Metformin antinociceptive effect in models of nociceptive and neuropathic pain is partially mediated by activation of opioidergic mechanisms

Augusto, Paulo Sérgio de Almeida; Braga, Alysson Vinícius; Rodrigues, Felipe F.; Morais, Marcela I.; Dutra, Marcela M.G.B.; Batista, Carla R.A.; Melo, Ivo S.F.; Costa, Sarah O.A.M.; Goulart, Franciele A.; Coelho, Márcio M.; Machado, Renes R.

doi:10.1016/j.ejphar.2019.172497

Cited by 25 publications

(15 citation statements)

References 33 publications

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“…Metformin is an AMP-activated protein kinase (AMPK) activator in the liver, which leads to decrease of fatty acid synthesis and gluconeogenesis. Recently, it was showed that D r a f t metformin decreased the nociceptive response in the hot-plate model and inhibited the mechanical allodynia induced by chronic constriction injury in mice (Augusto et al 2019). This last result does not agree with the lack of antinociceptive activity of metformin alone in our study (Figure 4).…”

Section: R a F Tcontrasting

confidence: 81%

Citral inhibits the nociception in the rat formalin test: effect of metformin and blockers of opioid receptor and the NO-cGMP-K⁺ channel pathway

Ortiz

Cariño-Cortés

Pérez

et al. 2022

Can. J. Physiol. Pharmacol.

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The objective of the present study was to scrutinize the effect of nitric oxide (NO), cGMP, potassium channel blockers and metformin on the citral-produced peripheral antinociception. The rat paw 1% formalin test was used to assess nociception and antinociception. Rats were treated with local peripheral administration of citral (10-100 µg/paw). The antinociception of citral (100 µg/paw) was evaluated with and without the local pretreatment of naloxone, NG-L-nitro-arginine methyl ester (L-NAME, a NO synthesis inhibitor), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, a soluble guanylyl cyclase inhibitor), metformin, opioid receptors antagonists, and K+ channel blockers. Injection of citral in the rat paw significantly decreased the nociceptive effect of formalin administration during the two phases of the test. Local pretreatment of the paws with L-NAME and ODQ did not reduced the citral-induced antinociception. Glipizide or glibenclamide (Kir6.1-2; ATP-sensitive K+ channel blockers), tetraethylammonium or 4-aminopyridine (KV; voltage-gated K+ channel blockers) or charybdotoxin (KCa1.1; big conductance calcium-activated K+ channel blocker) or apamin (KCa2.1-3; small conductance Ca2+-activated K+ channel antagonist), or metformin, but not the opioid antagonists, reduced the antinociception of citral. Citral produced peripheral antinociception during both phases of the formalin test. These effects were due to the activation of K+ channels and a biguanide-dependent mechanism.

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Section: R a F Tcontrasting

confidence: 81%

Citral inhibits the nociception in the rat formalin test: effect of metformin and blockers of opioid receptor and the NO-cGMP-K⁺ channel pathway

Ortiz

Cariño-Cortés

Pérez

et al. 2022

Can. J. Physiol. Pharmacol.

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“…The analgesic effect of curcumin was explained by its ability to attenuate neurotransmitters related to pain (substance P), suppress the immune response, and prostaglandin E2 production by suppressing cyclooxygenase-2 (COX-2), modulating purinergic and chemokine receptors, and activate the opioid system 49 . The pharmacodynamic interaction between curcumin and metformin is plausible as metformin shows a distinct mechanism of analgesia to curcumin: activation of AMPK, opioidergic mechanisms, and suppressing peripheral and central inflammation 6 , 13 , 14 , 50 . Consequently, metformin showed synergistic analgesia with several other analgesics, including ibuprofen, aspirin, tramadol, and pregabalin 51 .…”

Section: Resultsmentioning

confidence: 99%

“…Metformin is a well-tolerated antidiabetic drug (Fig. 1 A), and recently several pre-clinical and clinical studies have shown the potential analgesic effects of metformin 6 – 10 . Given that this drug is a disease-modifying agent in type II diabetes mellitus, it is possible that it has similar properties for reducing pain and its comorbidities 11 .…”

Section: Introductionmentioning

confidence: 99%

“…Given that this drug is a disease-modifying agent in type II diabetes mellitus, it is possible that it has similar properties for reducing pain and its comorbidities 11 . Metformin has been shown to alleviate pain-like behaviors by activating the AMP-activated protein kinase (AMPK) and opioidergic pathways 6 , 12 . In rodent models of pain, metformin was found to inhibit peripheral and central inflammation, major contributing factors of pain progression, along with reflexive and non-reflexive pain behaviors 13 , 14 .…”

Section: Introductionmentioning

confidence: 99%

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Curcumin and metformin synergistically modulate peripheral and central immune mechanisms of pain

