Authors: Li, Xiongjuan MD et al

Anesthesia & Analgesia 140(3):p 616-627, March 2025

Abstract

One of the functions of organism cells is to maintain energy homeostasis to promote metabolism and adapt to the environment. The 3 major pathways of cellular energy metabolism are glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS). Neurons, astrocytes, and microglia are crucial in allodynia, hyperalgesia, and sensitization in nociceptive pathways. This review focused on these 3 major cellular energy metabolism pathways, aiming to elucidate the relationship between neurocyte and pain sensation and present the reprogramming of energy metabolism on pain, as well as the cellular and molecular mechanism underlying various forms of pain. The clinical and preclinical drugs involved in pain treatment and molecular mechanisms via cellular energy metabolism were also discussed.

The glycolysis, tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS) are believed to be at the core of the metabolic pathway; however, little is known about the relationship between cellular energy metabolism and pain. Therefore, this narrative review focused on the 3 major energy metabolism pathways of neurocyte and pain sensation, elaborating the involvement in energy metabolism of neurocyte and the modulation of pain sensation (Supplemental Digital Content 1, Supplemental Figure 1, https://links.lww.com/AA/E972 ). In addition, we considered the role of energy metabolism reprogramming on pain modulation and molecular mechanisms underlying different types of pain. Finally, we reviewed pain treatment drugs acting via cellular energy metabolism.

METHODS

Our narrative review was informed by a literature search (see Supplemental Digital Content 2, Supplement 2, https://links.lww.com/AA/E908, for our search strategy) that yielded 102 articles, including 26 review and editorial articles, 16 clinical studies, and 65 laboratory studies. Five articles encompassed a combination of clinical and laboratory studies.

GLYCOLYSIS OF NEUROCYTES MODULATES PAIN SENSATION

The Inhibition of Glycolysis Can Relieve Pain

The enhanced glycolytic response is associated with neuropathic pain,¹ diabetic neuropathy,² and chemotherapeutic-induce peripheral neuropathic pain.³^,⁴ 2-deoxy-D-glucose (2-DG, glycolytic inhibitor) downregulates the release of inflammation-related and migraine-related factors from microglia activation, thus inhibiting the onset of migraine.⁵

Glucose Sensor of Neurocytes

The glucose sensor localized into the membrane primarily includes facilitative glucose transporters (GLUTs) and the sodium-glucose-linked cotransporter (SGLT) family.⁶ GLUT3 and SGLT3 serving as a glucose sensor can sense extracellular glucose and participate in energy metabolism regulation of neurons and glial cells through glycolysis.⁷ Decreased levels of GLUT3 in the cortex are associated with neuropathic pain reduction.⁸

Figure 1.:

Glycolysis of neurocytes modulate pain sensation. 2-DG is able to inhibit the glycolysis pathway. Extracellular glucose is transported to the cytosol via glucose sensors GLUT and SGLT located on the membrane. HK2, PFK1, and PKM2 are 3 key enzymes (pink) in glycolysis. HK2, GPI1, PFK1, PGK1, PGAM1, and ENO1 might regulate neuronal impulses (*dotted black arrows*) by affecting the activity of neurons and/or glial cells. PKM2, LDH, and LA are directly associated with pain (*black solid arrows*). Dexmedetomidine inhibits the activity of GLUT, HK2, and PFK, thus reducing the levels of glucose, pyruvate, and lactic acid, eventually regulating pain.¹² PGK1 activator may affect the activity of neurocytes to regulate pain signals. Tat-PGAM1 inhibits microglial activation and the release proinflammatory cytokines.¹³ PKM2 inhibitors can alleviate pain response in astrocytes. Lactic acid shows a significant correlation with pain sensation.2-DG indicates 2-deoxy-D-glucose; ENO1, enolase 1; GLUT, glucose transporter; GPI1, glucose-6-phosphate isomerase 1; HK2, hexokinase 2; LA, lactic acid; LDH, lactate dehydrogenase; PFK-1, phosphofurctokinase-1; PGK1, phosphoglycerate kinase 1; PGAM1, phosphoglycerate mutase 1; PKM2, pyruvate kinase M2; SGLT, sodium-glucose-linked cotransporter; Tat-PGAM1, Tat-phosphoglycerate mutase 1.

Figure 2.:

TCA cycle in mitochondria regulates the pain sensation of neurocytes. CS, IDH, α-ketoglutarate dehydrogenase are 3 key enzymes (pink) in TCA metabolism. CS, succinyl-CoA synthetase may modulate pain sensation by affecting mitochondrial function (*dotted black arrows*). Aconitase, IDH, α-ketoglutarate, succinyl-CoA synthetase possibly regulate pain signal transduction by influencing neurocyte activity (*dotted black arrows*). KGDHC can catalyze its own posttranslational modification and that of other enzymes (including IDH and fumarase). The decrease in IDH activity, and the increased activities of KGDHC, fumarase, and pyruvate dehydrogenase complex are also demonstrated after succinylation. PDKs are capable of suppressing the activity of PDH. CS indicates citrate synthase; IDH, isocitrate dehydrogenase; KGDHC, α-ketoglutarate dehydrogenase complex; PDH, pyruvate dehydrogenase; PDKs, pyruvate dehydrogenase kinase; TCA, tricarboxylic acid.

Figure 3.:

OXPHOS serves as an essential pathway for pain regulation in neurocytes. The electron transfer chain is a series of complexes located on the inner mitochondrial membrane, promoting the oxidation of NADH and FADH₂ produced by glycolysis and TCA cycle, and pumping protons (H⁺) out of the inner mitochondrial membrane, then utilizes a series of electron transfer reactions via OXPHOS for ATP generation. Complexes I to V are associated with multiple pain conditions. The mechanism of relevant drugs is also related to electron transfer chains and OXPHOS. ROS and ATP also closely correlate with peripheral and central pain signaling. Excessive ROS and overdose ATP could induce pain response, ROS scavenger, and suitable ATP dosage provide pain relief. ATP indicates adenosine triphosphate; FADH₂, reduced flavin adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species; TCA, tricarboxylic acid.

SGLT2 inhibitors empagliflozin is a novel pleiotropic hypoglycemic agent, which can regulate the neurotransmitters, the survival and plasticity of neurons, and exert protective effects for the function of astrocyte and microglia.⁹ SGLT2 inhibitors decrease interleukin-1β (IL-1β) release by reducing microglial burden, thus protecting the function of neurocytes and improving patients’ prognosis.¹⁰ In addition, SGLT1 inhibitors have been shown to be connected with a decrease of incident gout.¹¹

Various Enzymes in Glycolysis May Affect the Pain Sensation

Although most glycolytic enzymes have not been proven to be directly associated with pain, they may affect neurocytes and play a role in pain modulation (Figure 1).

