A Review of Treatment Modalities for Comorbid Neuropathic Pain and Depression

Abstract

Over the past years, a number of clinical and preclinical investigations have been documented, suggesting treatment strategies and pharmaceuticals for neuropathic pain and depressive disorders, potentially beneficial in cases where these conditions are comorbid. This review lists these potential treatment options and discusses the proposed underlying mechanisms of action and their limitations, in terms of both physiotherapy and pharmacotherapy. Physiotherapy includes electroacupuncture and repetitive transcranial magnetic stimulation therapy, both of which affect neuronal function by altering the physiological state of the neurons. Pharmacological treatments include tricyclic antidepressants, gabapentin, ketamine, minocycline, and Chinese medicine, which alter ion channel activity, affect neurotransmitter release, and exert anti-inflammatory effects. As such, this review may help to improve future research endeavors and therapeutic options for this frequently occurring comorbidity.

Graphical abstract

Keywords

neuropathic pain / depression / co-morbidity / behavioral disorder

1. Introduction

Chronic neuropathic pain, stemming from somatosensory system damage or disease, encompasses conditions like postherpetic neuralgia, painful nerve lesions, trigeminal neuralgia, and postamputation pain [1, 2]. This type of pain is characterized primarily by allodynia, which is pain triggered by stimuli that are not typically painful, and hyperalgesia, a heightened sensitivity to pain that results in an exaggerated response to normally painful stimuli [3]. Depression is medically classified as a mental or behavioral disorder [4]. The primary symptoms of depression include ongoing feelings of sadness, diminished interest in activities, alterations in sleep and appetite, fatigue, self-deprecation, concentration difficulties, and suicidal ideation [5]. In the event that neuropathic pain persists for a period exceeding three months, it will likely evolve into chronic pain [6]. Chronic neuropathic pain is frequently associated with mood disorders, particularly depression [7].

The precise etiology of pain and depression comorbidity remains unclear. However, recent research has identified the involvement of a monoamine neurotransmitter, brain-derived neurotrophic factor (BDNF), and an inflammatory factor, glutamate, and its receptor subtypes, in the origin of comorbidities. Monoamine neurotransmitters: Monoamine neurotransmitters, such as 5-hydroxytryptamine (5-HT), dopamine, and norepinephrine (NE), are key players in the nervous system [8]. According to the traditional monoamine hypothesis, depression is linked to a diminished presence of these neurotransmitters, including 5-HT and NE, within the central nervous system (CNS) [9]. The descending pain modulation system comprises three principal elements: the periaqueductal gray of the midbrain, the medial ventral reticular formation of the medulla oblongata, and the dorsal lateral pontine tegmentum [10]. Collectively, these components suppress nociceptive signals in the spinal cord’s dorsal horn through the action of neurotransmitters like 5-HT and NE. A reduction in serotonin and norepinephrine impairs the modulatory function of the descending pain system, culminating in heightened nociceptive responses [7]. BNDF: BDNF is a neurotrophic factor that plays a vital role in regulating neuroplasticity [11]. Depression undeniably reduces BDNF expression in the prefrontal cortex, hippocampus, and other structures associated with depression [12]. Extensive studies have confirmed the crucial role of BDNF in the onset and development of pain. Specifically, Yajima et al. [13] have shown that BDNF, originating from the spinal cord, interacts with the TrkB receptor to initiate a signaling cascade. This cascade triggers the activation of protein kinase C in spinal neurons, which in turn modulates the sensitivity to pain [13]. Inflammatory factors: The relationship between inflammatory and the central nervous system is becoming more evident. Studies have demonstrated that the inflammatory reactions in the periphery can trigger both pain and depressive disorders. Consequently, pain that is induced by inflammatory reactions could have a stronger link to depression [14, 15]. Crossing the blood-brain barrier, inflammatory messengers impact regions within the brain that are associated with depression, leading to alterations in neurotransmitter synthesis, neuroendocrine activities, and neuroplasticity [14]. Glutamate and Its Receptor Subtypes: Glutamate, an indisputable key excitatory neurotransmitter within the CNS, is present in brain synapses extensively [16]. This neurotransmitter, along with its receptor subtypes—the N-methyl-D-aspartate (NMDA) and the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors—plays a role in the genesis of chronic pain and depressive conditions [17]. It is clear that increased activity of the excitatory system and a concomitant decrease in the inhibitory system in the spinal cord contribute to central nociceptive hypersensitivity and ultimately to the progression of pathological pain.

Once neuropathic pain and depression form a co-morbidity, they reinforce each other in a vicious cycle [18]. Addressing comorbid conditions presents a greater challenge compared to managing neuropathic pain or depression individually. This review aimed to provide an overview of the most effective therapeutic methods and drugs for these comorbidities (Fig. 1), highlighting their potential therapeutic mechanisms from both physiological and pharmacological perspectives. This information is expected to assist clinicians and researchers in identifying rapid and effective therapeutic strategies.

2. Physiotherapy

2.1 Repetitive Transcranial Magnetic Stimulation

Varying the electric current can generate a magnetic field, whereas varying the magnetic field can produce an electric current. Transcranial magnetic stimulation (TMS) utilizes figure-of-eight- or H-shaped coils to generate a fluctuating magnetic field that affects the CNS in the brain, altering the membrane potential of nerve cells [19, 20]. Additionally, TMS can change the state of the electron spin system, thereby affecting the chemical activity of compounds and achieving therapeutic effects [21]. In the United States, the Food and Drug Administration (FDA) approved the use of repetitive transcranial magnetic stimulation (rTMS) in the treatment of obsessive-compulsive disorder (OCD) [22], depression, and migraine headaches. Furthermore, the efficacy of high-frequency rTMS in treating depression has been graded as A when administered to the left dorsolateral prefrontal cortex [22, 23].

