The relationship between abnormal glucose metabolism and chronic pain

Abstract

Chronic pain has a serious impact on the quality of patients' life. Currently, the mechanism of chronic pain has not been fully studied, and the treatments are often ineffective. Abnormal glucose metabolism plays an important role in the occurrence and development of chronic pain. It has been found that the abnormal glucose metabolism in anterior cingulate cortex (ACC), visual cortex, occipital cortex, brain stem, hippocampus, orbitofrontal cortex (OFC), thalamus and insula is involved in the primary headache (migraine); In addition, the abnormal glucose metabolism in the medial prefrontal cortex (mPFC), ACC, hippocampus, thalamus, primary somatosensory cortices (SI), OFC and cerebellum is involved in the neuropathic pain (NP); the abnormal glucose metabolism in the thalamus and brain stem is also involved in other types of chronic pain. Pain relieving therapies, such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), electroacupuncture (EA) and acupuncture treatment can alleviate chronic pain by reversing abnormal glucose metabolism in some of the above brain regions. In conclusion, although further research is needed, the abnormal glucose metabolism and related treatment may be an important direction for the treatment of chronic pain, and relevant mechanisms still need to be further explored.

Introduction

Pain was redefined as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” according to the International Association for the Study of Pain (IASP) in 2020 [1]. Chronic pain is defined as a disease characterized by pain lasting longer than 3 months, with a global prevalence of approximately 20% in the general population [2, 3]. Chronic pain is closely related to a complex combination of neurological, immune, psychological and social factors [4]. As a medical condition, it seriously affects patients’ quality of life. With the increase of the amount of surgery and the high prevalence of obesity, immune system diseases and cardiovascular diseases, these diseases interact with chronic pain, increasing the incidence of chronic pain [5]. In addition to the suffering caused by itself, pain is often accompanied by various comorbidities [6–9], making it more difficult to treat. Therefore, due to the complexity of pain and its significant impact on patients, it deserves more attention. Despite advances in understanding pain mechanisms, therapeutic options remain inadequate, with many patients experiencing insufficient relief or adverse effects from current analgesics. This unmet clinical need underscores the urgency to explore novel pathophysiological pathways.

Growing evidence suggests a strong link between glucose metabolism and the development of pain [10]. Glucose has long been an indispensable fuel for the brain and spinal cord, which are areas closely related to the chronic pain. And it performs many key functions, including the production of ATP, oxidative stress management, and the synthesis of neurotransmitters, neuromodulators, and structural components [11]. Besides, synapses have a high demand for energy, so glucose metabolism also plays an important role in synaptic plasticity. This plasticity is a central mechanism driving the maladaptive changes in the nervous system that underlie the development and maintenance of chronic pain [12]. Abnormal energy metabolism is an important reason for the occurrence and development of pain, in which abnormal glucose metabolism plays a vital role. For example, several studies have identified abnormalities in glucose metabolism at multiple sites in pain, the correction of which can provide pain relief [13–15].

In this review, we highlighted recent advances in the role of abnormal glucose metabolism in multiple chronic pain conditions, including migraine, neuropathic pain (NP), and other types of chronic pain. Additionally, we discussed the potential of targeting abnormal glucose metabolism as a therapeutic strategy for chronic pain.

Glucose metabolism in the central nervous system associated with chronic pain

Transport of glucose to the central nervous system

Glucose is the main energy substrate of the brain and spinal cord. Glucose is mainly utilized through three major pathways: glycolysis, pentose phosphate, and glycogen turnover [11]. The entry of glucose from the bloodstream into the central nervous system (CNS) and its distribution and utilization between cells involves multiple steps and the collaboration of different cell types. Glucose crosses the blood-brain barrier mainly through the glucose transporter GLUT1, which is highly expressed on the endothelial cells of the blood-brain barrier [16, 17]. Once it enters the brain parenchyma, glucose can be taken up by different cells.