Upregulation of hexokinase 2 (HK2), the first rate-limiting enzyme in glycolysis, has been linked to migraine attacks.⁵
Glucose-6-phosphate isomerase 1 (GPI1) can protect the function of dopaminergic neurons via glycolysis.¹⁴ The potential role of association between Gpi1 decrease and visceral pain may warrant attention and further study.¹⁵
The most potent allosteric activator of phosphofurctokinase-1 (PFK-1) is fructose-2,6-bisphosphate, whose biosynthesis relies almost entirely on 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3). Nitric oxide-mediated inhibition of mitochondrial respiration increases PFK1 activity, redistributing glucose flow into glycolysis in astrocytes. Owing to the presence of anaphase-promoting complex/cyclosome-Cdh1, leading to degradation of PFKFB3, neurons lacking PFKFB3 cannot activate the glycolysis by increasing PFK-1 activity, thus being unable to maintain energy production.¹⁶^,¹⁷ The repression of microglial activation reduces glucose uptake, PFK-1 activity during neuroinflammation.¹⁸
Aldolase A (ALDOA) might be a key target gene that is involved in synaptic vesicle-mediated substance transport and adenosine triphosphate (ATP) metabolism, thereby affecting the function of neurons.¹⁹
Some evidence showed that the expression of the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is markedly elevated in neuropathic pain models.²⁰
The enhancement of phosphoglycerate kinase 1 (PGK1) activity can promote the ATP generation in the brain, and reduce neuronal degradation.²¹ Intraventricular injection of extracellular PGK1, which can localize to dopaminergic neurons, participates in energy supply and promotes the survival of dopaminergic neurons.²² Moreover, PGK1 reduces microglial M1-type polarization that can promote the release of proinflammatory factors and toxic substances to exacerbate cell damage.²³
The presence of phosphoglycerate mutase 1 (PGAM1) accelerates the rate of glycolysis. Tat-PGAM1 can cross the blood-brain barrier (BBB) and cell membrane, facilitates ATP use, mitigating neuronal damage,²⁴ inhibiting the microglial activation and proinflammatory factors released in the ischemic spinal cord.¹³
Enolase 1 (ENO1) upregulation was mainly involved in the modulation of synapses between neurons, synaptic vesicle-mediated transport, and related pathways in neurodegenerative diseases.¹⁹ Overexpression of ENO1 alleviates neuronal spine loss and the length reduction of the dendrite, thereby protecting the neuronal function²⁵ and simultaneously promoting M2-type polarization of microglia.²⁶
The inhibition of pyruvate kinase M2 (PKM2) directly alleviates neuropathic pain.²⁷ Astrocytes can be activated during inflammatory pain, accompanying the increase of PKM2 and lactic acid (LA), PKM2 can translocate into the nucleus and then activate the signal transducer and activator of transcription 3 (STAT3) signaling pathway, which can be reversed by inhibiting PKM2-mediated aerobic glycolysis, thus alleviating pain response.²⁸

Anaerobic Glycolysis Metabolites Lactic Acid Modulate Pain Signaling

The metabolic product pyruvate produced by glycolysis enters mitochondria under aerobic conditions and then drives the TCA cycle. During hypoxia, lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to LA. A high postoperative pain level is associated with a significant rise in LDH, which can predict moderate to severe postoperative pain, thus providing an effective clinical biological indicator.²⁹ LA is a natural chiral molecule that includes L- and D-LA. Clinical determination of LA is mainly based on L-LA, the lactate shuttle hypothesis posits that L-LA can shuttle between neurons and astrocytes to regulate cellular energy metabolism.³⁰ Intrathecal administration of L-LA can induce hyperalgesia, which can be alleviated by inhibiting the L-LA delivery from activated astrocytes to neurons. LDH inhibitors can also decrease the sensitivity of the spinal cord to nociceptive stimuli, thereby reducing neuropathic pain.³¹ In addition, LA could be used as a metabolic biomarker of discogenic back pain due to its obvious relevance in pain sensation.³² Initial study has discovered that patients experiencing chronic widespread pain exhibit elevated levels of LA and glutamate in trapezius muscle and plasma.³³ In patients with rheumatoid arthritis (RA), intercellular and articular cavities of inflammatory joints result in the increase of LA, migration, and activation of immune cells. This process enhances the body’s immune response, aggravating the patient’s condition.³⁴

MITOCHONDRIAL TCA CYCLE REGULATES THE PAIN SENSATION

It seems that the total number and area of mitochondria in the dendrites of neurons exceed 60%, these highly expressed mitochondria are tightly related to the pain signaling of sensory neurons.³⁵ Various enzymes and metabolites in the TCA cycle participate in neuronal activity and pain sensation (Figure 2).

The activity of pyruvate dehydrogenase (PDH) can be inhibited by pyruvate dehydrogenase kinases (PDKs). PDK2 and/or PDK4 deficiency promotes anti-inflammatory M2 and inhibits proinflammatory M1 response during inflammatory pain; they can also decrease neuronal sensitization, glial activation, and LA generation in peripheral localized inflammation.³⁶^,³⁷
Intriguingly, in patients with back pain and intervertebral disk degeneration, the more severe intervertebral disk degeneration, the lower level of citrate synthase (CS) in annulus cells, accompanied by abnormalities in mitochondrial ultrastructure.³⁸
The activity of aconitase is reduced during inflammation in cholinergic neurons and microglia.³⁹ Moreover, it exhibits a reduction in the metabolites of aconitate during a migraine attack.⁴⁰
Type 1 interferon (IFNβ) inhibits the isocitrate dehydrogenase (IDH) activity and the accumulation of its metabolite α-ketoglutarate, and the treatment of α-ketoglutarate reverses IFNβ-mediated analgesia effect.⁴¹ IDH2 is likely to become a therapeutic target for treating spinal deformity and alleviating clinical symptoms such as decreased physical function and pain.⁴²
As a transsuccinylase, α-ketoglutarate dehydrogenase complex (KGDHC) mediates succinylation in an α-ketoglutarate dependent way.⁴³ KGDHC can catalyze its own posttranslational modification and that of other enzymes (including IDH and fumarase) via succinylation. The decrease in IDH activity and increased activities of KGDHC, fumarase, and pyruvate dehydrogenase complex have been observed after succinylation. The lower KGDHC activity contributes to inhibiting the strong succinylation of mitochondria and cytosolic proteins in neurons.⁴⁴
The deletion of Succinyl-CoA synthetase A-β subunit induces severe mitochondrial dysfunction, leading to the reduction of synapse density and neuronal stress response.⁴⁵ The accumulation of its metabolite succinate was proven to be associated with inflammatory pain.⁴⁶ The analgesic action of IFNβ is also correlated with the increase of succinate level and the decrease of α-ketoglutarate/succinate ratio.⁴¹
A previous study revealed that the activity of succinic dehydrogenase (SDH) enhanced in laminae VIII and X neurons of arthritis.⁴⁷
Fumarase acts as a part of the TCA cycle, currently, more studies are needed when the evidence regarding the effect of fumarase on pain sensation is still lacking.
The only relevant correlation that is currently known is between elevated malate dehydrogenase (MDH) levels and arthritis pain,⁴⁸ while its regulatory role in pain sensation remains to be clarified.

OXPHOS SERVES AS AN ESSENTIAL PATHWAY FOR PAIN REGULATION

OXPHOS Participates in Pain Modulation

OXPHOS is the process of coupling oxidative energy release with ATP generation. Reactive oxygen species (ROS) are generated by aberrant electron transfer during OXPHOS, while excessive ROS production results in oxidative stress and cellular damage (Figure 3). The inhibition of OXPHOS can lead to mitochondrial dysfunction, causing various pathological pain.³⁵^,⁴⁹^,⁵⁰

Role of Complexes I to V in Mitochondrial Electron Transport Chain for Pain Regulation

The activity of Complexes I, II, and III decreased in chondrocytes of osteoarthritis patients, which may lead to chondrocyte degradation and oxidative stress, aggravating the inflammatory pain responses.⁵¹ Chemotherapy-induced neuropathic pain is associated with Complex-I- and Complex-II-mediated mitochondrial respiratory dysfunction.⁵²^,⁵³ The muscle pain caused by simvastatin treatment may be due to a considerable reduction of coenzyme Q10- and Complex I/Complex II-mediated OXPHOS in patients’ myofibers.⁵⁴ Ndufv2 (a core subunit of complex I) is correlated with single-nucleotide polymorphism rs145497186, they act together to influence the susceptibility to lumbar disk degeneration and the severity of chronic low back pain.⁵⁵

