TY  - 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 .

TY  - CONF
AU  - Pecikoza, Uroš
AU  - Lasica, Anđelka
AU  - Tomić, Maja
AU  - Micov, Ana
AU  - Nastić, Katarina
AU  - Stepanović-Petrović, Radica
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4577
AB  - Several lines of (pre)clinical evidence have emerged that the antidiabetic drug
metformin can alleviate inflammatory/neuropathic pain (1). Although the mechanism is not
completely understood, there are reports that metformin can affect neurotransmitters
involved in pain modulation, such as its ability to increase peripheral serotonin release (2).
Here, we evaluated metformin’s efficacy following local peripheral administration in an
inflammatory pain model and examined the potential involvement of serotonin receptors.
We used the formalin test in mice, where we measured duration of nociceptive behavior in
the first and second phase of the test. First, we examined the metformin’s antinociceptive
effects following intraplantar administration. Additionally, the highest tested metformin
dose was applied contralateral to the formalin-injected side, to exclude possible systemic
effects. In the second part, we evaluated the effects of a 5-HT1A (WAY100635) and 5-HT1B/1D
antagonist (GR127935) on the antinociceptive effects of a fixed, effective dose of metformin
(antagonists were co-administered intraplantarly with metformin). Metformin (0.1-2
mg/paw) produced significant and dose-dependent antinociceptive effects (32-72%) in the
second (inflammatory) phase. Contralateral application of metformin (2 mg/paw) had no
significant antinociceptive effects. Both antagonists significantly reduced the antinociceptive
effects of metformin (1 mg/paw). The levels of inhibition of metformin’s antinociceptive
effect produced by WAY100635 were 56% (5 μg/paw) and 82% (7.5 μg/paw), whereas
GR127935 inhibited metformin’s efficacy by 24% (3.75 μg/paw) and 80% (5 μg/paw). This
study demonstrates that peripheral metformin application can produce antinociceptive
effects against inflammatory pain and that activation of peripheral 5-HT 1A and 5-HT1B/1D
receptors contributes to these effects.
AB  - Postoje brojni dokazi iz (pre)kliničkih studija da metformin, lek iz grupe
antidijabetika, može ublažiti inflamatorni/neuropatski bol (1). Iako mehanizam dejstva nije
u potpunosti razjašnjen, podaci ukazuju da metformin može uticati na neurotransmitere
uključene u modulaciju bola, poput sposobnosti da poveća oslobađanje serotonina na
periferiji (2). U ovom radu je ispitana efikasnost metformina nakon lokalne periferne
primene u modelu inflamatornog bola, kao i potencijalna uključenost serotoninskih
receptora. Korišćen je formalinski test kod miševa, u kome je mereno vreme provedeno u
nociceptivnom ponašanju, u prvoj i drugoj fazi testa. Prvo su ispitani antinociceptivni efekti
metformina nakon intraplantarne primene. Dodatno, najveća testirana doza metformina je
primenjena kontralateralno u odnosu na mesto injektovanja formalina, kako bi se isključili
mogući sistemski efekti. U drugom delu studije, ispitani su efekti antagoniste 5-HT 1A
(WAY100635) i 5-HT1B/1D (GR127935) receptora na antinociceptivno dejstvo fiksne,
efektivne doze metformina (antagonisti su primenjeni intraplantarno, istovremeno sa
metforminom). Metformin (0,1-2 mg/šapi) je ispoljio značajan i dozno-zavisan
antinociceptivni efekat (32-72%) u drugoj (inflamatornoj) fazi testa. Kontralateralna
primena metformina (2 mg/šapi) nije imala značajan antinociceptivni efekat. Primenjeni
antagonisti su značajno smanjili antinociceptivne efekte metformina (1 mg/šapi). Stepeni
inhibicije antinociceptivnog dejstva metformina koje je postigao WAY100635 su bili 56% (5
μg/šapi) i 82% (7,5 μg/šapi), dok je GR127935 inhibirao efikasnost metformina za 24%
(3,75 μg/šapi) i 80% (5 μg/šapi). Ova studija je pokazala da periferna primena metformina
proizvodi antinociceptivni efekat kod inflamatornog bola i da aktivacija perifernih 5-HT1A i 5-
HT1B/1D receptora doprinosi ovom efektu.
PB  - Savez farmaceutskih udruženja Srbije (SFUS)
C3  - Arhiv za farmaciju
T1  - Activation of peripheral serotonin 5-HT1A and 5-HT1B/1D receptors contributes to the antinociceptive properties of metformin
T1  - Aktivacija perifernih serotoninskih 5‐HT1A i 5‐HT 1B/1D receptora doprinosi antinociceptivnom dejstvu metformina
VL  - 72
IS  - 4 suplement
SP  - S446
EP  - S447
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4577
ER  - 

