Abstract
Background
Electroacupuncture (EA) is a traditional Chinese therapeutic technique that has a
beneficial effect on neuropathic pain; however, the specific mechanism remains unclear.
In this study, we investigated whether EA inhibits spinal Ca/calmodulin-dependent
protein kinase II (CaMKIIα) phosphorylation through Sirtuin 3 (SIRT3) protein, thus
relieving neuropathic pain.
Materials and Methods
We used wild-type and SIRT3 knockout (SIRT3−/−) mice and used chronic constriction injury (CCI) as a pain model. We performed Western
blotting, immunostaining, von Frey, and Hargreaves tests to gather biochemical and
behavioral data. Downregulation and overexpression and spinal SIRT3 protein were achieved
by intraspinal injection of SIRT3 small interfering RNA and intraspinal injection
of lentivirus-SIRT3. To test the hypothesis that CaMKIIα signaling was involved in
the analgesic effects of EA, we expressed CaMKIIα-specific designer receptors exclusively
activated by designer drugs (DREADDs) in the spinal dorsal horn (SDH) of mice.
Results
These results showed that the mechanical and thermal hyperalgesia induced by CCI was
related to the decreased spinal SIRT3 expression in the SDH of mice. A significant
reduction of mechanical and thermal thresholds was found in the SIRT3−/− mice. SIRT3 overexpression or EA treatment alleviated CCI-induced neuropathic pain
and prevented the spinal CaMKIIα phosphorylation. Most importantly, EA increased the
expression of spinal SIRT3 protein in the SDH. Downregulation of spinal SIRT3 or CaMKIIα
Gq-DREADD activation inhibited the regulatory effect of EA on neuropathic pain.
Conclusion
Our results showed that CaMKIIα phosphorylation was inhibited by spinal SIRT3 in neuropathic
pain and that EA attenuated CCI-induced neuropathic pain mainly by upregulating spinal
SIRT3 expression in the SDH of mice.
Keywords
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References
- Electroacupuncture: mechanisms and clinical application.Biol Psychiatry. 1998; 44: 129-138
- Glucocorticoid receptor contributes to electroacupuncture-induced analgesia by inhibiting Nav1.7 expression in rats with inflammatory pain induced by complete Freund's adjuvant.Neuromodulation. 2022; 25: 1393-1402
- Spinal neuronal GRK2 contributes to preventive effect by electroacupuncture on cisplatin-induced peripheral neuropathy in mice.Anesth Analg. 2022; 134: 204-215
- Electroacupuncture alleviates inflammatory pain via adenosine suppression and its mediated substance P expression.Arq Neuro Psiquiatr. 2020; 78: 617-623
- Electroacupuncture attenuates cancer-induced bone pain via NF-κB/CXCL12 signaling in midbrain periaqueductal gray.ACS Chem Neurosci. 2021; 12: 3323-3334
- Electroacupuncture modulates spinal BDNF/TrκB signaling pathway and ameliorates the sensitization of dorsal horn WDR neurons in spared nerve injury rats.Int J Mol Sci. 2020; 21: 6524
- SIRT3 as a potential therapeutic target for heart failure.Pharmacol Res. 2021; 165105432
- Sirtuin3 in Neurological disorders.Curr Drug Res Rev. 2021; 13: 140-147
- Caloric restriction increases brain mitochondrial calcium retention capacity and protects against excitotoxicity.Aging Cell. 2017; 16: 73-81
- Mitochondrial SIRT3 mediates adaptive responses of neurons to exercise and metabolic and excitatory challenges.Cell Metab. 2016; 23: 128-142
- SIRT3 regulates neuronal excitability of Alzheimer's disease models in an oxidative stress-dependent manner.Neuromolecular Med. 2022; 24: 261-267
- SIRT3 deficiency-induced mitochondrial dysfunction and inflammasome formation in the brain.Sci Rep. 2018; 817547
- Yes-associated protein reduces neuroinflammation through upregulation of Sirt3 and inhibition of JNK signaling pathway.J Recept Signal Transduct Res. 2019; 39: 479-487
- Natural antioxidant control of neuropathic pain-exploring the role of mitochondrial SIRT3 pathway.Antioxidants (Basel). 2020; 9: 1103
- SIRT3 alleviates neuropathic pain by deacetylating FoxO3a in the spinal dorsal horn of diabetic model rats.Reg Anesth Pain Med. 2021; 46: 49-56
- Neuronal excitability and calcium/calmodulin-dependent protein kinase type II: location, location, location.Epilepsia. 2012; 53: 45-52
- Photoactivatable CaMKII induces synaptic plasticity in single synapses.Nat Commun. 2021; 12: 751
- Calcium/calmodulin-dependent kinase (CaMKII) inhibition protects against Purkinje cell damage following CA/CPR in mice.Mol Neurobiol. 2020; 57: 150-158
- CaMKIIalpha underlies spontaneous and evoked pain behaviors in Berkeley sickle cell transgenic mice.Pain. 2016; 157: 2798-2806
- The inhibitor of calcium/calmodulin-dependent protein kinase II KN93 attenuates bone cancer pain via inhibition of KIF17/NR2B trafficking in mice.Pharmacol Biochem Behav. 2014; 124: 19-26