The therapeutic effects of rTMS on neuropathic pain and depressive comorbidities primarily manifest as analgesic, anti-inflammatory, and modulatory effects on neurotransmitters (Fig. 2). Analgesic effects: A single 10 Hz rTMS stimulation of the motor cortex for a period of three weeks in right-handed patients with intractable pain (resulting from thalamic stroke, brainstem stroke, spinal cord injury, brachial plexus injury, or trigeminal nerve injury) has been demonstrated to produce a notable reduction in pain levels as assessed by means of a visual analog scale (VAS) in the treatment group compared to the sham treatment group [24]. Furthermore, rTMS has been shown to drive downward pathways, thereby inhibiting pain production through electrophysiological alterations [24]. Modulatory effect on neurotransmitters: Studies indicate that under rTMS stimulation, more dopamine is released from the mesial reticular, mesolimbic, and striatal regions, whereas more \gamma-aminobutyric acid (GABA) is released from the left dorsolateral prefrontal cortex [25, 26]. Anti-inflammatory effects: Research by Hu et al. [27] has demonstrated that rTMS at a frequency of 10 Hz significantly decreased levels of inflammatory markers in rats subjected to chronic constriction injury of the nerve. This reduction included key cytokines such as tumor necrosis tumor necrosis factor alpha (TNF-\alpha), interleukin 6 (IL-6), and IL-1\beta, particularly in the anterior agranular insular cortex (AId). Furthermore, in these rats, IL-1\beta concentrations were observed to increase in various brain regions, including the prefrontal cortex, brainstem, hippocampus, and peripheral brain areas [27].

Clinical and preclinical evidence suggests that rTMS treatment for comorbidities reduces pain and alleviates depressive behaviors. A clinical study suggested that in patients with postherpetic neuralgia, treatment of the motor cortex with rTMS at 10 Hz for more than 10 days can have an analgesic effect. Patients were assessed at the end of treatment. The findings indicated that rTMS therapy not only alleviated pain but also enhanced the sleep quality of the participants [28]. Furthermore, in a preclinical study, Hu et al. [27] used 10 Hz rTMS to treat the left dorsal AId of rats with chronic constriction injury (CCI) and comorbid depression for 4 weeks. Using behavioral measures, they found that rTMS ameliorated nociceptive hypersensitivity and despair behavior in rats. They found that rTMS decreased the expression of mGluR5, NMDAR2B, TNF-\alpha, IL-1\beta, and IL-6 in the comorbid group. This suggests that the regulatory mechanism of rTMS is related to the mGluR5/NMDAR2B-related inflammatory pathway [27].

Although rTMS has demonstrated good therapeutic efficacy in a clinical study, the treatment process protocols and parameter settings of therapeutic equipment for rTMS have not been standardized or regulated, which presents a challenge for promoting rTMS as a treatment for comorbidities [29].

2.2 Electroacupuncture

Acupuncture involves the insertion of disposable sterile needles at specific anatomical points on the body. When used for pain management, these needles deliver electrical stimulation to acupuncture points, activating the neural network and thus regulating organ function to treat various illnesses. This technique, known as electroacupuncture (EA) [30, 31], combines traditional acupuncture and modern electrotherapy and is gaining increasing acceptance worldwide owing to its favorable therapeutic effects and lack of side effects [32].

EA has both analgesic and antidepressant effects. Analgesic effects: EA increases endogenous opioid production via two pathways: (1) Stimulation of the sympathetic nervous system facilitates the movement of opioid-producing cells towards inflammatory regions [32]. Research has shown that such stimulation can upregulate the expression of intracellular adhesion molecule-1 (ICAM-1) within the vasculature of affected tissues, thereby enhancing the migration of polymorphonuclear and mononuclear cells containing \beta-endorphins and met-enkephalins in rats experiencing hind paw inflammation induced by complete freund^′s adjuvant (CFA) [33]. (2) Activation of the hypothalamic-pituitary-adrenal (HPA) axis, which reduces COX-2 and interferes with endogenous cannabinoid metabolism, leads to increased opioid levels at the site of inflammation. These endogenous opioids then induce analgesia via µ-, \delta-, and \kappa-opioid receptors [32]. Research suggests that electroacupuncture is capable of stimulating the hypothalamic-pituitary-adrenal (HPA) axis, which results in a notable elevation of plasma corticosterone in rats with inflammation-induced pain from CFA [34]. Furthermore, it has been shown to markedly suppress the expression of COX-1 and COX-2 mRNA, along with the proteins they encode, which are provoked by carrageenan exposure [35]. It is known that endocannabinoids are metabolized by COX-2 [36]. Therefore, electroacupuncture-induced cortisol may inhibit COX-2, interfering with the metabolism of endocannabinoids, leading to their elevation at the site of inflammation, resulting in increased opioid medication. Antidepressant effects: Preclinical and clinical evidence suggests that EA can effectively treat depression [37]. A clinical study indicates that receiving electroacupuncture three times a week for a period of 8 months can significantly improve the sleep quality of patients with depression [38]. A preclinical study has indicated that EA treatment can improve depressive behaviors in mice with chronic unpredictable mild stress (CUMS) modeling. Researchers have found that EA may exert antidepressant effects by regulating the abundance of Lactobacillus and Staphylococcus in the gut [39]. Another preclinical study has shown that electroacupuncture effectively treats depressive-like behaviors in CUMS mice, possibly by enhancing the presence of astrocytes in the active brain environment to protect the brain from stress-induced pathological deformations [40].

EA treatment for comorbidities has only been tested in animal experiments and has not yet been administered to patients in clinical settings. One study showed that after EA treatment, mice exhibited increased mechanical and thermal pain thresholds, relieved depressive behavior, and significantly reversed downregulation of BDNF and 5-HT expression in the anterior cingulate cortex and spinal cord after chronic constriction injury [41]. Additional research has shown that EA administered to mice subjected to spared nerve injury (SNI) leads to an elevation in the population of short-chain fatty acid-generating bacteria, including Akkermansia, Ruminococcaceae, and Lachnospiraceae, in the intestinal tract. This was accompanied by alterations in histone acetylation and BDNF up-regulation. These findings suggest that EA treatment may produce therapeutic effects through the brain-gut microbiota axis [42].

Although the efficacy of EA has been demonstrated in animal models, several challenges persist before it can be effectively implemented in a clinical setting. One primary concern is the lack of consensus on the standardization of treatment parameters and the variability in treatment outcomes observed among patients. Second, the analgesic effect of EA is subject to tolerance, which is comparable to that of opioids [43, 44]. Extended treatment duration may also influence the final outcome.

3. Drug Therapy

3.1 Tricyclic Antidepressants (TCAs)

TCAs were among the first antidepressants to be developed. Their molecular composition is characterized by a trio of atomic rings, featuring a central heterocyclic ring with seven members, which is bordered by a pair of benzene rings. Initially, TCAs were designed and marketed for depression treatment. However, it became evident over time that they were associated with many side effects and were potentially fatal in cases of overdose. Consequently, they have been gradually replaced by selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the treatment of depression [45, 46].

