumačenja motorne inkoordinacije. Metformin (50-200 mg/kg) je pokazao značajno i dozno-zavisno antinociceptivno dejstvo (17-81%) u drugoj (inflamatornoj) fazi testa. Primena antagonista je značajno smanjila antinociceptivni efekat metformina (150 mg/kg). GR127935 je inhibirao efekte metformina za 67% (1 mg/kg) i 100% (3 mg/kg), dok su inhibitorni efekti WAY100635 bili 19% (1 mg/kg) i 68% (3 mg/kg). Deplecija serotonina korišćenjem PCPA (100 mg/kg/dan) je značajno smanjila antinociceptivne efekte metformina primenjenog u većim dozama (150 i 200 mg/kg). Metformin (200 mg/kg) nije imao značajan uticaj na performanse miševa u rotarod testu. Ova studija je pokazala uključenost 5-HT1B/1D i 5-HT1A receptora u antinociceptivnom dejstvu metformina, koje je verovatno posledica indirektnog uticaja leka na receptore (posredstvom oslobađanja endogenog serotonina od strane metformina). PB - Savez farmaceutskih udruženja Srbije (SFUS) C3 - Arhiv za farmaciju T1 - The involvement of serotonergic mechanisms in the antinociceptive effect of metformin T1 - Učešće serotonergičkih mehanizama u antinociceptivnom dejstvu metformina VL - 72 IS - 4 suplement SP - S448 EP - S449 UR - https://hdl.handle.net/21.15107/rcub_farfar_4578 ER -
@conference{ author = "Lasica, Anđelka and Tomić, Maja and Nastić, Katarina and Pecikoza, Uroš and Micov, Ana and Stepanović-Petrović, Radica", year = "2022", 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 (1,2). 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)., Metformin je dobro poznat antidijabetik, za koji je pokazano da poseduje analgetička svojstva u modelima inflamatornog bola. Međutim, mehanizmi njegovog antinociceptivnog dejstva nisu u potpunosti rasvetljeni (1,2). Cilj ovog rada je bio ispitati učešće serotonergičkih mehanizama u antinociceptivnom dejstvu metformina u inflamatornom modelu bola – korišćenjem formalinskog testa kod miševa. Inicijalno su ispitani antinociceptivni efekti metformina, nakon intraperitonealne primene, u prvoj i drugoj fazi testa. Uključenost serotoninskih receptora je procenjena nakon intraperitonealne primene antagonista 5-HT 1B/1D (GR127935) ili 5-HT1A (WAY100635) receptora. U nastavku eksperimenata, efekat metformina je ispitan nakon deplecije endogenog serotonina, primenom inhibitora triptofan-hidroksilaze (PCPA; primenjen intraperitonealno tokom 4 dana). Dodatno, efekat najveće testirane doze metformina je ispitan u rotarod testu, kako bi se isključila mogućnost pogrešnog tumačenja motorne inkoordinacije. Metformin (50-200 mg/kg) je pokazao značajno i dozno-zavisno antinociceptivno dejstvo (17-81%) u drugoj (inflamatornoj) fazi testa. Primena antagonista je značajno smanjila antinociceptivni efekat metformina (150 mg/kg). GR127935 je inhibirao efekte metformina za 67% (1 mg/kg) i 100% (3 mg/kg), dok su inhibitorni efekti WAY100635 bili 19% (1 mg/kg) i 68% (3 mg/kg). Deplecija serotonina korišćenjem PCPA (100 mg/kg/dan) je značajno smanjila antinociceptivne efekte metformina primenjenog u većim dozama (150 i 200 mg/kg). Metformin (200 mg/kg) nije imao značajan uticaj na performanse miševa u rotarod testu. Ova studija je pokazala uključenost 5-HT1B/1D i 5-HT1A receptora u antinociceptivnom dejstvu metformina, koje je verovatno posledica indirektnog uticaja leka na receptore (posredstvom oslobađanja endogenog serotonina od strane metformina).", publisher = "Savez farmaceutskih udruženja Srbije (SFUS)", journal = "Arhiv za farmaciju", title = "The involvement of serotonergic mechanisms in the antinociceptive effect of metformin, Učešće serotonergičkih mehanizama u antinociceptivnom dejstvu metformina", volume = "72", number = "4 suplement", pages = "S448-S449", url = "https://hdl.handle.net/21.15107/rcub_farfar_4578" }
Lasica, A., Tomić, M., Nastić, K., Pecikoza, U., Micov, A.,& Stepanović-Petrović, R.. (2022). The involvement of serotonergic mechanisms in the antinociceptive effect of metformin. in Arhiv za farmaciju Savez farmaceutskih udruženja Srbije (SFUS)., 72(4 suplement), S448-S449. https://hdl.handle.net/21.15107/rcub_farfar_4578
Lasica A, Tomić M, Nastić K, Pecikoza U, Micov A, Stepanović-Petrović R. The involvement of serotonergic mechanisms in the antinociceptive effect of metformin. in Arhiv za farmaciju. 2022;72(4 suplement):S448-S449. https://hdl.handle.net/21.15107/rcub_farfar_4578 .
Lasica, Anđelka, Tomić, Maja, Nastić, Katarina, Pecikoza, Uroš, Micov, Ana, Stepanović-Petrović, Radica, "The involvement of serotonergic mechanisms in the antinociceptive effect of metformin" in Arhiv za farmaciju, 72, no. 4 suplement (2022):S448-S449, https://hdl.handle.net/21.15107/rcub_farfar_4578 .