A higher proportion of Complex IV-negative fibers could be seen in patients with higher pain and more painful areas in female trapezius myalgia.⁵⁶ Neurons in C and Aδ fiber of dorsal root ganglion (DRG) exhibit reduced Complex V levels in neuropathic pain; intrathecal injection of ATP significantly attenuates these hyperalgesic responses. This symptom is likely due to the reduction of complex V leading to the decrease of ATP synthesis, thus contributing to the pain development.⁵⁷ Complex V inhibitors (eg, oligomycin) prevent hyperalgesia induced by endothelin-1.⁵⁸ Biopsy findings revealed a 45% reduction in the complex V subunit ATPase of skeletal muscle in patients with tubular aggregate myopathy. Chronic inhibition of complex V contributes to the formation of tubular aggregate, thereby promoting the onset of such disease, causing severe sarcomere disorders and muscle pain.⁵⁹

The Impact of OXPHOS Products ATP and ROS on Pain Sensation

There is substantial evidence that extracellular ATP is strongly tied to peripheral and central pain signaling transduction.⁶⁰ Appropriate doses of ATP injection could produce a long-lasting analgesic effect in patients with neuropathic pain, but an overdose of ATP might elicit pain,⁶¹ excessive intracellular ATP in the resting state evokes neuropathic pain due to increased extracellular ATP release.⁶²

ROS is directly or indirectly involved in the initiation and development of neuropathic pain, diabetic peripheral neuropathy, gout, endometriosis-induced pain, and intervertebral disk degeneration-induced low back pain.^63–67 ROS scavengers can effectively alleviate visceral pain, chemotherapy-mediated and diabetic neuropathic pain. They can also inhibit the pain signaling transduction by reducing peripheral and central oxidative stress.^68–70

METABOLIC REPROGRAMMING AFFECTS PAIN SENSATION

Normal cells primarily rely on mitochondrial OXPHOS, providing energy to cells, while most tumor cells are dependent on aerobic glycolysis, a phenomenon known as “Warburg effect.” This metabolic shift is driven by various stimulation and energy requirements. Neuroinflammation stimulates cellular metabolic reprogramming, enhancing the glycolysis by promoting glucose uptake, increasing PFK-1 activity and LA levels, thus eliciting an effect similar to the “Warburg effect.”¹⁸ Glycolysis enhancement in neuropathic pain exhibits the accumulation of LA, succinate, citric acid, and α-ketoglutarate. They promote microglia to further release the proinflammatory cytokines. Also, astrocytes can increase glucose uptake and induce anaerobic glycolysis. The increased LA can shuttle from astrocytes to neurons, affecting synaptic remodeling and central sensitization.⁷¹ This abnormal “astrocyte-to-neuron lactate shuttle” is believed to be the driving force behind the altered lactate metabolism, where astrocytes, supply activated neurons with energy via LA,⁷² thereby mediating pain signal transduction.

PKM2 is directly related to pain and metabolic reprogramming,⁷³ and hypoxia-inducible factor 1α (HIF-1α) is also an essential factor for regulating metabolic reprogramming and inflammatory response.⁷⁴ PKM2 activation inhibits the direct binding of PKM2/HIF-1α complex and IL-1β promoter under inflammatory stimuli, then decreases the expression of HIF-1α and IL-1β, thus restricting the glycolysis. The regulation of HIF-1α and IL-1β via PKM2 precisely determines factors that mediate the “Warburg effect.”⁷⁵ Isoschaftoside suppresses the inflammatory process in microglia by decreasing the expression of HIF-1α, HK2, PFKFB3 levels, and mitigating HIF-1α-mediated metabolic reprogramming.⁷⁶

Increased expression of PDKs and the subsequent inhibition of PDH activity lean more toward the transition of energy metabolism from OXPHOS to glycolysis and then increase the production of LA, which in turn regulates neuronal excitability and glial activation³⁶^,⁷⁷ The deficiency of PDK2/4 downregulates the levels of LA in DRG and inhibits microglia activation, thus preventing diabetic neuropathic pain.⁷⁸ The elevation of PDK3 is the typical characteristic of osteoarthritis patients with invasive and proliferative fibroblast-like synoviocytes. PDK inhibition transits cellular energy metabolism from glycolysis to OXPHOS, then suppresses the cytokines release and cell proliferation phenotype, leading to metabolic reprogramming without affecting the cellular steady oxidative state, which may restore the healthy phenotype of cells, thereby alleviating the progression of osteoarthritis.⁷⁹

MITOCHONDRIAL BIOGENESIS-RELATED REGULATORY MECHANISM IN PAIN SENSATION

The key regulators of mitochondrial biogenesis, including peroxisome proliferative activated receptor-γ coactivator-1α (PGC-1α), sirtuin 1 (SIRT1), and AMP-activated protein kinase (AMPK), are involved in pain sensation (Supplemental Digital Content 1, Supplemental Figure 2, https://links.lww.com/AA/E972).

The nociceptive pain (such as musculoskeletal pain, and headaches) involves signaling pathways that are activated by AMPK and regulate mitochondrial biogenesis via PGC-1α-SIRT3 positive feedback loop.⁵⁰^,⁸⁰^,⁸¹ In neuropathic pain, PGC-1α serves as a principal regulator and potential therapeutic target, which is regulated by SIRT1 and AMPK, then operating via the nuclear respiratory factor-1 and -2 (Nrf-1/2) and mitochondrial transcription factor A (TFAM) axis.⁸² In osteoarthritis, mitochondrial biogenetic processes are regulated by PGC-1α, along with Nrf-1/2, which subsequently increase the level of TFAM and nuclear-encoded mitochondrial proteins (NEMPs). Pathways such as AMPK/SIRT1/PGC-1α have emerged as promising targets for alleviating osteoarthritis cartilage lesions.⁸³ In RA, PGC-1α mRNA is controlled by both methyltransferase-like 3 (METTL3) and YTHN-6-methyladenosine RNA binding protein 2 (YTHDF2), which inhibit mitochondrial biogenesis and mediate synovial inflammation via PGC-1α/Nrf1/TFAM pathway. Simultaneously, mitochondrial neogenesis can be directly stimulated by activating the AMPK/SIRT1/PGC-1α pathway.⁸⁴

CELLULAR AND MOLECULAR MECHANISMS OF ENERGY METABOLISM IN DIFFERENT TYPES OF PAIN

Cellular energy metabolism has the capacity to modulate diverse forms of pain, encompassing the signaling pathways in both nerve cells and peripheral cells (Supplemental Digital Content 1, Supplemental Figure 3, https://links.lww.com/AA/E972).

Nociceptive Pain

The upregulation of HK2, PKM2, and LDH in glycolysis results in an elevation of IL-1β and IL-6, thereby playing a significant role in the initiation of migraine.⁵ The myalgia induced by simvastatin therapy may be attributed to the impairment of Complex I/Complex II-mediated OXPHOS within the myofibers of patients.⁵⁴

Neuropathy Pain

In glycolysis, PKM2 is linked to neuropathic pain, potentially initiating the activation of extracellular regulated protein kinase (ERK) and STAT3 signaling pathways, thereby resulting in an elevation of tumor necrosis factor-α (TNF-α) and IL-1β.²⁷ Excessive supply of LA by activated astrocyte through an aberrant astrocyte-neuron lactate shuttle contributes to the maintenance of mechanical hyperalgesia.³¹ The decline in CS activity may result in mitochondrial dysfunction, as well as the activation of astrocytes and microglia within the TCA cycle.⁸⁵ In OXPHOS, the diminishment of complex V in C and Aδ fibers of DRG neurons could potentially precipitate a decline in ATP synthesis, consequently leading to the manifestation of pain hypersensitivity responses.⁵⁷ However, an excessive intracellular accumulation of ATP can lead to the subsequent extracellular release of ATP, consequently inducing neuropathic pain via the P2X prinoreceptor 4 (P2X4) receptor.⁶² The heightened mechanical sensitivity exhibited by peripheral Aδ/C fiber terminals, coupled with the augmented intensity of spinal excitatory synaptic activity in the central nervous system, contributes to the development of chemotherapy-induced neuropathic pain in an ROS-dependent manner.⁶⁹ Also, the involvement of ROS in the progression of diabetic neuropathic pain is facilitated via the thioredoxin-interacting protein/NOD-like receptor protein 3/NMDA receptor 2B (TXNIP/NLPR3/NR2B) pathway in both neurons and microglia.⁷⁰