The analgesic and antidepressant effects of TCAs in the treatment of neuropathic pain and depressive comorbidities are inherently linked to their core pharmacological mechanism: binding to and inhibiting the reuptake of norepinephrine or 5-HT transporter proteins [47].Analgesic effects: Small doses of TCAs are sufficient for treating neuropathic pain, although they require prolonged administration [48]. TCAs inhibit transporter proteins, leading to increased neurotransmitter levels (norepinephrine and serotonin) in the synaptic cleft. These chemical messengers engage in a sequence of actions that dampen the transmission of pain signals within the spinal cord, with norepinephrine seemingly having a more significant impact than serotonin in this particular pathway [49]. In addition, TCAs can voltage-dependently block glutamate NMDA receptors, thereby relieving pain [50]. Antidepressant effects: The buildup of neurotransmitters within the synaptic gap results in higher levels of norepinephrine and serotonin, neurotransmitters known for their antidepressant properties [51].

Support for employing TCAs in managing concurrent disorders is primarily derived from preclinical research. A preclinical study has demonstrated the efficacy of amitriptyline in alleviating nociceptive sensitization associated with thermal and mechanical pain in rats with spared nerve injury and depressive behaviors [52]. Another preclinical study showed that combination of citicoline with imipramine produced analgesic and antidepressant effects [53]. Citicoline is a mononucleotide that comprises cytosine, choline, pyrophosphate, and ribose. It plays a dual role as both an essential intermediate and inducer in the synthesis pathways of structural membrane phospholipids, specifically phosphatidylcholine [54]. Additionally, acetylcholine, a crucial neurotransmitter, aids in the integration of phospholipids into cell membranes and boosts the production of structural phospholipids [55]. Moreover, it increases the concentrations of acetylcholine, norepinephrine, dopamine, and serotonin in particular brain regions [54]. Researchers employed a combination of imipramine (50 mg/kg) and citicoline (1.25, 2.5, and 5 mg/kg) via intraperitoneal injection in mice and observed the effects of imipramine and citicoline. The effects of imipramine and citicoline on pain and depressive behavior in mice were observed using a series of behavioral tests. The findings revealed that the co-administration of imipramine and citicoline extended the tail-flick latency and decreased the resting period during the forced swimming test (FST) in mice, suggesting potential for pain-relieving and mood-enhancing activities. Notably, a synergistic interaction was observed between imipramine and citicoline in eliciting these analgesic and antidepressant effects [53].

Although TCAs have shown promising therapeutic effects in animal experiments, their clinical application is hindered by severe side effects. TCAs impede the transport of norepinephrine and serotonin, and also occupy various receptors including post-synaptic histamine, alpha-adrenergic, and muscarinic-acetylcholine, which can result in a spectrum of side effects like xerostomia, disorientation, and diminished cognitive function. Other reported side effects included hypotension, orthostatic hypotension, blurred vision, urinary retention, somnolence, and sedation. Owing to their anticholinergic properties, TCAs are not recommended for patients with heart disease, glaucoma, or urinary retention issues [56, 57, 58]. To circumvent the deleterious side effects that impose additional suffering on patients, a treatment regimen analogous to the combination of citicoline and imipramine may be beneficial. This regimen involves reducing the dosage of TCAs and leveraging the synergistic effect of drugs to maintain therapeutic efficacy. This approach may serve as a model for the application of TCAs for the treatment of comorbidities.

3.2 Dihydromyricetin

Dihydromyricetin (DHM), is a flavonoid derived from the plant Ampelopsis glandulosa, which is prevalent in southern China. This compound exhibits a broad spectrum of therapeutic benefits, such as anti-inflammatory, antioxidant, antimicrobial, anticancer, and liver-protective actions. It is also utilized in the prevention and management of conditions like nephritis, hepatitis, and anorexia nervosa. While in the United States, DHM is solely sanctioned as a dietary supplement to counteract alcohol-induced hangovers, it possesses the potential to address neuropathic pain and associated depressive symptoms [59, 60].

While the principal molecular actions of DHM remain unclear, it is known to alleviate pain and exhibit antidepressant properties by inhibiting the activation of glial cells, inhibiting pain signaling, enhancing the expression of BDNF, and anti-inflammatory effects. Inhibition of glial cell activation: An increasing amount of research suggests that DHM administration can enhance the activity of Aldehyde Dehydrogenase 2 (ALDH2) and facilitate the shift of microglial cells from the inflammatory pro-inflammatory microglia/macrophages (M1) phenotype to the anti-inflammatory and reparative anti-inflammatory microglia/macrophages (M2) phenotype [61]. Inhibition of pain signaling: DHM decreases the levels of P2X7 receptor expression in the dorsal root ganglia (DRG), spinal cord, and hippocampus. These receptors, which belong to the ATP-activated ion channel family, are associated with the transmission of pain signals and the development of depressive disorders [62]. Additionally, DHM provides protection against P2X7 receptor-mediated damage to astrocytes in the hippocampus [63]. Upregulation of BNDF: BDNF is a crucial element in the pathophysiology of depression, as indicated by the lower BDNF concentrations found in the brains of individuals with major depressive disorder when contrasted with healthy controls. Furthermore, the direct application of BDNF to the midbrain or hippocampus has been shown to alleviate behaviors associated with depression [64]. Research has shown that DHM triggers the ERK1/2-CREB signaling pathway, enhances the phosphorylation at the ser-9 residue of glycogen synthase kinase 3\beta (GSK-3\beta), boosts the expression of Brain-Derived BDNF in hippocampal tissues and cultured hippocampal cells, and exhibits a more rapid therapeutic onset compared to conventional antidepressants [63, 64, 65]. Anti-inflammatory effects: A number of investigations have established that DHM is capable of mitigating neuroinflammation and alleviating depressive symptoms through the activation of the AGE-RAGE signaling axis [66].

Currently, only preclinical evidence of DHM in the treatment of comorbidities has shown that it reduces pain and alleviates depression. Researchers used a high-sugar, high-fat diet; injections of streptozotocin (STZ); and chronic unpredictable stress to create a comorbid rat model of diabetic neuropathic pain and depression, followed by intraperitoneal injections of DHM to comorbid rats, and found that DHM reduced pain and alleviated depressive behavior. Simultaneously, they measured BDNF and TrkB expression before and after modeling and found that BDNF/TrkB expression levels were reduced in the hippocampus and increased in the spinal cord and DRG after modeling, and DHM could reverse these changes [67]. Another study used the same model as the previous one and found that DHM reduced pain and alleviated depressive behaviors by reducing the P2X7 receptor [63].