The role of glial cells and neuron in glucose metabolism and energy supply

Astrocytes express high-affinity glucose transporter GLUT1^{16, 17} and are the main type of glial cells that take up glucose. Astrocytes metabolize part of the glucose they take up into lactic acid through glycolysis [18]. Subsequently, lactate is released into the extracellular space and taken up by neurons, serving as the primary fuel source for supporting oxidative phosphorylation (OXPHOS) in neuronal mitochondria [19]. This demonstrates the important role of glial cells in converting glucose into a more suitable energy substrate (lactic acid) for neurons.

While neurons primarily take up glucose through the neuron-specific high-affinity glucose transporter GLUT3 [20]. Genetic studies have shown that specific knockout of neuronal GLUT3 (GLUT3cKO) leads to decreased glucose uptake and ATP levels at neuronal synapses, triggering compensatory changes in mitochondrial bioenergetics and galactose metabolism [21]. It has showed that under specific high metabolic demand conditions (such as during learning), the insulin signaling pathway can promote the transport of intracellularly stored GLUT4 to the neuronal plasma membrane through an AKT-dependent mechanism, thereby enhancing glucose influx [22, 23]. Under basal conditions, neurons primarily generate ATP through mitochondrial OXPHOS [18, 24]. Metabolomics research has confirmed that human neurons can indeed metabolize glucose through glycolysis and rely on glycolysis to provide metabolites for the tricarboxylic acid (TCA) cycle [21]. However, in the OXPHOS process of neurons, electron leakage in the electron transport chain and partial reduction of oxygen lead to the accumulation of reactive oxygen species (ROS) [25]. To counteract the ROS generated by OXPHOS, neurons can utilize the pentose phosphate pathway to produce NADPH, thereby maintaining their antioxidant defense capabilities [26]. In addition, aerobic glycolysis (the conversion of pyruvate produced by glycolysis into lactic acid rather than entering the mitochondria) is also considered to be another way for neurons to reduce excessive ROS production [27] (Fig. 1).

Fig. 1.

Glucose-related metabolism chart

Glucose metabolism and synaptic plasticity in chronic pain

Chronic pain is caused by persistent pathological changes in the peripheral nervous system and/or CNS [28, 29]. Synaptic plasticity has been reported in many structures known to be involved in pain processing, including the spinal cord and brain [30]. Long-term potentiation (LTP) and long-term depression (LTD) are forms of synaptic plasticity that have been extensively studied in the context of learning and memory [31, 32]. Chronic pain can be considered a persistent sensory memory, and there is growing evidence indicating that LTP and LTD are present in the spinal dorsal horn and brain [30, 33, 34]. Glucose metabolism plays an important role in maintaining neuronal activity, which related to the LTP and LTD [35].

Abnormal glucose metabolism and pain

Abnormal glucose metabolism in primary headache

Primary headaches include migraines, cluster headaches and tension-type headaches, but current research has focused only on migraines. A previous clinical study has found that compared with the healthy control group, the age-related increases in migraineurs were positively correlated with increased metabolism in the brain stem (especially posterior), hippocampus, fusiform gyrus, and parahippocampus [36]. Compared with healthy controls, migraineurs also showed activation of neurons in the visual cortex and increased resting glucose uptake ratio [37]. During the attack of vestibular migraine, the increased metabolism of the temporo-parieto-insular areas and bilateral thalamus indicates that the vestibular-thalamus-cortex pathway is activated, while the metabolism of the occipital cortex is reduced [38, 39]. In familial hemiplegic migraine (FHM), positron emission tomography performed on the 6th day showed hypermetabolism of glucose in the left hemisphere’s fronto-basal cortex, caudate nucleus, and thalamus [40]. Furthermore, in addition to the attack period, there are corresponding changes in glucose metabolism during the interictal period of migraine. Compared with healthy subjects, migraineurs had significant hypometabolism in several regions known to be involved in central pain processing, including bilateral insula, bilateral anterior cingulate cortex (ACC), during the interictal period. And the progressive decrease of glucose metabolism is related to the increase of headache duration and headache frequency [41].

