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
Authors
Pecikoza, Uroš
Lasica, Anđelka
Tomić, Maja

Micov, Ana

Nastić, Katarina

Stepanović-Petrović, Radica

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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) rec...eptora 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.
Source:
Arhiv za farmaciju, 2022, 72, 4 suplement, S446-S447Publisher:
- 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 - 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 .