However, DHM is highly insoluble and dissolves only in hot water and ethanol. Most of the DHM compounds and their metabolites are eliminated through feces, with a small fraction being absorbed in the small intestine. The absorbed substances then enter the systemic circulation through the portal vein, subsequently reaching the liver. In the liver, these compounds are subjected to additional metabolic processes, including glucuronidation, sulfonation, and methylation, to form phase II metabolites, which are then assimilated into the body. DHM is inherently unstable and undergoes degradation when exposed to light, pH buffers, pepsin, and pancreatic enzymes [68, 69, 70]. In conclusion, the low bioavailability and chemical instability of DHM restricts its pharmacological effects and clinical applications.

3.3 Palmatine

Palmatine, an isoquinoline alkaloid derived from traditional Chinese medicinal herbs, exists naturally. It is characterized as an ammonium salt with four methoxy groups attached to phenyl rings at the C2 and C3 positions. Over recent years, a plethora of studies has been dedicated to exploring the pharmacological properties of palmatine, revealing its potential as a neuroprotectant, an anticarcinogenic agent, a bactericide, a viricide, an antioxidant, an anti-inflammatory, and a lipid-modulating compound [71, 72].

Palmatine has both analgesic and antidepressant effects. Analgesic effects Palmatine exerts analgesic effects by inhibiting neuroinflammation via the Clec7a-MAPK/NF-\kappaB-NLRP3 inflammatory vesicle axis. Wu et al. [73] conducted behavioral tests to assess the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) in rats with chronic constriction injury after administering palmatine orally. They observed that rats exhibited prolonged MWT and TWL. Meanwhile, researchers used RNA sequencing and bioinformatics analysis to determine the target of palmatine’s action and found that it was mainly enriched in Clec7a-MAPK/NF-\kappaB-NLRP3, which was subsequently verified using western blotting and immunofluorescence. Palmatine exerts analgesic effects by inhibiting neuroinflammation [73]. Activation of the NLRP3 inflammasome complex leads to the assembly of NLRP3 with ASC and pro-Caspase-1, thereby triggering Caspase-1 activation and a subsequent surge in inflammatory cytokines like IL-1\beta and IL-18. This process is considered pivotal in the initiation and escalation of inflammatory reactions [74]. Antidepressant effects: Palmatine has been shown to mitigate depressive symptoms in mice. In a study, mice were subjected to chronic unpredictable mild stress for a period of 21 days to elicit depressive-like behaviors, after which they received daily intraperitoneal injections of palmatine at a dosage of 10 mg/kg for another 21 days. The antidepressant effects were evaluated using the tail suspension test (TST), FST, and sucrose preference test (SPT). The treated mice exhibited reduced immobility times and an amelioration of stress-induced anhedonia, as indicated by an increase in sucrose preference. It is hypothesized that excessive monoamine oxidase activity, oxidative stress, and an overactive hypothalamic-pituitary-adrenal (HPA) axis could lead to a depletion of monoamine neurotransmitters. The study assessed catalase levels in brain cells, monoamine oxidase-A (MAO-A) activity, lipid peroxidation, nitric oxide levels in plasma, and corticosterone levels. Results indicated that palmatine administration led to a reduction in MAO-A activity, nitric oxide, and corticosterone levels in the mice, suggesting that palmatine’s antidepressant effects are mediated through these mechanisms [75].

For preclinical comorbidities, only preclinical data are available, with no clinical application results. Preclinical studies have shown that preclinical treatment can reduce nociceptive hypersensitivity and behaviors. Shen et al. [76] employed STZ to develop a rat model for type 2 diabetes, which led to the onset of diabetic peripheral neuropathy and depressive symptoms in the rats. Following this, researchers administered palmatine intraperitoneally and evaluated its impact on the rats’ behavior, discovering that it lessened pain sensitivity and improved depressive symptoms. Through using western blot analysis, and immunohistochemical techniques, it was determined that palmatine decreased hippocampal expression levels of P2X7 receptors, GFAP, TNF-\alpha, and IL-1\beta, along with the phosphorylation of ERK1/2. These findings propose that palmatine could mitigate both diabetic peripheral neuropathic pain and comorbid depression by suppressing hippocampal P2X7 receptor expression and potentially by curbing the production of TNF-\alpha and IL-1\beta, as well as the phosphorylation of ERK1/2 [76].

The side effects of palmatine are relatively mild, with isolated cases of gastrointestinal discomfort, appetite loss, and constipation. Palmatine has low bioavailability in vivo and is hepatotoxic at high doses [77]. Interestingly, when used at low doses, palmatine exerts a hepatoprotective effect, suggesting that it may have a biphasic effect of activation at low concentrations and inhibition at high concentrations [78]. Palmatine has fewer side effects than other treatments for neuropathic pain and depressive comorbidities, making it a viable option for clinical trials.

3.4 Ketamine

Ketamine, a phencyclidine derivative, exerts analgesic and anesthetic effects primarily by inhibiting NMDA receptors [79]. However, this is not the sole mechanism of action. Ketamine shows a high affinity for dopamine and serotonin binding sites, which may contribute to its various clinical effects. The fact that serotonin antagonists, such as methysergide, antagonize the analgesic effects of ketamine also suggests its involvement in analgesia via the serotonergic pathway [80]. Additionally, ketamine has been shown to antagonize muscarinic receptors, leading to increased sympathetic tone, pupil dilation, and bronchodilation [80, 81, 82].

Ketamine possesses dual properties of analgesia and antidepressant activity. Analgesic effects: The spinal cord’s dorsal horn is equipped with both ionotropic glutamate receptors, including NMDA, AMPA, and kainate, as well as metabotropic glutamate receptors, all of which play a role in the genesis of neuropathic pain. The interaction of excitatory amino acids with NMDA receptors is believed to be a key factor in neuronal hyperexcitability, which leads to abnormal nociceptive hypersensitivity. Therefore, medications that modulate NMDA receptor activity may alleviate neuropathic pain [83, 84].