Animal studies have found that in a rat model of migraine, trigeminal vasomotor sensory processing by modulation of the parabrachial pigment nucleus in the ventral tegmental area also leads to a reduction in circulating glucose levels [42]. Besides, nitroglycerin (NTG)-induce migraine rats showed a significant increase in glucose uptake in the hypothalamus (HT) [43]. In a rat model of migraine triggered by application of applying inflammatory soup (IS) to the dura mater, the key glycolytic enzyme phosphofructokinase platelet (PFKP) was significantly higher than that in the control group, demonstrating that the migraine significantly increased glucose metabolism in the medullary dorsal horn [44].

In summary, the occurrence and development of migraine is accompanied by abnormal glucose metabolism in multiple regions of the brain, but different regions of glucose metabolism show different differences. This may be related to the type of migraine and may also be related to the progression of the disease.

Abnormal glucose metabolism in neuropathic pain (NP)

In right brachial plexus avulsion (BPA) induced NP of patients, glucose metabolism in the right thalamus and primary somatosensory cortices (SI) was significantly reduced, while glucose metabolism in the right orbitofrontal cortex (OFC), left rostral insula cortex and left dorsolateral prefrontal cortex (DLPFC) was significantly increased [45]. In brain regions related to emotion, glucose metabolism also changed in BPA. It was found that in BPA induced NP of rats, glucose metabolism was up-regulated in the anterodorsal hippocampus and dorsolateral thalamus, while down-regulated in the contralateral somatosensory cortex and ipsilateral cingulate cortex [46]. In addition to the above brain regions, another study found that glucose metabolism increased in left caudate putamen, left medial prefrontal cortex, and right caudate putamen compared with before and 7 days after BPAI in rats [47]. In central post-stroke pain (CPSP), increased pain intensity was associated with decreased metabolism in the ipsilesional supplementary motor area and contralesional angular gyrus in patients [48].

In contrast to formalin-induced acute pain, spared nerve injury (SNI)-induced NP was observed as sustained high activity in the contralateral hindlimb SI [49]. SNI also can regulated the glucose metabolism in the thalamus, cerebellar vermis and medial prefrontal cortex (mPFC) in rats [50]. In tibial and sural nerve transection (TST) rat model, cerebellum was activated significantly [51]. In addition to the brain, abnormal glucose metabolism in the spinal cord is also a manifestation of NP. Fifteen days after L5 spinal nerve ligation (SNL) in rats, glucose metabolism increased in the ipsilateral dorsal horn, reflecting excessive excitability of neurons [52]. This is due to the increased synthesis of GABA by astrocyte monoamine oxidase B (MAOB). Inhibition of MAOB restores GABA-mediated neuronal excitability throughout astrocytes, eliminates increased glucose metabolism, and relieves pain [52]. Besides, cognitive dysfunction caused by SNI is also accompanied by changes in brain metabolism. And it was found that positron emission tomography showed decreased brain glucose metabolism in the prefrontal cortex and hippocampus of adult SNI rats [53]. The levels of GABA2 and Glu4 in the hippocampus, frontal cortex and temporal cortex were significantly decreased, and the expression of GLUT3 and GLUT4 in the prefrontal cortex and hippocampus of SNI rats was also significantly down-regulated [53].

We found that the three parts of mPFC, hippocampus and thalamus have opposite metabolic characteristics in NP. We speculate that it may be related to the different pathogenesis of different NP, and there are opposite results in the same NP, which may be related to the time of disease development.

Abnormal glucose metabolism in other chronic pain

Human research has found that post-stroke pain is closely related to the decrease of glucose in the contralateral thalamus of the pain area. Ito et al. reported the case that the cerebral metabolic rate of glucose before motor cortex stimulation (MCS) in 6 patients with post-stroke pain, finding that the patients all accompanied by a decrease in thalamic glucose [14]. In a patient with chronic pain 8 years after total hip arthroplasty, glucose metabolism in the joint capsule and around the prosthesis neck was found to be enhanced [54]. Another similar case reported a painful degenerative scoliosis with preoperative low back pain accompanied by increased glucose metabolism in the paravertebral muscles. And one year after operation, low back pain disappeared completely. At the same time, according to her clinical manifestations, (18) F-FDG-PET imaging showed no uptake in the paravertebral muscles 1 year after surgery [55]. Besides, fibromyalgia (FM) also can down-regulated the metabolic rate of glucose in the skeletal muscle (lumbar region) [56].