Inflammatory Pain

The activation of PKM2 translocation and subsequent pSTAT3 and high mobility group box-1 protein (HMGB1) signaling were observed to lead to the sustained activation of astrocytes.²⁸ LA plays a significant role in the migration and activation of immune cells, which subsequently undergo proliferation and release ILs and inflammatory mediators.³⁴ PDK2/4 that inhibit PDH activity promote peripheral LA surge and central sensitization, leading to the increase of TNF-α, IL-1β, IL-6, and pERK, indicating that PDK-PDH-LA axis as an essential link between metabolism and inflammation-driven pain hypersensitivities.³⁶^,³⁷ IFN-β induces lower IDH activity and controls the cellular α-ketoglutarate/succinate ratio in macrophages, consequently leading to the suppression of Jumonji domain-containing protein 3/interferon regulatory factor 4 (JMJD3-IRF4) dependent responses, which can be reversed by α-ketoglutarate supplement.⁴¹ The aggregation of succinate resulting from reduced SDH activity triggers the activation of the succinate/SUCNR1(succinate receptor 1)-HIF-1α/NLPR3 pathway.⁴⁶ The diminished activity of Complex I, II, and III affects several pathways in osteoarthritis, including mitochondrial DNA mutation-induced mitochondrial dysfunction, increased inflammatory mediators, and oxidative stress.⁵¹

ANALGESIC DRUGS RELATED TO CELL ENERGY METABOLISM

Clinical and Potential Preclinical Analgesics and Acting on Glucose Sensors and Glycolysis

Dexmedetomidine possesses analgesic and sedative properties, which can inhibit glucose sensor GLUT1 and HK2 and PFK1, thus significantly reducing the levels of glucose, pyruvate, and LA, eventually regulating neuropathic pain.⁸⁶ SGLT1 inhibitors may serve as one of the therapeutic agents for the treatment of gout with or without comorbid diabetes.¹¹ SGLT2 inhibitors may improve diabetic neuropathy by increasing the conduction velocity of sensory and motor nerves and reducing sympathetic nerve activity, which may help alleviate pain.¹²

Table 1. – Clinical and Potential Preclinical Analgesics Acting on Glycolysis

Drugs	Metabolic pathway	Target	Pain type/model	Subjects/route/dose	Results/related mechanism	References
Clinical
Dexmedetomidine	Glucose sensor glycolysis	GLUT1↓ HK2↓, PFK↓	Neuropathic pain	DRG neurons/cell culture/20.84 μM	Inhibit neuronal apoptosis and ROS, and reduce glucose, pyruvic acid, and lactic acid levels	⁸⁶
SGLT1 inhibitor (eg, mizaglifozin)	Glucose sensor	SGLT1 ↓	Gout	Mendelian randomization study	May serve as a novel therapeutic option for gout treatment in patients with or without diabetes	¹¹
SGLT2 inhibitor	Glucose sensor	SGLT2 ↓	Diabetic neuropathy pain	Systematic review and meta-analysis	Increase the sensory and motor nerve conduction velocity, and reduce sympathetic nervous system activity	¹²
Preclinical
PGK1 activator	Glycolysis	PGK1	Oxidative stress model	PC12 cells/cell culture/1.5625–12.5μM	Potential neuroprotective drugs against oxidative stress and ameliorate neuronal apoptosis	^87,88
Tat-PGAM1	Glycolysis	PGAM1	Ischemic damage	i.p., 2.5 mg/kg NSC34 cells/ cell culture/3 μM	Decrease spinal oxidative stress, microglia activation, and proinflammatory cytokines release	¹³
PKM2 inhibitor (PKM2 siRNA or PKM2-IN-1)	Glycolysis	PKM2	Neuropathic pain Inflammatory pain	i.th. PKM2 siRNA 15 µg/20 μL i.th. PKM2-IN-1 20 μL	Reduce pain via central ERK and STAT3 signaling pathway	^27,28
4-CIN	Glycolysis	Lactic acid	Neuropathic pain	i.th. 500 ng	Maintain hyperalgesia by excessive L-lactate supplied by activated astrocytes via an abnormal .;	³¹
Isosafrole	Glycolysis	LDH	Neuropathic pain	i.th. 100 nM		³¹

Abbreviations: ANLS, astrocyte-neuron lactate shuttle; 4-CIN, α-cyano-4-hydroxycinnamate; DRG, dorsal root ganglion; ERK, regulated protein kinase; GLUT1, glucose transporter 1; HK2, hexokinase 2; LDH, lactate dehydrogenase; NSC34, neuroblastoma x spinal cord cells; PC12, pheochromocytoma cells; PFK, phosphofurctokinase; PGAM1, phosphoglycerate mutase 1; PGK1, phosphoglycerate kinase 1; PKM2, pyruvate kinase M2; PKM2-IN-1, a specific inhibitor of PKM2; ROS, reactive oxygen species; SGLT1, sodium-glucose-linked cotransporter 1; siRNA, small interfering ribonucleic acid; STAT3, signal transducer and activator of transcription 3; Tat-PGAM1, Tat-phosphoglycerate mutase 1.

Table 2. – Clinical and Potential Preclinical Analgesics Acting on Mitochondrial TCA Cycle

Drugs	Metabolic pathway	Target	Pain type/model	Subjects/route/dose	Results/related mechanism	References
Clinical
Celecoxib	TCA cycle	PDH	Acute inflammatory pain	DRG/i.p., 30 mg/kg	Suppress pain by inhibiting PGE2-induced hyperalgesia and PDH phosphorylation	⁸⁹
Traditional Chinese medicine
Sesame oil	TCA cycle	CS	Osteoarthritis	Quadriceps muscle/oral/1.2 or 4 mL/kg/d	Decrease IL-6, lipid peroxidation, nuclear NRF2, ROS, increase CS activity, MHC IIa mRNA	⁹⁰
Crocin	TCA cycle	CS	Osteoarthritis	Quadriceps muscle/oral/30mg/kg	Decrease IL-6 and increase CS activity	⁹¹
Paeoniflorin	TCA cycle	SDH	Inflammatory pain	DRG/i.p./30 mg/kg	Inhibit the activation of TRPV1 and succinate/SUCNR1-HIF-1α/ NLPR3 pathway	⁴⁶
Preclinical
Dichloroacetate	TCA cycle	PDK/PDH	Inflammatory pain	Spinal cord/oral/ 500 mg/L in drinking water	Improve mitochondrial respiratory function, and reduce glial reactivity. Involve in PDK-PDH-lactic acid axis	^36,92
Itaconate	TCA cycle	Originate from cis-aconitate	Neuropathic pain	spinal cord/i.p. 10–200 mg/kg i.th./10–100 μM	Increase IL-10 levels and activate STAT3/β-endorphin pathway	⁹³

Abbreviations: CS, citrate synthase; DRG, dorsal root ganglion; HIF-1α, hypoxia-inducible factor 1α; IL-10, interleukin-10; i.p., intraperitoneal; i.th., intrathecal; LDH, lactate dehydrogenase; MHC IIa, myosin heavy chains Ⅱa; NLPR3, NOD-like receptor protein 3; NRF-2, nuclear respiratory factor-2; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; PGE2, prostaglandin E2; SDH, succinic dehydrogenase; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3; SUCNR1, succinate receptor 1; TCA, tricarboxylic acid; TRPV1, transient receptor potential vanilloid 1.