Furthermore, ketamine is believed to prevent and reduce the intensity of neuropathic pain by suppressing inflammatory signaling within diverse neuroglial cells that contribute to the establishment of painful conditions [85]. Antidepressant effects: Ketamine, when administered in subanesthetic doses, has become a novel approach for treating depression that is unresponsive to conventional therapies, demonstrating swift and potent antidepressant properties shortly after its application (Fig. 3). Compared to traditional antidepressants, which often have a delayed onset of action, depressive symptoms improve significantly after 40 minutes of ketamine treatment and maintain their efficacy for up to 72 hours [86, 87]. Ketamine blocks NMDA receptors in GABA neurons in the brain, preventing eEF2 phosphorylation and increasing BDNF levels. This, in turn, promotes AMPA receptor expression in synapses and increases synaptic connectivity [88]. A recent study showed that ketamine operates by blocking NMDA receptors on the lateral habenula, inhibiting bursts of electrical activity in neurons, which subsequently disengages the downstream reward centers [89]. The engagement of the reward system is crucial in the context of depression [90].

Ketamine only has preclinical evidence to show its effectiveness in treating comorbidities. In a preclinical study, a single subanesthetic dose of ketamine (10 mg/kg) was administered to mice with SNI depressive comorbidities. This treatment improved depression-related behaviors compared to the sham-operated group. However, nerve injury-induced nociceptive sensitization was not alleviated, possibly because a lower dose of ketamine did not have a better analgesic effect [91].

Regarding adverse effects, the repeated and high-dose use of ketamine carries the risk of developing tolerance and dependency. Prolonged misuse of ketamine can lead to urinary system symptoms and a condition known as ulcerative cystitis. Even with subanesthetic doses, ketamine has been associated with acute side effects such as increased blood pressure, nausea, headaches, blurred vision, altered perceptions, drowsiness, lightheadedness, psychotic episodes, and feelings of anxiety [92, 93, 94]. Though ketamine in doses below those used for anesthesia is utilized to address neuropathic pain and associated depressive symptoms, and it holds promise for the swift amelioration of depressive behaviors, concerns persist regarding its potential side effects and the development of tolerance.

3.5 Gabapentin

Gabapentin is an antiepileptic drug, a derivative of GABA, with distinct pharmacology compared to existing antiepileptic drugs. Gabapentin is frequently employed as an adjunctive medication when traditional antiepileptic drugs are ineffective or intolerable to the patient. Several studies have demonstrated that the frequency of seizures significantly decreases when gabapentin is added to the treatment regimen. Furthermore, the long-term effects of gabapentin have been proven satisfactory, with fewer adverse effects. Over the past decade, it has been increasingly used for the treatment of neuropathic pain in adults and has become the preferred analgesic of choice [95, 96].

Gabapentin exhibits analgesic effects but lacks antidepressant properties. Analgesic effects: Gabapentin inhibits calcium channels via the \alpha2\delta auxiliary subunit, inhibits synaptic transmission, and reduces neurotransmitter release, thus acting as a treatment for neuropathic pain [97]. A recent study has shown that \alpha2\delta not only acts as a subunit of calcium channels but also as a potent modulator of NMDA receptor function, which in turn affects neuropathic pain [98].

Clinical data does not substantiate the efficacy of gabapentin for managing concurrent disorders. However, preclinical investigations have indicated that gabapentin may alleviate depression associated with pain by altering the activity of dopaminergic neurons and reducing \theta-wave fluctuations in the ventral tegmental region. Such findings offer novel insights into the pathways that could be implicated in the co-occurrence of neuropathic pain and depressive disorders [99].

Gabapentin is generally well tolerated and has very few serious side effects. The predominant adverse effects included somnolence, lightheadedness, and exhaustion. Serious complications, including respiratory distress, visual impairments, and muscle disease, are seldom documented [100, 101]. Nevertheless, there is a potential for misuse and dependency with gabapentin among patients who have a history of or are currently struggling with substance use disorders (SUD) [102]. Therefore, physicians should exercise caution when prescribing gabapentin.

3.6 Minocycline

Minocycline is a second-generation tetracycline drug known for its improved pharmacokinetics compared to first-generation tetracyclines; it is completely absorbed when administered orally. This extensive-spectrum antibiotic has an antibacterial range akin to tetracycline, exerting a potent impact on Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, and Neisseria gonorrhea among the Gram-negative strains. Its antimicrobial properties stem from its ability to attach to the A site of the 30S ribosomal subunit, which hinders peptide chain elongation and, in turn, curbs bacterial protein synthesis. Primarily classified as a bacteriostatic agent, minocycline can exhibit bactericidal properties at elevated concentrations [103, 104, 105].

Minocycline has both analgesic and antidepressant effects. Analgesic effects: By suppressing the activation of microglia, minocycline produces analgesic effects, with microglia being crucial in the context of neuropathic pain. Research demonstrated that administering minocycline to rats post-spinal cord injury resulted in the inhibition of the IL-6/JAK2/STAT3 signaling cascade within microglia, thereby alleviating hyperalgesia in these animals [106]. This indicates that minocycline potentially mitigates pain by targeting the JAK2/STAT3 signaling pathway within microglial cells. Furthermore, minocycline activates the autophagy system via the PI3K/Akt/mTOR signaling pathway. This activation may facilitate neuroprotection and functional recovery through the upregulation of Beclin-1 and LC3B in the early stages of spinal cord injury [107] (Fig. 4). Antidepressant effects: Minocycline prevents the polarization of activated microglia towards the pro-inflammatory M1 phenotype and encourages their shift towards the anti-inflammatory M2 phenotype [108] (Fig. 4). Moreover, Minocycline is capable of crossing the blood-brain barrier and counteracting the activity of NMDA receptors within the central nervous system, thereby eliciting anti-inflammatory effects and potentially offering therapeutic benefits in the treatment of depression [109, 110]. Additional research has demonstrated that minocycline provides therapeutic benefits by curbing the release of high mobility group box-1 protein (HMGB1) from neurons and microglia, hinting that HMGB1 could serve as a promising therapeutic target for depression treatment [111].

Clinical data does not support the efficacy of minocycline for managing concurrent conditions. Preclinical studies have demonstrated that minocycline treatment can attenuate olfactory bulbectomy-induced depression-like behavior and alleviate spinal nerve ligation (SNL)-induced mechanical nociceptive hypersensitivity in olfactory bulbectomized rats [112]. However, minocycline has not been clinically used to treat comorbidities.