Wasana

Hasriadi

Muangnoi

et al. 2022

Sci Rep

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Metformin is a well-tolerated antidiabetic drug and has recently been repurposed for numerous diseases, including pain. However, a higher dose of metformin is required for effective analgesia, which can potentiate its dose-dependent gastrointestinal side effects. Curcumin is a natural polyphenol and has beneficial therapeutic effects on pain. Curcumin has been used as an analgesic adjuvant with several analgesic drugs, allowing synergistic antinociceptive effects. Nevertheless, whether curcumin can exert synergistic analgesia with metformin is still unknown. In the present study, the nature of curcumin-metformin anti-inflammatory interaction was evaluated in in vitro using lipopolysaccharide-induced RAW 264.7 macrophage and BV-2 microglia cells. In both macrophage and microglia, curcumin effectively potentiates the anti-inflammatory effects of metformin, indicating potential synergistic effects in both peripheral and central pathways of pain. The nature of the interaction between curcumin and metformin was further recapitulated using a mouse model of formalin-induced pain. Coadministration of curcumin and metformin at a 1:1 fixed ratio of their ED50 doses significantly reduced the dose required to produce a 50% effect compared to the theoretically required dose in phase II of the formalin test with a combination index value of 0.24. Besides, the synergistic interaction does not appear to involve severe CNS side effects indicated by no motor alterations, no alterations in short-term and long-term locomotive behaviors, and the general well-being of mice. Our findings suggest that curcumin exerts synergistic anti-inflammation with metformin with no potential CNS adverse effects.

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“…Recent studies provide evidence for AMPK and mTOR's different role in the acute and neuropathic pain models [43][44][45][46]. Numerous studies reported that the activation of AMPK might contribute to their antinociceptive effect [47,48].…”

Section: Discussionmentioning

confidence: 99%

The changes of nociception and the signal molecules expression in the dorsal root ganglia and the spinal cord after cold water swimming stress in mice

Feng

Sim

Park

et al. 2021

Korean J Physiol Pharmacol

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Several studies have previously reported that exposure to stress provokes behavioral changes, including antinociception, in rodents. In the present study, we studied the effect of acute cold-water (4°C) swimming stress (CWSS) on nociception and the possible changes in several signal molecules in male ICR mice.Here, we show that 3 min of CWSS was sufficient to produce antinociception in tailflick, hot-plate, von-Frey, writhing, and formalin-induced pain models. Significantly, CWSS strongly reduced nociceptive behavior in the first phase, but not in the second phase, of the formalin-induced pain model. We further examined some signal molecules' expressions in the dorsal root ganglia (DRG) and spinal cord to delineate the possible molecular mechanism involved in the antinociceptive effect under CWSS. CWSS reduced p-ERK, p-AMPK1, p-AMPK2, p-Tyk2, and p-STAT3 expression both in the spinal cord and DRG. However, the phosphorylation of mTOR was activated after CWSS in the spinal cord and DRG. Moreover, p-JNK and p-CREB activation were significantly increased by CWSS in the spinal cord, whereas CWSS alleviated JNK and CREB phosphorylation levels in DRG. Our results suggest that the antinociception induced by CWSS may be mediated by several molecules, such as ERK, JNK, CREB, AMPK1, AMPK2, mTOR, Tyk2, and STAT3 located in the spinal cord and DRG.

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Metformin antinociceptive effect in models of nociceptive and neuropathic pain is partially mediated by activation of opioidergic mechanisms

Cited by 25 publications

References 33 publications

Citral inhibits the nociception in the rat formalin test: effect of metformin and blockers of opioid receptor and the NO-cGMP-K⁺ channel pathway

Citral inhibits the nociception in the rat formalin test: effect of metformin and blockers of opioid receptor and the NO-cGMP-K⁺ channel pathway

Curcumin and metformin synergistically modulate peripheral and central immune mechanisms of pain

The changes of nociception and the signal molecules expression in the dorsal root ganglia and the spinal cord after cold water swimming stress in mice

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Metformin antinociceptive effect in models of nociceptive and neuropathic pain is partially mediated by activation of opioidergic mechanisms

Cited by 25 publications

References 33 publications

Citral inhibits the nociception in the rat formalin test: effect of metformin and blockers of opioid receptor and the NO-cGMP-K+ channel pathway

Citral inhibits the nociception in the rat formalin test: effect of metformin and blockers of opioid receptor and the NO-cGMP-K+ channel pathway

Curcumin and metformin synergistically modulate peripheral and central immune mechanisms of pain

The changes of nociception and the signal molecules expression in the dorsal root ganglia and the spinal cord after cold water swimming stress in mice

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Product

Resources

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Citral inhibits the nociception in the rat formalin test: effect of metformin and blockers of opioid receptor and the NO-cGMP-K⁺ channel pathway

Citral inhibits the nociception in the rat formalin test: effect of metformin and blockers of opioid receptor and the NO-cGMP-K⁺ channel pathway