PGK1 activator protects the neuronal cells by inhibiting the inflammatory cascade and neuronal apoptosis. The candidate drugs such as 7979989, Z112553128, and terazosin analogs may become potential targets for treating neurological diseases and pain.⁸⁷^,⁸⁸ Using Tat-PGAM1 (fusion protein) that can easily cross the BBB and reach target cells can inhibit spinal microglial activation and release proinflammation¹³ (Table 1).

Clinical and Potential Preclinical Analgesics Acting on Mitochondrial TCA Cycle

Systemic administration of celecoxib reduces prostaglandin E2 (PGE2) induced acute inflammatory pain by inhibiting PDH activity.⁸⁹ The treatment with sesame oil and crocin reduces pain response in mice with osteoarthritis, accompanied by increased CS activity and decreased IL-6 level.⁹⁰^,⁹¹ The antinociceptive mechanism of traditional Chinese medicine paeoniflorin is related to the succinate-mediated SUCNR1/HIF-α/NLPR3 signaling pathway.⁴⁶ Oral or topical injection of PDK inhibitor dichloroacetate effectively decreases inflammatory pain in rodent models.³⁶^,⁹² Itaconate is synthesized from cis-aconitate of the TCA cycle in macrophages, it exerts an analgesic effect in neuropathic pain by activating STAT3/β-endorphin signaling and increasing the levels of anti-inflammatory cytokine IL-10⁹³ (Table 2).

Clinical and Potential Preclinical Analgesics/Anesthetic Acting on OXPHOS Pathway

Carbamazepine is the first-line class drug for trigeminal neuralgia treatment, combined coenzyme Q10 (CoQ10) therapy reduces mitochondrial oxidative stress and alleviates pain more effectively.⁹⁴

The pain control mechanism of local anesthetic ropivacaine is associated with the inhibition of Complex I and Complex II activity, subsequently leading to energy depletion and oxidative stress.⁹⁵ Propofol can inhibit complex I, complex II, and cytochrome C, and suppress the mitochondrial function as an uncoupling agent in OXPHOS.⁹⁶ The action of isoflurane includes the direct inhibition of complex I, restriction of excitatory vesicle endocytosis and exocytosis, and the reduction of presynaptic recycling and ATP production.⁹⁷^,⁹⁸ ATP can be used as the treatment of neuropathic pain,⁵⁷^,⁶¹ but overdose ATP is a contributing factor of pain.⁶²

Table 3. – Clinical and Potential Preclinical Analgesics/Anesthetic Acting on OXPHOS Pathway

Drugs	Metabolic pathway	Target	Pain type/model	Subjects/route/dose	Results/related mechanism	References
Clinical
Carbamazepine	Electron transport	ROS	Trigeminal neuralgia	PBMCs/isolated cells oral/initial dose: 200 mg/d additional dose: 200 mg/w	Involve in increase oxidative stress, which can be reversed by CoQ10 supplements.	⁹⁴
Ropivacaine	Electron transport	Complexes I and II	Breast cancer pain	Breast cancer cells/0.1, 0.5, and 1 mM	Inhibit the Akt/mTOR pathway and mitochondrial functions	⁹⁵
Propofol	Electron transport	Complexes I, II, III, IV, and cytochrome C	Anesthetic	iv, 2–2.5 mg/kg	Interrupt the electron flow in the mitochondrial membrane	⁹⁶
Isoflurane	Electron transport	Complex I	Anesthetic	Hippocampal cultured neurons/ 2EC₅₀: 0.25/0.5/0.74 mM	Direct inhibit complex I, limit synaptic ATP production, excitatory vesicle endocytosis and exocytosis	^97,98
ATP	OXPHOS	ATP	Neuropathic pain Perioperative pain acute/chronic pain	i.th., 10 μL at 150 nmol intravenous infusion 100–130 μg/kg·min	Relate to C-fiber and Aδ fiber neurons. But overdose intracellular ATP induce pain	^57,61,62
Overdose toxic effect
Acetaminophen	Electron transport	Complex I	Overdose toxic effect	Hepatocytes, HepG2 cells, platelets/2.5–10 mM	Inhibit mitochondrial respiration, it can be restored by cell-permeable succinate prodrug NV241 (250 μM)	⁹⁹
Bupivacaine	Electron transport	ROS	Overdose toxic effect	Spinal cord/i.th., 0.75% 5 μL; twice at an interval of 1 h	Induce neurotoxicity via CaMK2α-MCU-mitochondrial oxidative stress	¹⁰⁰
Preclinical
P66hsc siRNA nanoparticles	OXPHOS	ROS	Osteoarthritis	Local injection into knee joints; 200 μL of 20 μM	Decrease mitochondrial dysfunction-induced cartilage damage	¹⁰¹
MOTS-c	Mitochondrial-derived peptide	Oxidative damage	Neuropathic pain	Spinal cord/i.th., 0.1, 0.5, 1 μg; i.pl., 1.5.10 μg; iv, 5.10 μg	Inhibit microglia activation and neuronal oxidative damage via AMPK pathway	¹⁰²
ROS scavenger (Tempol, PBN)	OXPHOS	ROS	Visceral pain Neuropathic pain	Tempol:100 mM into CeA PBN: i.p.,100 mg/kg; i.d. or i.th., 100 µg/5 μL i.p., 100 mg/kg·d	Central and peripheral mechanism: ROS mediate amygdala plasticity, oxidative stress, and via TXNIP/NLRP3/ NR2B pathway	^68–70

Abbreviations: Akt, serine/threonine kinase; AMPK, AMP-activated protein kinase; ATP, adenosine triphosphate; CaMK2α-MCU, Ca²⁺/calmodulin dependent protein kinase 2α-mitochondrial Ca²⁺ uniporter; CeA, central nuclei; CoQ10, coenzyme Q10; EC₅₀, 50% effective concentrations; HepG2, hepatocyte carcinoma cell line; i.d., intradermal; i.p., intraperitoneal; i.pl., intraplantar; i.th., intrathecal; iv, intravenous; MOTS-c, mitochondrial-derived peptide; mTOR, mammalian target of rapamycin; NV241, a cell-permeable succinate produrg (a mitochondrially targeted alternative energy substrate); OXPHOS, oxidative phosphorylation; P66hsc, an isoform of the shcA adaptor protein family; PBMCs, peripheral blood mononuclear cells; PBN, N-tert-butyl-α-phenylnitrone; ROS, reactive oxygen species; siRNA, small interfering ribonucleic acid; TXNIP/NLRP3/NR2B, thioredoxin-interacting protein/NOD-like receptor protein 3/N-methyl-D-aspartic acid receptor 2B pathway.

The toxicity caused by an overdose of some analgesics is also related to OXPHOS. Overdose of acetaminophen leads to mitochondrial toxicity by inhibiting complex I; the use of succinate prodrug NV241 with cell permeability can alleviate its mitochondrial respiratory inhibition.⁹⁹ Bupivacaine can induce mitochondrial stress and neuronal apoptosis, and affected by the Ca²⁺/calmodulin dependent protein kinase 2α-mitochondrial Ca²⁺ uniporter (CaMK2α-MCU) signaling pathway, the inhibition of CaMK2α-MCU can effectively reduce the neuronal toxicity of bupivacaine.¹⁰⁰

High expression of p66shc was found in the cartilage of patients with osteoarthritis. The local injection of p66shc siRNA nanoparticles into the knee joint alleviates arthritis pain by improving mitochondrial dysfunction and inhibiting ROS production.¹⁰¹ Mitochondrial-derived peptide MOTS-c produces analgesic effects, which have been found to correlate with the inhibition of AMPK-induced microglia activation and reduction of neuronal oxidative stress.¹⁰² The analgesic effect of ROS scavenger tempol and PBN is linked to the central and peripheral conduction systems of pain. The mechanism includes the inhibition of excitability and excitatory synaptic transmission in central amygdala neurons, the mechanical sensitivity of Aδ and C fiber terminals, and the block of the TXNIP/NLRP3/NR2B signaling pathway^68–70 (Table 3).