The side effects of minocycline primarily include vestibular toxicity, hepatotoxicity, and gastrointestinal discomfort. Vestibular toxicity: Vestibular toxicity is a rare but well-documented phenomenon that manifests as dizziness, tinnitus, and imbalance in some individuals following ingestion of minocycline. Gastrointestinal discomfort: Gastrointestinal discomfort, on the other hand, is a more common adverse reaction that often presents as nausea, vomiting, and other digestive issues. Hepatotoxicity: Hepatotoxicity is also a concern because the liver predominantly metabolizes minocycline. Individuals with poor liver function may experience elevated transaminase levels after minocycline injection, potentially leading to manifestations of drug-induced hepatitis [113, 114, 115]. The available literature on the use of minocycline for addressing neuropathic pain and associated depressive disorders is sparse, which necessitates careful consideration of its application due to potential side effects.

4. Conclusions and Outlook

The complexity of neuropathic pain and depression comorbidities has resulted in a lack of clarity regarding the underlying mechanisms. Current treatment problems include suboptimal treatment protocols, high side effects associated with single-drug therapy, excessive side effects from multiple drugs, drug resistance, and nonuniformity of the physiotherapy treatment process, all of which hinder treatment efficacy. Learning from the citicoline and imipramine combination treatment plan, we can explore the use of multiple-drug regimens to minimize the side effects of a single drug and assess synergistic effects. In addition, drugs can be developed against effective targets, such as inhibition of glial cell activation, modulation of BNDF, and regulation of P2X4/P2X7. Providing patients with meticulous care and positive psychological counseling is essential. Ultimately, we hope that our endeavors will lead to expeditious eradication of the disease in patients.

References

[1] Baron R, Binder A, Wasner G. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. The Lancet. Neurology. 2010; 9: 807–819. https://doi.org/10.1016/S1474-4422(10)70143-5.

[2] Rosenberger DC, Blechschmidt V, Timmerman H, Wolff A, Treede RD. Challenges of neuropathic pain: focus on diabetic neuropathy. Journal of Neural Transmission (Vienna, Austria: 1996). 2020; 127: 589–624. https://doi.org/10.1007/s00702-020-02145-7.

[3] Jensen TS, Finnerup NB. Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. The Lancet. Neurology. 2014; 13: 924–935. https://doi.org/10.1016/S1474-4422(14)70102-4.

[4] McCarron RM, Shapiro B, Rawles J, Luo J. Depression. Annals of Internal Medicine. 2021; 174: ITC65–ITC80. https://doi.org/10.7326/AITC202105180.

[5] Disner SG, Beevers CG, Haigh EAP, Beck AT. Neural mechanisms of the cognitive model of depression. Nature Reviews. Neuroscience. 2011; 12: 467–477. https://doi.org/10.1038/nrn3027.

[6] Treede RD, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, et al. A classification of chronic pain for ICD-11. Pain. 2015; 156: 1003–1007. https://doi.org/10.1097/j.pain.0000000000000160.

[7] Bair MJ, Robinson RL, Katon W, Kroenke K. Depression and pain comorbidity: a literature review. Archives of Internal Medicine. 2003; 163: 2433–2445. https://doi.org/10.1001/archinte.163.20.2433.

[8] Jiang Y, Zou D, Li Y, Gu S, Dong J, Ma X, et al. Monoamine Neurotransmitters Control Basic Emotions and Affect Major Depressive Disorders. Pharmaceuticals (Basel, Switzerland). 2022; 15: 1203. https://doi.org/10.3390/ph15101203.

[9] Haase J, Brown E. Integrating the monoamine, neurotrophin and cytokine hypotheses of depression–a central role for the serotonin transporter? Pharmacology & Therapeutics. 2015; 147: 1–11. https://doi.org/10.1016/j.pharmthera.2014.10.002.

[10] Millan MJ. Descending control of pain. Progress in Neurobiology. 2002; 66: 355–474. https://doi.org/10.1016/s0301-0082(02)00009-6.

[11] Colucci-D’Amato L, Speranza L, Volpicelli F. Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer. International Journal of Molecular Sciences. 2020; 21: 7777. https://doi.org/10.3390/ijms21207777.

[12] Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008; 455: 894–902. https://doi.org/10.1038/nature07455.

[13] Yajima Y, Narita M, Usui A, Kaneko C, Miyatake M, Narita M, et al. Direct evidence for the involvement of brain-derived neurotrophic factor in the development of a neuropathic pain-like state in mice. Journal of Neurochemistry. 2005; 93: 584–594. https://doi.org/10.1111/j.1471-4159.2005.03045.x.

[14] Walker AK, Kavelaars A, Heijnen CJ, Dantzer R. Neuroinflammation and comorbidity of pain and depression. Pharmacological Reviews. 2014; 66: 80–101. https://doi.org/10.1124/pr.113.008144.

[15] Sheng J, Liu S, Wang Y, Cui R, Zhang X. The Link between Depression and Chronic Pain: Neural Mechanisms in the Brain. Neural Plasticity. 2017; 2017: 9724371. https://doi.org/10.1155/2017/9724371.

[16] Sanacora G, Zarate CA, Krystal JH, Manji HK. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nature Reviews. Drug Discovery. 2008; 7: 426–437. https://doi.org/10.1038/nrd2462.

[17] Paoletti P, Bellone C, Zhou Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nature Reviews. Neuroscience. 2013; 14: 383–400. https://doi.org/10.1038/nrn3504.

[18] Zhang Y, Ma H, Bai Y, Hou X, Yang Y, Wang G, et al. Chronic Neuropathic Pain and Comorbid Depression Syndrome: From Neural Circuit Mechanisms to Treatment. ACS Chemical Neuroscience. 2024; 15: 2432–2444. https://doi.org/10.1021/acschemneuro.4c00125.

[19] Lanza G, Fisicaro F, Cantone M, Pennisi M, Cosentino FII, Lanuzza B, et al. Repetitive transcranial magnetic stimulation in primary sleep disorders. Sleep Medicine Reviews. 2023; 67: 101735. https://doi.org/10.1016/j.smrv.2022.101735.