Animal studies have also found that in sleep restriction-induced hyperalgesia, the competition of regulatory T cells (Tregs) for glucose leads to impaired glycolysis in endothelial cells (ECs), which ultimately aggravated the pain in mice [57]. Incision induced long-lasting postoperative pain resulted in increased glucose uptake in the cerebellum, hippocampus, and posterior cortex, and extended to thethalamus, hypothalamus, and brainstem on 6th and 7th days. And these changes persisted for 21 days after incision in rats [13].

Therefore, different types of chronic pain are accompanied by abnormal glucose metabolism in different aeras, so abnormal glucose metabolism may be a common manifestation of chronic pain (Table 1).

Table 1.

The class of type of pain, research object, area, glucose metabolism related to chronic pain

Type of pain	Research object	Area	Glucose metabolism	Reference
Migraine	Human	Brain stem, hippocampus, fusiform gyrus, and parahippocampus	↑	[36]
Migraine	Human	OFC	↓	[58]
Migraine	Human	Visual cortex	↑	[37]
Migraine	Human	Temporo-parieto-insular areas and bilateral thalamus occipital cortex	↑ ↓	[38, 39]
Migraine	Human	Left hemisphere’s fronto-basal cortex, caudate nucleus, and thalamus	↑	[40]
Migraine	Human	Bilateral insula, bilateral anterior cingulate cortex	↓	[41]
Migraine	Rat	HT	↑	[43]
Migraine	Rat	Blood glucose	↓	[42]
Migraine	Rat	Medullary dorsal horn	↑	[44]
BPA induced NP	Rat	Anterodorsal hippocampus and dorsolateral thalamus Contralateral somatosensory cortex and ipsilateral cingulate cortex	↑ ↓	[46]
BPA induced NP	Rat	Left caudate putamen, left mPFC, and right caudate putamen	↑	[47]
BPA induced NP	Human	Right thalamus, OFC, left rostral insula cortex and left DLPFC	↓ ↑	[45]
TST	Rat	Cerebellum	↑	[51]
SNL	Rat	Ipsilateral dorsal horn	↑	[52]
SNI	Rat	Prefrontal cortex and hippocampus	↓	[53]
SNI	Rat	Contralateral hindlimb S1	↑	[49]
SNI		mPFC, thalamus and cerebellar vermis	↑	[50]
Post-stroke pain	Human	Thalamus	↓	[14]
CPSP	Human	Ipsilesional supplementary motor area and contralesional angular gyrus	↓	[48]
Sleep restriction-induced hyperalgesia	Mice	Blood-spinal cord barrier	-	[57]
Incision induced long-lasting postoperative	Rat	Thalamus, hypothalamus, and brain stem	↑	[13]
Total hip arthroplasty induced chronic pain	Human	Joint capsule and around the prosthesis neck	↑	[54]
Painful degenerative scoliosis	Human	Paravertebral muscles	↑	[55]
FM	Human	Skeletal muscle (lumbar region)	↓	[56]

The relationship between diabetes and chronic pain

Clinical studies have provided substantial evidence that diabetes is an important risk factor for the development and progression of chronic pain. Epidemiological investigation found that chronic pain is strongly correlated with blood glucose fluctuation parameters in elderly type 2 diabetes mellitus (T2 DM) patients [59, 60]. For example, elevated blood glucose (≥ 6.1 mmol/L) and diabetes increased the risk of chronic pain in adults by about 2.5 times [61]. Besides, the prevalence of musculoskeletal pain such as low back pain [62, 63] and osteoarthritis [64] in diabetic patients was also significantly increased. Interestingly, there is a clinical study indicated that diabetic therapeutic neuropathy (also known as insulin neuritis) is considered to be a rare iatrogenic small fiber neuropathy caused by a sudden improvement in blood glucose control under chronic hyperglycemia [65].