CONCLUSIONS

The current review aims to provide an overview of anesthesia and analgesic drugs that target the cellular energy metabolism pathway, both in preclinical and clinical settings, providing novel insights and support for future advancements in clinical pain research and management.

ACKNOWLEDGMENTS

The authors are grateful for the help of colleagues at the Department of Anesthesiology, Shenzhen Second People’s Hospital.

DISCLOSURES

This manuscript was handled by: Jianren Mao, MD, PhD.

REFERENCES

1. Kong E, Li Y, Ma P, et al. Lyn-mediated glycolysis enhancement of microglia contributes to neuropathic pain through facilitating IRF5 nuclear translocation in spinal dorsal horn. J Cell Mol Med. 2023;27:1664–1681.

2. Calcutt NA. Diabetic neuropathy and neuropathic pain: a (con)fusion of pathogenic mechanisms? Pain. 2020;161:S65–S86.

3. Ludman T, Melemedjian OK. Bortezomib-induced aerobic glycolysis contributes to chemotherapy-induced painful peripheral neuropathy. Mol Pain. 2019;15:1744806919837429.

4. Duggett NA, Griffiths LA, Flatters SJL. Paclitaxel-induced painful neuropathy is associated with changes in mitochondrial bioenergetics, glycolysis, and an energy deficit in dorsal root ganglia neurons. Pain. 2017;158:1499–1508.

5. Qiu T, Zhou Y, Hu L, et al. 2-Deoxyglucose alleviates migraine-related behaviors by modulating microglial inflammatory factors in experimental model of migraine. Front Neurol. 2023;14:1115318.

6. Lopez-Gambero AJ, Martinez F, Salazar K, Cifuentes M, Nualart F. Brain Glucose-sensing mechanism and energy homeostasis. Mol Neurobiol. 2019;56:769–796.

7. Welcome MO, Mastorakis NE. Emerging concepts in brain glucose metabolic functions: from glucose sensing to how the sweet taste of glucose regulates its own metabolism in astrocytes and neurons. Neuromolecular Med. 2018;20:281–300.

8. Jiang M, Chen X, Zhang L, et al. Electroacupuncture suppresses glucose metabolism and GLUT-3 expression in medial prefrontal cortical in rats with neuropathic pain. Biol Res. 2021;54:24.

9. Pawlos A, Broncel M, Wozniak E, Gorzelak-Pabis P. Neuroprotective effect of SGLT2 inhibitors. Molecules. 2021;26:7213.

10. Kounatidis D, Vallianou N, Evangelopoulos A, et al. SGLT-2 inhibitors and the inflammasome: what’s next in the 21st century? Nutrients. 2023;15:2294.

11. Zhao SS, Rajasundaram S, Karhunen V, Alam U, Gill D. Sodium-glucose cotransporter 1 inhibition and gout: Mendelian randomisation study. Semin Arthritis Rheum. 2022;56:152058.

12. Kandeel M. The outcomes of sodium-glucose co-transporter 2 inhibitors (SGLT2I) on diabetes-associated neuropathy: a systematic review and meta-analysis. Front Pharmacol. 2022;13:926717.

13. Jung HY, Kwon HJ, Kim W, et al. Phosphoglycerate mutase 1 prevents neuronal death from ischemic damage by reducing neuroinflammation in the rabbit spinal cord. Int J Mol Sci . 2020;21:7425.

14. Knight AL, Yan X, Hamamichi S, et al. The glycolytic enzyme, GPI, is a functionally conserved modifier of dopaminergic neurodegeneration in Parkinson’s models. Cell Metab. 2014;20:145–157.

15. Cisneros E, Martinez-Padilla A, Cardenas C, Márquez J, Ortega de Mues A, Roza C. Identification of potential visceral pain biomarkers in colon exudates from mice with experimental colitis: an exploratory in vitro study. J Pain. 2023;24:874–887.

16. Zhang F, Qian X, Qin C, et al. Phosphofructokinase-1 negatively regulates neurogenesis from neural stem cells. Neurosci Bull. 2016;32:205–216.

17. Herrero-Mendez A, Almeida A, Fernandez E, Maestre C, Moncada S, Bolaños JP. The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol. 2009;11:747–752.

18. Vizuete AFK, Froes F, Seady M, et al. Early effects of LPS-induced neuroinflammation on the rat hippocampal glycolytic pathway. J Neuroinflammation. 2022;19:255.

19. Jia E, Sheng Y, Shi H, et al. Spatial transcriptome profiling of mouse hippocampal single cell microzone in Parkinson’s disease. Int J Mol Sci . 2023;24:1810.

20. Zhang Y, Wang YH, Zhang XH, et al. Proteomic analysis of differential proteins related to the neuropathic pain and neuroprotection in the dorsal root ganglion following its chronic compression in rats. Exp Brain Res. 2008;189:199–209.

21. Cai R, Zhang Y, Simmering JE, et al. Enhancing glycolysis attenuates Parkinson’s disease progression in models and clinical databases. J Clin Invest. 2019;129:4539–4549.

22. Lin CY, Tseng HC, Chu YR, Wu C-L, Zhang P-H, Tsai H-J. Cerebroventricular injection of Pgk1 attenuates MPTP-induced neuronal toxicity in dopaminergic cells in zebrafish brain in a glycolysis-independent manner. Int J Mol Sci . 2022;23:4150.

23. Cao W, Feng Z, Zhu D, et al. The role of PGK1 in promoting ischemia/reperfusion injury-induced microglial M1 polarization and inflammation by regulating glycolysis. Neuromolecular Med. 2023;25:301–311.

24. Kim W, Kwon HJ, Jung HY, Yoo DY, Kim DW, Hwang IK. Phosphoglycerate mutase 1 reduces neuronal damage in the hippocampus following ischemia/reperfusion through the facilitation of energy utilization. Neurochem Int. 2020;133:104631.

25. Jiang W, Tian X, Yang P, et al. Enolase1 alleviates cerebral ischemia-induced neuronal injury via its enzymatic product phosphoenolpyruvate. ACS Chem Neurosci. 2019;10:2877–2889.

26. Liang X, Wang Z, Dai Z, et al. Glioblastoma glycolytic signature predicts unfavorable prognosis, immunological heterogeneity, and ENO1 promotes microglia M2 polarization and cancer cell malignancy. Cancer Gene Ther. 2023;30:481–496.

27. Wang B, Liu S, Fan B, et al. PKM2 is involved in neuropathic pain by regulating ERK and STAT3 activation in rat spinal cord. J Headache Pain. 2018;19:7.

28. Wei X, Jin XH, Meng XW, et al. Platelet-rich plasma improves chronic inflammatory pain by inhibiting PKM2-mediated aerobic glycolysis in astrocytes. Ann Transl Med. 2020;8:1456.

29. Gonzalez-Callejas C, Aparicio VA, De Teresa C, Nestares T. Association of body mass index and serum markers of tissue damage with postoperative pain. the role of lactate dehydrogenase for postoperative pain prediction. Pain Med. 2020;21:1636–1643.

30. Mosienko V, Teschemacher AG, Kasparov S. Is L-lactate a novel signaling molecule in the brain? J Cereb Blood Flow Metab. 2015;35:1069–1075.

31. Miyamoto K, Ishikura KI, Kume K, Ohsawa M. Astrocyte-neuron lactate shuttle sensitizes nociceptive transmission in the spinal cord. Glia. 2019;67:27–36.

