AMPK activation attenuates central sensitization in a recurrent nitroglycerin-induced chronic migraine mouse model by promoting microglial M2-type polarization.

Lu G, Xiao S, Meng F, Zhang L, Chang Y, Zhao J, Gao N, Su W, Guo X, Liu Y, Li C, Tang W, Zou L, Yu S, Liu R

The journal of headache and pain8 Mar 2024Cited by 27 (Europe PMC)

PMID38454376PMCIDPMC10921743DOI10.1186/s10194-024-01739-wPepBankPUB-38454376

Summary

BackgroundEnergy metabolism disorders and neurogenic inflammation play important roles in the central sensitization to chronic migraine (CM). AMP-activated protein kinase (AMPK) is an intracellular energy sensor, and its activation regulates inflammation and reduces neuropathic pain. However, studies on the involvement of AMPK in the regulation of CM are currently lacking. Therefore, this study aimed to explore the mechanism underlying the involvement of AMPK in the central sensitization to CM.MethodsMice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC). Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured. The expression of calcitonin gene-related peptide (CGRP) and cytokines, M1/M2 microglia, and NF-κB pathway activation were detected after the intervention.ResultsRepeated NTG injections resulted in a gradual decrease in AMPK protein expression, and the negative regulation of AMPK by increased ubiquitin-like plant homeodomain and RING finger domain 1 (UHRF1) expression may counteract AMPK activation by increasing ADP/ATP. AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1β, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10. Moreover, AMPK in TNC was mainly located in microglia. AICAR could reduce the expression of inducible NO synthase (iNOS) in M1 microglia and increase the expression of Arginase 1 (Arg1) in M2 microglia by inhibiting the activation of NF-κB pathway.ConclusionsAMPK was involved in the central sensitization of CM, and the activation of AMPK reduced neuroinflammation in NTG-induced CM mice. AMPK may provide new insights into interventions for energy metabolism disorders and neurogenic inflammation in migraine.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study12

12 results from studies that gave the peptide. No result from this study comes from people.