[20] McClintock SM, Reti IM, Carpenter LL, McDonald WM, Dubin M, Taylor SF, et al. Consensus Recommendations for the Clinical Application of Repetitive Transcranial Magnetic Stimulation (rTMS) in the Treatment of Depression. The Journal of Clinical Psychiatry. 2018; 79: 16cs10905. https://doi.org/10.4088/JCP.16cs10905.

[21] Brandt SJ, Oral HY, Arellano-Bravo C, Plawecki MH, Hummer TA, Francis MM. Repetitive Transcranial Magnetic Stimulation as a Therapeutic and Probe in Schizophrenia: Examining the Role of Neuroimaging and Future Directions. Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics. 2021; 18: 827–844. https://doi.org/10.1007/s13311-021-01046-1.

[22] Gogulski J, Ross JM, Talbot A, Cline CC, Donati FL, Munot S, et al. Personalized Repetitive Transcranial Magnetic Stimulation for Depression. Biological Psychiatry. Cognitive Neuroscience and Neuroimaging. 2023; 8: 351–360. https://doi.org/10.1016/j.bpsc.2022.10.006.

[23] Klooster DCW, Ferguson MA, Boon PAJM, Baeken C. Personalizing Repetitive Transcranial Magnetic Stimulation Parameters for Depression Treatment Using Multimodal Neuroimaging. Biological Psychiatry. Cognitive Neuroscience and Neuroimaging. 2022; 7: 536–545. https://doi.org/10.1016/j.bpsc.2021.11.004.

[24] Lefaucheur JP, Drouot X, Menard-Lefaucheur I, Zerah F, Bendib B, Cesaro P, et al. Neurogenic pain relief by repetitive transcranial magnetic cortical stimulation depends on the origin and the site of pain. Journal of Neurology, Neurosurgery, and Psychiatry. 2004; 75: 612–616. https://doi.org/10.1136/jnnp.2003.022236.

[25] Pogarell O, Koch W, Pöpperl G, Tatsch K, Jakob F, Zwanzger P, et al. Striatal dopamine release after prefrontal repetitive transcranial magnetic stimulation in major depression: preliminary results of a dynamic [123I] IBZM SPECT study. Journal of Psychiatric Research. 2006; 40: 307–314. https://doi.org/10.1016/j.jpsychires.2005.09.001.

[26] Levitt JG, Kalender G, O’Neill J, Diaz JP, Cook IA, Ginder N, et al. Dorsolateral prefrontal γ-aminobutyric acid in patients with treatment-resistant depression after transcranial magnetic stimulation measured with magnetic resonance spectroscopy. Journal of Psychiatry & Neuroscience: JPN. 2019; 44: 386–394. https://doi.org/10.1503/jpn.180230.

[27] Hu Y, Zhu Y, Wen X, Zeng F, Feng Y, Xu Z, et al. Repetitive transcranial magnetic stimulation regulates neuroinflammation, relieves hyperalgesia and reverses despair-like behaviour in chronic constriction injury rats. The European Journal of Neuroscience. 2022; 56: 4930–4947. https://doi.org/10.1111/ejn.15779.

[28] Wang H, Hu YZ, Che XW, Yu L. Motor cortex transcranial magnetic stimulation to reduce intractable postherpetic neuralgia with poor response to other threapies: Report of two cases. World Journal of Clinical Cases. 2023; 11: 2015–2020. https://doi.org/10.12998/wjcc.v11.i9.2015.

[29] Gayduk AJ, Shishkovskaia TI, Cumming P, Koutsomitros T, Sack AT, Vlasov YV, et al. Association between Neuropathic Pain and Depression: Focusing on the Transcranial Magnetic Stimulation As a Promising Treatment Approach. Psychiatria Danubina. 2022; 34: 105–111.

[30] Ulloa L. Electroacupuncture activates neurons to switch off inflammation. Nature. 2021; 598: 573–574. https://doi.org/10.1038/d41586-021-02714-0.

[31] Wu R, Ma H, Hu J, Wang D, Wang F, Yu X, et al. Electroacupuncture stimulation to modulate neural oscillations in promoting neurological rehabilitation. Brain Research. 2024; 1822: 148642. https://doi.org/10.1016/j.brainres.2023.148642.

[32] Zhang R, Lao L, Ren K, Berman BM. Mechanisms of acupuncture-electroacupuncture on persistent pain. Anesthesiology. 2014; 120: 482–503. https://doi.org/10.1097/ALN.0000000000000101.

[33] Mousa SA, Shaqura M, Brendl U, Al-Khrasani M, Fürst S, Schäfer M. Involvement of the peripheral sensory and sympathetic nervous system in the vascular endothelial expression of ICAM-1 and the recruitment of opioid-containing immune cells to inhibit inflammatory pain. Brain, Behavior, and Immunity. 2010; 24: 1310–1323. https://doi.org/10.1016/j.bbi.2010.06.008.

[34] Li A, Lao L, Wang Y, Xin J, Ren K, Berman BM, et al. Electroacupuncture activates corticotrophin-releasing hormone-containing neurons in the paraventricular nucleus of the hypothalammus to alleviate edema in a rat model of inflammation. BMC Complementary and Alternative Medicine. 2008; 8: 20. https://doi.org/10.1186/1472-6882-8-20.

[35] Lee JH, Jang KJ, Lee YT, Choi YH, Choi BT. Electroacupuncture inhibits inflammatory edema and hyperalgesia through regulation of cyclooxygenase synthesis in both peripheral and central nociceptive sites. The American Journal of Chinese Medicine. 2006; 34: 981–988. https://doi.org/10.1142/S0192415X06004454.

[36] Jhaveri MD, Richardson D, Chapman V. Endocannabinoid metabolism and uptake: novel targets for neuropathic and inflammatory pain. British Journal of Pharmacology. 2007; 152: 624–632. https://doi.org/10.1038/sj.bjp.0707433.

[37] Wen J, Chen X, Yang Y, Liu J, Li E, Liu J, et al. Acupuncture Medical Therapy and its Underlying Mechanisms: A Systematic Review. The American Journal of Chinese Medicine. 2021; 49: 1–23. https://doi.org/10.1142/S0192415X21500014.

[38] Yin X, Li W, Liang T, Lu B, Yue H, Li S, et al. Effect of Electroacupuncture on Insomnia in Patients With Depression: A Randomized Clinical Trial. JAMA Network Open. 2022; 5: e2220563. https://doi.org/10.1001/jamanetworkopen.2022.20563.