32. Keshari KR, Lotz JC, Link TM, Hu S, Majumdar S, Kurhanewicz J. Lactic acid and proteoglycans as metabolic markers for discogenic back pain. Spine (Phila Pa 1976). 2008;33:312–317.

33. Gerdle B, Larsson B, Forsberg F, et al. Chronic widespread pain: increased glutamate and lactate concentrations in the trapezius muscle and plasma. Clin J Pain. 2014;30:409–420.

34. Wang Q, Asenso J, Xiao N, et al. Lactic acid regulation: a potential therapeutic option in rheumatoid arthritis. J Immunol Res. 2022;2022:2280973.

35. Flatters SJ. The contribution of mitochondria to sensory processing and pain. Prog Mol Biol Transl Sci. 2015;131:119–146.

36. Jha MK, Song GJ, Lee MG, et al. Metabolic connection of inflammatory pain: pivotal role of a pyruvate dehydrogenase kinase-pyruvate dehydrogenase-lactic acid axis. J Neurosci. 2015;35:14353–14369.

37. Jha MK, Rahman MH, Park DH, et al. Pyruvate dehydrogenase kinase 2 and 4 gene deficiency attenuates nociceptive behaviors in a mouse model of acute inflammatory pain. J Neurosci Res. 2016;94:837–849.

38. Gruber HE, Watts JA, Riley FE, Fulkerson M-B, Norton HJ, Hanley EN. Mitochondrial bioenergetics, mass, and morphology are altered in cells of the degenerating human annulus. J Orthop Res. 2013;31:1270–1275.

39. Klimaszewska-Lata J, Gul-Hinc S, Bielarczyk H, et al. Differential effects of lipopolysaccharide on energy metabolism in murine microglial N9 and cholinergic SN56 neuronal cells. J Neurochem. 2015;133:284–297.

40. Aczel T, Kortesi T, Kun J, et al. Identification of disease- and headache-specific mediators and pathways in migraine using blood transcriptomic and metabolomic analysis. J Headache Pain. 2021;22:117.

41. Ming-Chin Lee K, Achuthan AA, De Souza DP, et al. Type I interferon antagonism of the JMJD3-IRF4 pathway modulates macrophage activation and polarization. Cell Rep. 2022;39:110719.

42. Chae U, Park NR, Kim ES, et al. IDH2-deficient mice develop spinal deformities with aging. Physiol Res. 2018;67:487–494.

43. Gibson GE, Xu H, Chen HL, Chen W, Denton TT, Zhang S. Alpha-ketoglutarate dehydrogenase complex-dependent succinylation of proteins in neurons and neuronal cell lines. J Neurochem. 2015;134:86–96.

44. McKenna MC, Rae CD. A new role for alpha-ketoglutarate dehydrogenase complex: regulating metabolism through post-translational modification of other enzymes. J Neurochem. 2015;134:3–6.

45. Zhao Y, Tian J, Sui S, et al. Loss of succinyl-CoA synthase ADP-forming beta subunit disrupts mtDNA stability and mitochondrial dynamics in neurons. Sci Rep. 2017;7:7169.

46. Ruan Y, Ling J, Ye F, et al. Paeoniflorin alleviates CFA-induced inflammatory pain by inhibiting TRPV1 and succinate/SUCNR1-HIF-1alpha/NLPR3 pathway. Int Immunopharmacol. 2021;101:108364.

47. Schoenen J, Van Hees J, Gybels J, de Castro Costa M, Vanderhaeghen JJ. Histochemical changes of substance P, FRAP, serotonin and succinic dehydrogenase in the spinal cord of rats with adjuvant arthritis. Life Sci. 1985;36:1247–1254.

48. Lee CH, Butt YK, Wong MS, Lo SC. Differential protein expression induced by a lipid extract of Perna canaliculus in splenocytes of rats with adjuvant-induced arthritis. Inflammopharmacology. 2008;16:188–194.

49. Tchetina EV, Markova GA. Regulation of energy metabolism in the growth plate and osteoarthritic chondrocytes. Rheumatol Int. 2018;38:1963–1974.

50. Ye L, Li M, Wang Z, et al. Depression of mitochondrial function in the rat skeletal muscle model of myofascial pain syndrome is through down-regulation of the AMPK-PGC-1alpha-SIRT3 axis. J Pain Res. 2020;13:1747–1756.

51. Blanco FJ, Rego I, Ruiz-Romero C. The role of mitochondria in osteoarthritis. Nat Rev Rheumatol. 2011;7:161–169.

52. Zheng H, Xiao WH, Bennett GJ. Functional deficits in peripheral nerve mitochondria in rats with paclitaxel- and oxaliplatin-evoked painful peripheral neuropathy. Exp Neurol. 2011;232:154–161.

53. Zheng H, Xiao WH, Bennett GJ. Mitotoxicity and bortezomib-induced chronic painful peripheral neuropathy. Exp Neurol. 2012;238:225–234.

54. Larsen S, Stride N, Hey-Mogensen M, et al. Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance. J Am Coll Cardiol. 2013;61:44–53.

55. Wang Z, Chen L, Li Q, et al. Association between single-nucleotide polymorphism rs145497186 related to NDUFV2 and lumbar disc degeneration: a pilot case-control study. J Orthop Surg Res. 2022;17:473.

56. Kadi F, Waling K, Ahlgren C, et al. Pathological mechanisms implicated in localized female trapezius myalgia. Pain. 1998;78:191–196.

57. Chen KH, Lin CR, Cheng JT, Cheng J-K, Liao W-T, Yang C-H. Altered mitochondrial ATP synthase expression in the rat dorsal root ganglion after sciatic nerve injury and analgesic effects of intrathecal ATP. Cell Mol Neurobiol. 2014;34:51–59.

58. Joseph EK, Green PG, Levine JD. ATP release mechanisms of endothelial cell-mediated stimulus-dependent hyperalgesia. J Pain. 2014;15:771–777.

59. Sanchez-Gonzalez C, Herrero Martín JC, Salegi Ansa B, et al. Chronic inhibition of the mitochondrial ATP synthase in skeletal muscle triggers sarcoplasmic reticulum distress and tubular aggregates. Cell Death Dis. 2022;13:561.

60. Munoz MF, Griffith TN, Contreras JE. Mechanisms of ATP release in pain: role of pannexin and connexin channels. Purinergic Signal. 2021;17:549–561.

61. Hayashida M, Fukuda K, Fukunaga A. Clinical application of adenosine and ATP for pain control. J Anesth. 2005;19:225–235.

62. Nakajima N, Ohnishi Y, Yamamoto M, et al. Excess intracellular ATP causes neuropathic pain following spinal cord injury. Cell Mol Life Sci. 2022;79:483.

63. Dai CQ, Guo Y, Chu XY. Neuropathic pain: the dysfunction of Drp1, mitochondria, and ROS homeostasis. Neurotox Res. 2020;38:553–563.

64. Pang L, Lian X, Liu H, et al. Understanding diabetic neuropathy: focus on oxidative stress. Oxid Med Cell Longev. 2020;2020:9524635.

65. Yin C, Liu B, Li Y, et al. IL-33/ST2 induces neutrophil-dependent reactive oxygen species production and mediates gout pain. Theranostics. 2020;10:12189–12203.

66. Clower L, Fleshman T, Geldenhuys WJ, Santanam N. Targeting oxidative stress involved in endometriosis and its pain. Biomolecules. 2022;12:1055.

67. Zheng J, Zhang J, Zhang X, et al. Reactive oxygen species mediate low back pain by upregulating substance P in intervertebral disc degeneration. Oxid Med Cell Longev. 2021;2021:6681815.

68. Ji G, Li Z, Neugebauer V. Reactive oxygen species mediate visceral pain-related amygdala plasticity and behaviors. Pain. 2015;156:825–836.