Animal models provide a key window for understanding the molecular and cellular mechanisms of diabetes-related chronic pain. Excessive excitation and abnormal spontaneous impulse generation of damaged primary sensory neurons and their peripheral axons are recognized processes that strongly lead to pain associated with diabetic neuropathy [66, 67]. Neurons in the CNS, such as the thalamus and ventral posterior lateral thalamus, can become overexcited, firing at abnormally high frequencies and producing abnormal spontaneous activity [66]. Besides, neuroinflammation, microcirculatory disturbance and hypoxia [68–70] also involved in the diabetes induced neuropathic pain.

In summary, there is a profound and complex bidirectional association between diabetes and chronic pain. Therefore, it is particularly important to pay attention to pain caused by diabetes at an early stage.

Treatment and related side effects of pain-related abnormalities of glucose metabolism

Brain stimulation treatment

Studies have found that MCS and transcranial direct current stimulation (tDCS) can relieve chronic pain by regulating glucose metabolism. Patients with post-stroke pain are companied with reduced thalamic glucose metabolism before MCS, and MCS treatment significantly increases thalamic glucose metabolism in patients to relieve pain [14]. Sixteen patients suffering from NP due to traumatic spinal cord injury were treated with tDCS for 10 days. Post-treatment results showed a significant reduction in numerical rating scale (NRS) scores, accompanied by increased metabolism in the medulla, subgenual anterior cingulate cortex, and insula, alongside decreased metabolism in the left dorsolateral prefrontal cortex [71].

Acupuncture and electroacupuncture (EA) treatment

Acupuncture and EA stimulation can also relieve pain by regulating glucose metabolism. It was found that BPAI induced NP caused a decrease in metabolic connectivity between bilateral sensorimotor cortices from 4th to 14th week. At the 4th week after EA intervention (2/15 Hz, 30 min per day, five times per week for 11 weeks), the metabolic connection between SMC and pain-related areas in bilateral hemispheres increased, while the metabolic connection decreased at the 12th week. However, at 16th week, increased metabolic connectivity was found between SMC and pain-related areas in bilateral hemisphere [72]which eventually to relieve the NP. EA treatment also significantly reversed chronic constriction injury (CCI) induced mechanical allodynia, thermal pain, and increased glucose metabolism in the left mPFC. EA also significantly reduced GLUT-3 protein expression in the left mPFC [73].

Acupuncture and sham acupuncture stimulation also can relieve the pain in migraineurs. After acupuncture treatment, the brain glucose metabolism in the middle frontal gyrus, postcentral gyrus, the precuneus, parahippocampus, cerebellum and middle cingulate cortex (MCC) increased, while the brain glucose metabolism in the left hemisphere of middle temporal cortex (MTC) decreased [74]. After sham acupuncture treatment, the glucose metabolism in the poster cingulate cortex (PCC), insula, inferior temporal gyrus, MTC, superior temporal gyrus, postcentral gyrus, fusiform, inferior parietal lobe, superior parietal lobe, supramarginal gyrus, middle occipital lobe, angular and precuneus increased, while the glucose metabolism in cerebellum, parahippocampus decreased [74].

Analgesic drug therapy and side effects

Chronic pain is currently mainly treated with various analgesic drugs. For example, gabapentin (GBP) injection (100 mg/kg) can reverse central hypersensitivity and inhibit glucose metabolism in the medial prefrontal cortex of rats with SNI induced NP [50]. However, the use of analgesics, especially if overused, can cause side effects. In a study of patients with chronic pain who overuse analgesics (paracetamol–codeine and/or aspirin–paracetamol–caffeine), glucose metabolism in the brain was measured before drug withdrawal and 3 weeks after drug withdrawal. It was found that before drug withdrawal, glucose metabolism was low in the bilateral thalamus, orbitofrontal cortex (OFC), anterior cingulate gyrus, insula/ventral striatum and right inferior parietal lobule, and high in cerebellar vermis. After the withdrawal of analgesics, glucose uptake in all metabolically abnormal areas almost returned to normal, but OFC metabolism was found to be further decreased. Therefore, OFC may be the main area involved in the chronicity of migraine patients caused by excessive use of analgesics [58]. Compared with the healthy control group and the migraine group without overuse of analgesics (Paracetamol caffeine aspirin, PCA), the metabolism of thalamus in the migraine group with overuse of analgesics was significantly reduced, and the metabolism of middle temporal gyrus and insula was increased. However, in these regions, no difference was observed in migraine group with overuse of analgesics except for increased metabolism in the right insula relative to the control group. Therefore, the increased metabolism of the right insula may be related to the repeated overuse of PCA powder [75]. Twenty-one days after incisional pain, re-administration of naloxone or remifentanil induced nociceptive hypersensitivity, and administration of naloxone was accompanied by an increase in glucose uptake in the hypothalamus, cerebellum, entorhinal cortex, and brainstem, and a decrease in uptake in the ipsi- dorsolateral cortex, hippocampus, thalamus, and anterior cingulate cortex [13]. Above all, chronic pain should be treated with caution when using analgesic drugs. Excessive use of analgesic drugs may aggravate the occurrence and development of chronic pain (Table 2).