@conference{
author = "Pecikoza, Uroš and Lasica, Anđelka and Tomić, Maja and Micov, Ana and Nastić, Katarina and Stepanović-Petrović, Radica",
year = "2022",
abstract = "Several lines of (pre)clinical evidence have emerged that the antidiabetic drug
metformin can alleviate inflammatory/neuropathic pain (1). Although the mechanism is not
completely understood, there are reports that metformin can affect neurotransmitters
involved in pain modulation, such as its ability to increase peripheral serotonin release (2).
Here, we evaluated metformin’s efficacy following local peripheral administration in an
inflammatory pain model and examined the potential involvement of serotonin receptors.
We used the formalin test in mice, where we measured duration of nociceptive behavior in
the first and second phase of the test. First, we examined the metformin’s antinociceptive
effects following intraplantar administration. Additionally, the highest tested metformin
dose was applied contralateral to the formalin-injected side, to exclude possible systemic
effects. In the second part, we evaluated the effects of a 5-HT1A (WAY100635) and 5-HT1B/1D
antagonist (GR127935) on the antinociceptive effects of a fixed, effective dose of metformin
(antagonists were co-administered intraplantarly with metformin). Metformin (0.1-2
mg/paw) produced significant and dose-dependent antinociceptive effects (32-72%) in the
second (inflammatory) phase. Contralateral application of metformin (2 mg/paw) had no
significant antinociceptive effects. Both antagonists significantly reduced the antinociceptive
effects of metformin (1 mg/paw). The levels of inhibition of metformin’s antinociceptive
effect produced by WAY100635 were 56% (5 μg/paw) and 82% (7.5 μg/paw), whereas
GR127935 inhibited metformin’s efficacy by 24% (3.75 μg/paw) and 80% (5 μg/paw). This
study demonstrates that peripheral metformin application can produce antinociceptive
effects against inflammatory pain and that activation of peripheral 5-HT 1A and 5-HT1B/1D
receptors contributes to these effects., Postoje brojni dokazi iz (pre)kliničkih studija da metformin, lek iz grupe
antidijabetika, može ublažiti inflamatorni/neuropatski bol (1). Iako mehanizam dejstva nije
u potpunosti razjašnjen, podaci ukazuju da metformin može uticati na neurotransmitere
uključene u modulaciju bola, poput sposobnosti da poveća oslobađanje serotonina na
periferiji (2). U ovom radu je ispitana efikasnost metformina nakon lokalne periferne
primene u modelu inflamatornog bola, kao i potencijalna uključenost serotoninskih
receptora. Korišćen je formalinski test kod miševa, u kome je mereno vreme provedeno u
nociceptivnom ponašanju, u prvoj i drugoj fazi testa. Prvo su ispitani antinociceptivni efekti
metformina nakon intraplantarne primene. Dodatno, najveća testirana doza metformina je
primenjena kontralateralno u odnosu na mesto injektovanja formalina, kako bi se isključili
mogući sistemski efekti. U drugom delu studije, ispitani su efekti antagoniste 5-HT 1A
(WAY100635) i 5-HT1B/1D (GR127935) receptora na antinociceptivno dejstvo fiksne,
efektivne doze metformina (antagonisti su primenjeni intraplantarno, istovremeno sa
metforminom). Metformin (0,1-2 mg/šapi) je ispoljio značajan i dozno-zavisan
antinociceptivni efekat (32-72%) u drugoj (inflamatornoj) fazi testa. Kontralateralna
primena metformina (2 mg/šapi) nije imala značajan antinociceptivni efekat. Primenjeni
antagonisti su značajno smanjili antinociceptivne efekte metformina (1 mg/šapi). Stepeni
inhibicije antinociceptivnog dejstva metformina koje je postigao WAY100635 su bili 56% (5
μg/šapi) i 82% (7,5 μg/šapi), dok je GR127935 inhibirao efikasnost metformina za 24%
(3,75 μg/šapi) i 80% (5 μg/šapi). Ova studija je pokazala da periferna primena metformina
proizvodi antinociceptivni efekat kod inflamatornog bola i da aktivacija perifernih 5-HT1A i 5-
HT1B/1D receptora doprinosi ovom efektu.",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "Activation of peripheral serotonin 5-HT1A and 5-HT1B/1D receptors contributes to the antinociceptive properties of metformin, Aktivacija perifernih serotoninskih 5‐HT1A i 5‐HT 1B/1D receptora doprinosi antinociceptivnom dejstvu metformina",
volume = "72",
number = "4 suplement",
pages = "S446-S447",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4577"
}

Pecikoza, U., Lasica, A., Tomić, M., Micov, A., Nastić, K.,& Stepanović-Petrović, R.. (2022). Activation of peripheral serotonin 5-HT1A and 5-HT1B/1D receptors contributes to the antinociceptive properties of metformin. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije (SFUS)., 72(4 suplement), S446-S447.
https://hdl.handle.net/21.15107/rcub_farfar_4577

Pecikoza U, Lasica A, Tomić M, Micov A, Nastić K, Stepanović-Petrović R. Activation of peripheral serotonin 5-HT1A and 5-HT1B/1D receptors contributes to the antinociceptive properties of metformin. in Arhiv za farmaciju. 2022;72(4 suplement):S446-S447.
https://hdl.handle.net/21.15107/rcub_farfar_4577 .

Pecikoza, Uroš, Lasica, Anđelka, Tomić, Maja, Micov, Ana, Nastić, Katarina, Stepanović-Petrović, Radica, "Activation of peripheral serotonin 5-HT1A and 5-HT1B/1D receptors contributes to the antinociceptive properties of metformin" in Arhiv za farmaciju, 72, no. 4 suplement (2022):S446-S447,
https://hdl.handle.net/21.15107/rcub_farfar_4577 .