69. Shim HS, Bae C, Wang J, et al. Peripheral and central oxidative stress in chemotherapy-induced neuropathic pain. Mol Pain. 2019;15:1744806919840098.

70. Wang JW, Ye XY, Wei N, et al. Reactive oxygen species contributes to type 2 diabetic neuropathic pain via the thioredoxin-interacting protein-NOD-like receptor protein 3- N -methyl-D-aspartic acid receptor 2B pathway. Anesth Analg. 2022;135:865–876.

71. Kong E, Li Y, Deng M, et al. Glycometabolism reprogramming of glial cells in central nervous system: novel target for neuropathic pain. Front Immunol. 2022;13:861290.

72. Magistretti PJ, Pellerin L. Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging. Philos Trans R Soc Lond B Biol Sci. 1999;354:1155–1163.

73. Alquraishi M, Puckett DL, Alani DS, et al. Pyruvate kinase M2: a simple molecule with complex functions. Free Radic Biol Med. 2019;143:176–192.

74. Corcoran SE, O’Neill LA. HIF1alpha and metabolic reprogramming in inflammation. J Clin Invest. 2016;126:3699–3707.

75. Palsson-McDermott EM, Curtis AM, Goel G, et al. Pyruvate kinase M2 regulates Hif-1alpha activity and IL-1beta induction and is a critical determinant of the Warburg effect in LPS-activated macrophages. Cell Metab. 2015;21:65–80.

76. Guan S, Sun L, Wang X, Huang X, Luo T. Isoschaftoside inhibits lipopolysaccharide-induced inflammation in microglia through regulation of HIF-1alpha-mediated metabolic reprogramming. Evid Based Complement Alternat Med. 2022;2022:5227335.

77. Jha MK, Lee IK, Suk K. Metabolic reprogramming by the pyruvate dehydrogenase kinase-lactic acid axis: linking metabolism and diverse neuropathophysiologies. Neurosci Biobehav Rev. 2016;68:1–19.

78. Rahman MH, Jha MK, Kim JH, et al. Pyruvate dehydrogenase kinase-mediated glycolytic metabolic shift in the dorsal root ganglion drives painful diabetic neuropathy. J Biol Chem. 2016;291:6011–6025.

79. Damerau A, Kirchner M, Pfeiffenberger M, et al. Metabolic reprogramming of synovial fibroblasts in osteoarthritis by inhibition of pathologically overexpressed pyruvate dehydrogenase kinases. Metab Eng. 2022;72:116–132.

80. Alcocer-Gomez E, Garrido-Maraver J, Bullon P, et al. Metformin and caloric restriction induce an AMPK-dependent restoration of mitochondrial dysfunction in fibroblasts from Fibromyalgia patients. Biochim Biophys Acta. 2015;1852:1257–1267.

81. Shan Z, Wang Y, Qiu T, et al. SS-31 alleviated nociceptive responses and restored mitochondrial function in a headache mouse model via Sirt3/Pgc-1alpha positive feedback loop. J Headache Pain. 2023;24:65.

82. Zhai M, Hu H, Zheng Y, Wu B, Sun W. PGC1alpha: an emerging therapeutic target for chemotherapy-induced peripheral neuropathy. Ther Adv Neurol Disord. 2023;16:17562864231163361.

83. Liu D, Cai ZJ, Yang YT, et al. Mitochondrial quality control in cartilage damage and osteoarthritis: new insights and potential therapeutic targets. Osteoarthritis Cartilage. 2022;30:395–405.

84. Cui L, Weiyao J, Chenghong S, et al. Rheumatoid arthritis and mitochondrial homeostasis: the crossroads of metabolism and immunity. Front Med (Lausanne). 2022;9:1017650.

85. Micheli L, Testai L, Angeli A, et al. Inhibitors of mitochondrial human carbonic anhydrases VA and VB as a therapeutic strategy against paclitaxel-induced neuropathic pain in mice. Int J Mol Sci . 2022;23:6229.

86. Liu P, Chen T, Tan F, et al. Dexmedetomidine alleviated neuropathic pain in dorsal root ganglion neurons by inhibition of anaerobic glycolysis activity and enhancement of ROS tolerance. Biosci Rep. 2020;40:BSR20191994.

87. Qiang SJ, Shi YQ, Wu TY, et al. The discovery of novel PGK1 activators as apoptotic inhibiting and neuroprotective agents. Front Pharmacol. 2022;13:877706.

88. Wang Y, Qian S, Zhao F, Wang Y, Li J. Terazosin analogs targeting pgk1 as neuroprotective agents: design, synthesis, and evaluation. Front Chem. 2022;10:906974.

89. Goode DJ, Molliver DC. Regulation of mitochondrial function by Epac2 contributes to acute inflammatory hyperalgesia. J Neurosci. 2021;41:2883–2898.

90. Hsu DZ, Chu PY, Jou IM. Enteral sesame oil therapeutically relieves disease severity in rat experimental osteoarthritis. Food Nutr Res. 2016;60:29807.

91. Lei M, Guo C, Hua L, et al. Crocin attenuates joint pain and muscle dysfunction in osteoarthritis rat. Inflammation. 2017;40:2086–2093.

92. Lagos-Rodriguez V, Martinez-Palma L, Marton S, et al. Mitochondrial bioenergetics, glial reactivity, and pain-related behavior can be restored by dichloroacetate treatment in rodent pain models. Pain. 2020;161:2786–2797.

93. Sun Q, Hu T, Zhang Y, et al. IRG1/itaconate increases IL-10 release to alleviate mechanical and thermal hypersensitivity in mice after nerve injury. Front Immunol. 2022;13:1012442.

94. Khuankaew C, Apaijai N, Sawaddiruk P, et al. Effect of coenzyme Q10 on mitochondrial respiratory proteins in trigeminal neuralgia. Free Radic Res. 2018;52:415–425.

95. Gong X, Dan J, Li F, Wang L. Suppression of mitochondrial respiration with local anesthetic ropivacaine targets breast cancer cells. J Thorac Dis. 2018;10:2804–2812.

96. Chidambaran V, Costandi A, D’Mello A, D’Mello A. Propofol: a review of its role in pediatric anesthesia and sedation. CNS Drugs. 2015;29:543–563.

97. Zimin PI, Woods CB, Kayser EB, Ramirez JM, Morgan PG, Sedensky MM. Isoflurane disrupts excitatory neurotransmitter dynamics via inhibition of mitochondrial complex I. Br J Anaesth. 2018;120:1019–1032.

98. Jung S, Zimin PI, Woods CB, et al. Isoflurane inhibition of endocytosis is an anesthetic mechanism of action. Curr Biol. 2022;32:3016–3032.e3.

99. Piel S, Chamkha I, Dehlin AK, et al. Cell-permeable succinate prodrugs rescue mitochondrial respiration in cellular models of acute acetaminophen overdose. PLoS One. 2020;15:e0231173.

100. Liu Z, Zhao W, Yuan P, et al. The mechanism of CaMK2alpha-MCU-mitochondrial oxidative stress in bupivacaine-induced neurotoxicity. Free Radic Biol Med. 2020;152:363–374.

101. Shin HJ, Park H, Shin N, et al. p66shc siRNA nanoparticles ameliorate chondrocytic mitochondrial dysfunction in osteoarthritis. Int J Nanomedicine. 2020;15:2379–2390.

102. Jiang J, Xu L, Yang L, Liu S, Wang Z. Mitochondrial-derived peptide MOTS-c ameliorates spared nerve injury-induced neuropathic pain in mice by inhibiting microglia activation and neuronal oxidative damage in the spinal cord via the AMPK pathway. ACS Chem Neurosci. 2023;14:2362–2374.

Links Between Cellular Energy Metabolism and Pain Sensation