Table 2.

The class of type of pain, research object, treatment, area, glucose metabolism related to chronic pain

Type of pain	Research object	Treament	Area	Glucose metabolism	Reference
Post-stroke pain	Human	MCS	Ipsilateral thalamus	↓	[14]
Traumatic spinal cord injury induced NP	Human	tDCS	Medulla, subgenual anterior cingulate cortex and insula Left dorsolateral prefrontal cortex	↑ ↓	[71]
SNI induced NP	Rat	Gabapentin	Medial prefrontal cortex	↓	[50]
BPAI induced NP	Rat	EA	Connectivity between SMC and bilateral hemisphere	↑	[72]
CCI induced NP	Rat	EA	mPFC	↑	[73]
Migraine	Human	Acupuncture Sham acupuncture stimulation	Middle frontal gyrus, postcentral gyrus, precuneus, parahippocampal body, cerebellum and MCC Left hemisphere of MTC PCC, insula, inferior temporal gyrus, MTC, superior temporal gyrus, postcentral gyrus, fusiform, inferior parietal lobe, superior parietal lobe, supramarginal gyrus, middle occipital lobe, angular and precuneus Cerebellum, parahippocampus	↑ ↓ ↑ ↓	[74]
Migraine	Human	Overuse analgesics	OFC	↓	[58]
Migraine	Human	Overuse analgesics	Right insula	↑	[75]

Discussion and perspective

In this review, we summarized the role of abnormal glucose metabolism in various types of chronic pain, including primary headache (migraine), NP, and other types of chronic pain. It has been found that the abnormal glucose metabolism in ACC, visual cortex, occipital cortex, brain stem, hippocampus, OFC, thalamus and insula is involved in the migraine; the abnormal glucose metabolism in the mPFC, ACC, hippocampus, thalamus, SI, OFC and cerebellum is involved the NP; the abnormal glucose metabolism in the thalamus and brain stem also is involved in other types of chronic pain. Besides, MCS, tDCS, EA and acupuncture can act on some of the above brain regions to relieve chronic pain (Fig. 2).

Fig. 2.

The graphic image of this review

Recently, studies on abnormal glucose metabolism in chronic pain mainly focus on migraine. However, there are many types of primary headaches, so further research is needed, such as the performance of each stage of migraine pathogenesis. In addition, the current research on NP mainly focuses on the animal level, but there are few studies on NP patients. Direct research on NP patients is very important, so it may be the direction of future research.

Besides, the existing researches mainly focus on the appearance, and there are few studies on the mechanism, so it should be improved. In humans, the brain accounts for ~ 2% of body weight, but it consumes ~ 20% of glucose-derived energy, making it the main consumer of glucose [76]. Glucose metabolism provides fuel for physiological brain function by producing ATP (the basis for maintenance of neurons and non-neuronal cells) and neurotransmitters [76]. It is worth noting that this glucose metabolic disorder is not merely an accompanying phenomenon, but is actively involved in shaping the abnormal neuroplasticity of chronic pain. The increase of glycolysis flux can lead to the increase of lactic acid level, which may affect synaptic plasticity and gene expression related to pain sensitization as a signal molecule [77]. At the same time, oxidative stress caused by mitochondrial dysfunction or excessive production of ROS can damage neuronal structure, damage synaptic function and activate pro-inflammatory pathways, further exacerbating the excessive excitation and long-term potentiation LTP of the pain pathway [78, 79]. Therefore, the above reasons may be one of the mechanisms of chronic pain caused by abnormal glucose metabolism.