- Intrathecal injection of KN93 attenuates paradoxical remifentanil-induced postoperative hyperalgesia by inhibiting spinal CaMKII phosphorylation in rats.Pharmacol Biochem Behav. 2015; 134: 35-41
- Effects of electroacupuncture in a mouse model of fibromyalgia: role of N-methyl-D-aspartate receptors and related mechanisms.Acupunct Med. 2017; 35: 59-68
- Electroacupuncture attenuates CFA-induced inflammatory pain by regulating CaMKII.Neural Plast. 2020; 20208861994
- Electroacupuncture alleviates chemotherapy-induced pain through inhibiting phosphorylation of spinal CaMKII in rats.Eur J Pain. 2018; 22: 679-690
- A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man.Pain. 1988; 33: 87-107
- Electroacupuncture relieves neuropathic pain by inhibiting degradation of the ecto-nucleotidase PAP in the dorsal root ganglions of CCI mice.Eur J Pain. 2022; 26: 991-1005
- Chemogenetic manipulation of microglia inhibits neuroinflammation and neuropathic pain in mice.Brain Behav Immun. 2021; 92: 78-89
- TRPM3 channels play roles in heat hypersensitivity and spontaneous pain after nerve injury.J Neurosci. 2021; 41: 2457-2474
- Intrathecal morphine in mice: a new technique.Eur J Pharmacol. 1980; 67: 313-316
- Promotion of bone cancer pain development by decorin is accompanied by modification of excitatory synaptic molecules in the spinal cord.Mol Pain. 2019; 151744806919864253
- Astrocyte-neuron lactate shuttle sensitizes nociceptive transmission in the spinal cord.Glia. 2019; 67: 27-36
- DREADDs suppress seizure-like activity in a mouse model of pharmacoresistant epileptic brain tissue.Gene Ther. 2016; 23: 760-766
- Spinal distribution of c-Fos activated neurons expressing enkephalin in acute and chronic pain models.Brain Res. 2014; 1543: 83-92
- Electroacupuncture induces antihyperalgesic effect through endothelin-B receptor in the chronic phase of a mouse model of complex regional pain syndrome type I.Pflugers Arch. 2018; 470: 1815-1827
- Electroacupuncture suppresses glucose metabolism and GLUT-3 expression in medial prefrontal cortical in rats with neuropathic pain.Biol Res. 2021; 54: 24
- Effects of electroacupuncture at 2 and 100 Hz on rat type 2 diabetic neuropathic pain and hyperalgesia-related protein expression in the dorsal root ganglion.J Zhejiang Univ Sci B. 2017; 18: 239-248
- Effects of low- and high-frequency electroacupuncture on protein expression and distribution of TRPV1 and P2X3 in rats with peripheral nerve injury.Acupunct Med. 2021; 39: 478-490
- MiRNAs are involved in chronic electroacupuncture tolerance in the rat hypothalamus.Mol Neurobiol. 2017; 54: 1429-1439
- Antinociception of spirocyclopiperazinium salt compound LXM-10-M targeting α7 nicotinic receptor and M4 muscarinic receptor and inhibiting CaMKIIα/CREB/CGRP signaling pathway in mice.Eur J Pharmacol. 2016; 770: 92-98
- CaMKIIalpha mediates the effect of IL-17 to promote ongoing spontaneous and evoked pain in multiple sclerosis.J Neurosci. 2018; 38: 232-244
- CaMKIIalpha may modulate fentanyl-induced hyperalgesia via a CeLC-PAG-RVM-spinal cord descending facilitative pain pathway in rats.PLoS One. 2017; 12e0177412
- Parabrachial nucleus circuit governs neuropathic pain-like behavior.Nat Commun. 2020; 11: 5974
- Sirt3 ameliorates oxidative stress and mitochondrial dysfunction after intracerebral hemorrhage in diabetic rats.Front Neurosci. 2018; 12: 414
- Oxidized nicotinamide adenine dinucleotide-dependent mitochondrial deacetylase sirtuin-3 as a potential therapeutic target of Parkinson's disease.Ageing Res Rev. 2020; 62101107
- Sirt3 protects Against ischemic stroke injury by regulating HIF-1alpha/VEGF signaling and blood-brain barrier integrity.Cell Mol Neurobiol. 2021; 41: 1203-1215
- Mitochondrial SIRT3 and neurodegenerative brain disorders.J Chem Neuroanat. 2019; 95: 43-53
- SIRT3 promotes antimycobacterial defenses by coordinating mitochondrial and autophagic functions.Autophagy. 2019; 15: 1356-1375
- Reactive oxygen species contribute to neuropathic pain and locomotor dysfunction via activation of CamKII in remote segments following spinal cord contusion injury in rats.Pain. 2013; 154: 1699-1708
Article info
Publication history
Published online: August 24, 2022
Accepted:
July 22,
2022
Received in revised form:
June 29,
2022
Received:
March 31,
2022
Footnotes
Source(s) of financial support: This work was supported by the National Natural Science Foundation of China (no. 81971061; 81771195). The funders had no role in the study design, data collection or analysis, decision to publish, or in the preparation of the manuscript.
Conflict of Interest: The authors reported no conflict of interest.
Identification
Copyright
© 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.