01AnimalAnimal study (in vivo)Efficacy outcome
In chronic migraine mice, AICAR reduced hyperalgesia.
In plain wordsIn mice with chronic migraine, AICAR reduced excessive pain sensitivity.
Peptide
AICAR (acadesine)
Outcome
DecreaseHyperalgesia
Study
mousen: not reported in source
Nitroglycerin-induced chronic migraine
Outcome group
Pain · Nervous system and cognition
Studied dose
Dose not stated · intraperitonealAs given in this study (mouse).
Source sentences
Summary
AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1β, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10.
2 context sentences(design, population, supporting numbers)
Summary · context
Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC).
Summary · context
Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured.
Show in the study text Report a problemFND-3845437601
02AnimalAnimal study (in vivo)Efficacy outcome
In chronic migraine mice, AICAR reduced pain-like behaviors.
In plain wordsIn mice with chronic migraine, AICAR reduced pain-like behaviors.
Peptide
AICAR (acadesine)
Outcome
DecreasePain-like behaviors
Study
mousen: not reported in source
Nitroglycerin-induced chronic migraine
Outcome group
Pain · Nervous system and cognition
Studied dose
Dose not stated · intraperitonealAs given in this study (mouse).
Source sentences
Summary
AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1β, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10.
2 context sentences(design, population, supporting numbers)
Summary · context
Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC).
Summary · context
Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured.
Show in the study text Report a problemFND-3845437602
03AnimalAnimal study (in vivo)Efficacy outcome
In chronic migraine mice, AICAR improved activity.
In plain wordsIn mice with chronic migraine, AICAR improved activity.
Peptide
AICAR (acadesine)
Outcome
IncreaseActivity
Study
mousen: not reported in source
Nitroglycerin-induced chronic migraine
Outcome group
Exercise and physical function · Nervous system and cognition
Studied dose
Dose not stated · intraperitonealAs given in this study (mouse).
Source sentences
Summary
AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1β, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10.
2 context sentences(design, population, supporting numbers)
Summary · context
Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC).
Summary · context
Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured.
Show in the study text Report a problemFND-3845437603
04AnimalAnimal study (in vivo)Mechanism
In chronic migraine mice, AICAR reduced TNC CGRP expression.
In plain wordsIn mice with chronic migraine, AICAR reduced CGRP expression in the brainstem.
Peptide
AICAR (acadesine)
Outcome
DecreaseCGRP expression
Study
mousen: not reported in source
Nitroglycerin-induced chronic migraine
Outcome group
Inflammation markers · Nervous system and cognition
Studied dose
Dose not stated · intraperitonealAs given in this study (mouse).
Source sentences
Summary
AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1β, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10.
2 context sentences(design, population, supporting numbers)
Summary · context
Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC).
Summary · context
Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured.
Show in the study text Report a problemFND-3845437604
05AnimalAnimal study (in vivo)Mechanism
In chronic migraine mice, AICAR reduced TNC IL-1β expression.
In plain wordsIn mice with chronic migraine, AICAR reduced brainstem IL-1β expression.
Peptide
AICAR (acadesine)
Outcome
DecreaseIL-1beta expression
Study
mousen: not reported in source
Nitroglycerin-induced chronic migraine
Outcome group
Inflammation markers · Nervous system and cognition
Studied dose
Dose not stated · intraperitonealAs given in this study (mouse).
Source sentences
Summary
AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1β, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10.
2 context sentences(design, population, supporting numbers)
Summary · context
Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC).
Summary · context
Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured.
Show in the study text Report a problemFND-3845437605
06AnimalAnimal study (in vivo)Mechanism
In chronic migraine mice, AICAR reduced TNC IL-6 expression.
In plain wordsIn mice with chronic migraine, AICAR reduced brainstem IL-6 expression.
Peptide
AICAR (acadesine)
Outcome
DecreaseIL-6 expression
Study
mousen: not reported in source
Nitroglycerin-induced chronic migraine
Outcome group
Inflammation markers · Nervous system and cognition
Studied dose
Dose not stated · intraperitonealAs given in this study (mouse).
Source sentences
Summary
AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1β, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10.
2 context sentences(design, population, supporting numbers)
Summary · context
Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC).
Summary · context
Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured.
Show in the study text Report a problemFND-3845437606
07AnimalAnimal study (in vivo)Mechanism
In chronic migraine mice, AICAR reduced TNC TNF-α expression.
In plain wordsIn mice with chronic migraine, AICAR reduced brainstem TNF-α expression.
Peptide
AICAR (acadesine)
Outcome
DecreaseTNF-alpha expression
Study
mousen: not reported in source
Nitroglycerin-induced chronic migraine
Outcome group
Inflammation markers · Nervous system and cognition
Studied dose
Dose not stated · intraperitonealAs given in this study (mouse).
Source sentences
Summary
AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1β, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10.
2 context sentences(design, population, supporting numbers)
Summary · context
Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC).
Summary · context
Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured.
Show in the study text Report a problemFND-3845437607
08AnimalAnimal study (in vivo)Mechanism
In chronic migraine mice, AICAR increased IL-4 expression.
In plain wordsIn mice with chronic migraine, AICAR increased IL-4 expression.
Peptide
AICAR (acadesine)
Outcome
IncreaseIL-4 expression
Study
mousen: not reported in source
Nitroglycerin-induced chronic migraine
Outcome group
Inflammation markers · Nervous system and cognition
Studied dose
Dose not stated · intraperitonealAs given in this study (mouse).
Source sentences
Summary
AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1β, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10.
2 context sentences(design, population, supporting numbers)
Summary · context
Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC).
Summary · context
Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured.
Show in the study text Report a problemFND-3845437608
09AnimalAnimal study (in vivo)Mechanism
In chronic migraine mice, AICAR increased IL-10 expression.
In plain wordsIn mice with chronic migraine, AICAR increased IL-10 expression.
Peptide
AICAR (acadesine)
Outcome
IncreaseIL-10 expression
Study
mousen: not reported in source
Nitroglycerin-induced chronic migraine
Outcome group
Inflammation markers · Nervous system and cognition
Studied dose
Dose not stated · intraperitonealAs given in this study (mouse).
Source sentences
Summary
AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1β, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10.
2 context sentences(design, population, supporting numbers)
Summary · context
Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC).
Summary · context
Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured.
Show in the study text Report a problemFND-3845437609
10AnimalAnimal study (in vivo)Mechanism
In chronic migraine mice, AICAR reduced iNOS expression in M1 microglia.
In plain wordsIn mice with chronic migraine, AICAR reduced iNOS expression in M1 brain immune cells.
Peptide
AICAR (acadesine)
Outcome
DecreaseiNOS expression in M1 microglia
Study
mousen: not reported in source
Nitroglycerin-induced chronic migraine
Outcome group
Inflammation markers · Nervous system and cognition
Studied dose
Dose not stated · intraperitonealAs given in this study (mouse).
Source sentences
Summary
AICAR could reduce the expression of inducible NO synthase (iNOS) in M1 microglia and increase the expression of Arginase 1 (Arg1) in M2 microglia by inhibiting the activation of NF-κB pathway.
2 context sentences(design, population, supporting numbers)
Summary · context
Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC).
Summary · context
Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured.
Show in the study text Report a problemFND-3845437610
11AnimalAnimal study (in vivo)Mechanism
In chronic migraine mice, AICAR increased Arg1 expression in M2 microglia.
In plain wordsIn mice with chronic migraine, AICAR increased Arg1 expression in M2 brain immune cells.
Peptide
AICAR (acadesine)
Outcome
IncreaseArg1 expression in M2 microglia
Study
mousen: not reported in source
Nitroglycerin-induced chronic migraine
Outcome group
Inflammation markers · Nervous system and cognition
Studied dose
Dose not stated · intraperitonealAs given in this study (mouse).
Source sentences
Summary
AICAR could reduce the expression of inducible NO synthase (iNOS) in M1 microglia and increase the expression of Arginase 1 (Arg1) in M2 microglia by inhibiting the activation of NF-κB pathway.
2 context sentences(design, population, supporting numbers)
Summary · context
Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC).
Summary · context
Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured.
Show in the study text Report a problemFND-3845437611
12AnimalAnimal study (in vivo)Mechanism
In chronic migraine mice, AICAR inhibited NF-κB pathway activation.
In plain wordsIn mice with chronic migraine, AICAR inhibited activation of the NF-κB pathway.
Peptide
AICAR (acadesine)
Outcome
DecreaseNF-kappaB pathway activation
Study
mousen: not reported in source
Nitroglycerin-induced chronic migraine
Outcome group
Receptor activity and mechanism · Nervous system and cognition
Studied dose
Dose not stated · intraperitonealAs given in this study (mouse).
Source sentences
Summary
AICAR could reduce the expression of inducible NO synthase (iNOS) in M1 microglia and increase the expression of Arginase 1 (Arg1) in M2 microglia by inhibiting the activation of NF-κB pathway.
2 context sentences(design, population, supporting numbers)
Summary · context
Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC).
Summary · context
Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured.
Show in the study text Report a problemFND-3845437612

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
21 Oct 2026, 15:58 UTC
Study results updated
Version 1
21 Oct 2026, 12:50 UTC
First added · source update from Europe PMC

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Terms as the source lists them.

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Keywords

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