Chronic pain induces sustained hyperactivation of neurons in pain pathways, such as thalamus [80]ACC [81–84]insula [85]. This imbalance may be driven by glucose metabolic changes: impaired glucose metabolism reduces ATP production required for inhibitory (such as GABAergic) neurotransmission, while metabolic stress may promote excitatory (such as glutamatergic) signal transmission and impair the function of inhibitory interneurons [86–88]. For example, persistent nociceptive signaling increases glutamate release and overactivates N-methyl-d-aspartate receptor (NMDAR) [89]. This hyperactivity increases ATP consumption and is forced to switch to glycolysis metabolism even under aerobic conditions to meet urgent energy needs [90]. In summary, GABA/glutamate cycles involved in chronic pain caused by abnormal glucose metabolism.

Classical studies suggest that neurons, along with astrocytes, are the main glucose-consuming cells of the CNS [91–93]. Neurons have the highest energy requirements and interact with astrocytes, which extract glucose from the blood, mobilize glycogen, and release lactate in response to neuronal activity [94]. A study has shown that the transcription factor Nrf2 mediates cell stress adaptation by regulating the expression of genes related to antioxidant defense and energy metabolism. However, Nrf2 activity is inhibited during neuronal development. Therefore, neurons rely on Nrf2 in astrocytes to maintain their redox balance and energy homeostasis [95]. Live cell imaging revealed that Nrf2 activation enhances glucose uptake by neurons and astrocytes, and preferentially uses glucose for mitochondrial NADH/energy generation, rather than NADPH synthesis. This metabolic preference explains why Nrf2-inhibited neurons need to rely on astrocytes to maintain their redox and energy homeostasis during development [95]. The astrocyte-neuron lactate shuttle (ANLS) in the ACC promotes the development of chronic inflammatory pain [94]. Disrupting the ANLS in the ACC prior to inflammatory injury prevents pain hypersensitivity in mice [94]. However, the metabolism of glucose between neurons and astrocytes needs further study. For example, a recent study found that metabolomics was used on nearly homogeneous human neuronal cultures to demonstrate that neurons can indeed directly import glucose [21]. This may have the opportunity to provide some ideas for the treatment of abnormal glucose metabolism in chronic pain.

Next, many studies have found that brain regions exhibiting abnormal glucose metabolism in chronic pain conditions such as migraine and neuropathic pain are highly consistent with their core functions in pain processing. For example, ACC is involved in the emotional dimension and cognitive assessment of pain, and its metabolic abnormalities may be directly associated with anxiety, depression, and cognitions impairment accompanying chronic pain [96]. While the hippocampus, as a key center for learning and memory, may be associated with pain memory consolidation and contextual regulation disorders due to metabolic disorders [97–100]. Clinical studies indicated that depression patients often have abnormal glucose metabolism in brain [101–103]. Other studies have found that glucose metabolism in the hippocampus is reduced with depression [104, 105]. This region-specific metabolic pattern closely links energy metabolism disorders with the multidimensional pathophysiological processes (sensory, emotion, and cogitation) of chronic pain. This further highlights the importance of glucometabolic research in understanding the mechanisms of chronic pain and developing targeted therapies, which warrants further investigation.

Further, changes in plasticity with transcranial stimulation methods are thought to be due to activation of a combination of excitatory and inhibitory neurons in specific and selected cortical areas of the brain [15]. TMS and tDCS also promote plasticity changes in brain. Multiple studies have found brain stimulation can treat cognitive dysfunction and various psychiatric disorders [106–109]. Previous reviews summarized the transcranial Magnetic Stimulation (TMS) in chronic pain [110–112]. In addition to the brain, a review has also summarised the curative effects of stimulation at the spinal cord level on chronic pain [113]. There are also reviews summarizing the therapeutic effect of tDCS in multiple types of chronic pain [114–118]. Furthermore. many studies have shown that EA therapy can also relieve chronic pain [119–122]. In conclusion, brain stimulation and EA can treat chronic pain, but there are relatively few studies on whether it is through the regulation of brain glucose metabolism. In the following, we can explore more about the relationship between brain stimulation and EA and CNS glucose metabolism and its related mechanisms to treat chronic pain.

Lastly, in addition to antidepressants, calcium channel blockers (e.g., gabapentin, etc.), and the potent drugs for migraine, such as tretinoin and ergotamine, analgesic drugs are still the main treatment for chronic pain. Patients with prolonged pain are prone to overdose. Study proves analgesic overuse leads to pain chronicity, especially headaches [123–125]. Patients with primary headache have a high risk of chronicity due to overuse of analgesics to treat other pain disorders [126]. Zwart et al. found that overuse of analgesics can strongly predict chronic pain 11 years later and chronic pain associated with overuse of analgesics, especially in patients with chronic migraine [127]. Schwedt et al. reported that Chronic migraine with overuse of medication is associated with severe negative consequences, the degree of which is most closely associated with depressive symptoms [128]. As the above review has concluded that overuse of analgesic drugs chronicises pain and is accompanied by abnormalities in glucose metabolism in specific brain regions, the study of abnormalities in glucose metabolism in the brain and the corresponding mechanisms may be a major direction in preventing the chronicity of pain or the development of pain complications from the overuse of analgesic drugs.

Conclusion

Multiple studies have found that abnormal glucose metabolism plays a crucial role in the occurrence and development of chronic pain, and interventions targeting this metabolic dysfunction can also alleviate chronic pain by intervening abnormal glucose metabolism. Across various chronic pain conditions, abnormal glucose metabolism is mainly distributed in emotionally related brain regions, however, the underlying mechanisms remain poorly understood. In conclusion, although more in-depth researches are needed in the future, current researches show that abnormal glucose metabolism is a promising treatment target for chronic pain.

Abbreviations

ACC

Anterior cingulate cortex

BPA

Brachial plexus avulsion

CCI

Chronic constriction injury

CNS

Central nervous system

CPSP

Central post-stroke pain

DLPFC

Dorsolateral prefrontal cortex

EA

Electroacupuncture

ECs

Endothelial cells

FHM

Familial hemiplegic migraine

FM

Fibromyalgia

GBP

Gabapentin

HT

Hypothalamus

IASP

International Association for the Study of Pain

IS

Inflammatory soup

LTD

Long-term depression

LTP

Long-term potentiation

MAOB

Monoamine oxidase B

MCC

Middle cingulate cortex

MCS

Motor cortex stimulation

mPFC

Medial prefrontal cortex

MTC

Middle temporal cortex

NP

Neuropathic pain

NTG

Nitroglycerin

OFC

Orbitofrontal cortex

OXPHOS

Oxidative phosphorylation

PCA

Paracetamol caffeine aspirin

PCC

Poster cingulate cortex

PFKP

Phosphofructokinase platelet

ROS

Reactive oxygen species

SNI

Spared nerve injury

SNL

Spinal nerve ligation

tDCS

Transcranial direct current stimulation

TMS

Transcranial magnetic stimulation

TST

Tibial and sural nerve transection

Author contributions

This work was primarily conceived by CZ, TZ and LM. Manuscript was written by LM, YW, YZ, SM, TZ and CZ. Figures were produced by LM. All authors read and approved the final manuscript.

Funding

This work was supported by Open Fund Youth Project of the Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology) (No. 2023MZFS007 to LM); the Sichuan Provincial Department of Science and Technology (No. 2025ZNSFSC1647 to LM); the Sichuan Provincial Department of Science and Technology (No. 24NSFSC6864 To YZ ); the National Postdoctoral Researcher Program (No. GZC20231834 To YZ); the China Postdoctoral Science Foundation (No. 2024M752266 To YZ) and the Postdoctoral Researcher Fund of West China Hospital (No. 2023HXBH131 To YZ).

Data availability

No datasets were generated or analyzed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.