[39] Qiu X, Li Z, Huang S, Cai X, Qu S, Zheng Z, et al. Electroacupuncture Improves Depression-Like Behavior by Regulating the Abundance of Lactobacillus and Staphylococci in Mice. Journal of Integrative Neuroscience. 2023; 22: 28. https://doi.org/10.31083/j.jin2202028.

[40] Lin SS, Zhou B, Chen BJ, Jiang RT, Li B, Illes P, et al. Electroacupuncture prevents astrocyte atrophy to alleviate depression. Cell Death & Disease. 2023; 14: 343. https://doi.org/10.1038/s41419-023-05839-4.

[41] Cong W, Peng Y, Meng B, Jia X, Jin Z. The effect of electroacupuncture on regulating pain and depression-like behaviors induced by chronic neuropathic pain. Annals of Palliative Medicine. 2021; 10: 104–113. https://doi.org/10.21037/apm-20-1900.

[42] Li S, Huang J, Luo D, Fu W, Liu J. Electro-acupuncture inhibits HDAC2 via modulating gut microbiota to ameliorate SNI-induced pain and depression-like behavior in rats. Journal of Affective Disorders. 2024; 360: 305–313. https://doi.org/10.1016/j.jad.2024.02.069.

[43] Tian JH, Zhang W, Fang Y, Xu W, Grandy DK, Han JS. Endogenous orphanin FQ: evidence for a role in the modulation of electroacupuncture analgesia and the development of tolerance to analgesia produced by morphine and electroacupuncture. British Journal of Pharmacology. 1998; 124: 21–26. https://doi.org/10.1038/sj.bjp.0701788.

[44] Huang C, Long H, Shi YS, Han JS, Wan Y. Nocistatin potentiates electroacupuncture antinociceptive effects and reverses chronic tolerance to electroacupuncture in mice. Neuroscience Letters. 2003; 350: 93–96. https://doi.org/10.1016/s0304-3940(03)00863-2.

[45] Schneider J, Patterson M, Jimenez XF. Beyond depression: Other uses for tricyclic antidepressants. Cleveland Clinic Journal of Medicine. 2019; 86: 807–814. https://doi.org/10.3949/ccjm.86a.19005.

[46] Asensi-Cantó A, López-Abellán MD, Castillo-Guardiola V, Hurtado AM, Martínez-Penella M, Luengo-Gil G, et al. Antitumoral Effects of Tricyclic Antidepressants: Beyond Neuropathic Pain Treatment. Cancers. 2022; 14: 3248. https://doi.org/10.3390/cancers14133248.

[47] Moraczewski J, Awosika AO, Aedma KK. Tricyclic Antidepressants. StatPearls Publishing: Treasure Island (FL). 2024.

[48] Kremer M, Salvat E, Muller A, Yalcin I, Barrot M. Antidepressants and gabapentinoids in neuropathic pain: Mechanistic insights. Neuroscience. 2016; 338: 183–206. https://doi.org/10.1016/j.neuroscience.2016.06.057.

[49] Cayley WE, Jr. Antidepressants for the treatment of neuropathic pain. American Family Physician. 2006; 73: 1933–1934.

[50] Belinskaia DA, Shestakova NN. Structure- and Cation-Dependent Mechanism of Interaction of Tricyclic Antidepressants with NMDA Receptor According to Molecular Modeling Data. Biochemistry. Biokhimiia. 2024; 89: 507–522. https://doi.org/10.1134/S0006297924030106.

[51] Obata H. Analgesic Mechanisms of Antidepressants for Neuropathic Pain. International Journal of Molecular Sciences. 2017; 18: 2483. https://doi.org/10.3390/ijms18112483.

[52] Burke NN, Finn DP, Roche M. Chronic administration of amitriptyline differentially alters neuropathic pain-related behaviour in the presence and absence of a depressive-like phenotype. Behavioural Brain Research. 2015; 278: 193–201. https://doi.org/10.1016/j.bbr.2014.09.044.

[53] Khakpai F, Ramezanikhah M, Valizadegan F, Zarrindast MR. Synergistic effect between imipramine and citicoline upon induction of analgesic and antidepressant effects in mice. Neuroscience Letters. 2021; 760: 136095. https://doi.org/10.1016/j.neulet.2021.136095.

[54] Wignall ND, Brown ES. Citicoline in addictive disorders: a review of the literature. The American Journal of Drug and Alcohol Abuse. 2014; 40: 262–268. https://doi.org/10.3109/00952990.2014.925467.

[55] Emril DR, Wibowo S, Meliala L, Susilowati R. Cytidine 5’-diphosphocholine administration prevents peripheral neuropathic pain after sciatic nerve crush injury in rats. Journal of Pain Research. 2016; 9: 287–291. https://doi.org/10.2147/JPR.S70481.

[56] Roose SP. Considerations for the use of antidepressants in patients with cardiovascular disease. American Heart Journal. 2000; 140: 84–88. https://doi.org/10.1067/mhj.2000.109977.

[57] Nattel S. Frequency-dependent effects of amitriptyline on ventricular conduction and cardiac rhythm in dogs. Circulation. 1985; 72: 898–906. https://doi.org/10.1161/01.cir.72.4.898.

[58] Khawam EA, Laurencic G, Malone DA, Jr. Side effects of antidepressants: an overview. Cleveland Clinic Journal of Medicine. 2006; 73: 351–353, 356–61. https://doi.org/10.3949/ccjm.73.4.351.

[59] Li H, Li Q, Liu Z, Yang K, Chen Z, Cheng Q, et al. The Versatile Effects of Dihydromyricetin in Health. Evidence-based Complementary and Alternative Medicine: ECAM. 2017; 2017: 1053617. https://doi.org/10.1155/2017/1053617.

[60] Dong S, Zhu M, Wang K, Zhao X, Hu L, Jing W, et al. Dihydromyricetin improves DSS-induced colitis in mice via modulation of fecal-bacteria-related bile acid metabolism. Pharmacological Research. 2021; 171: 105767. https://doi.org/10.1016/j.phrs.2021.105767.

[61] Zhang W, Yang L, Li L, Feng W. Dihydromyricetin attenuates neuropathic pain via enhancing the transition from M1 to M2 phenotype polarization by potentially elevating ALDH2 activity in vitro and vivo. Annals of Translational Medicine. 2020; 8: 1151. https://doi.org/10.21037/atm-20-5838.

[62] Guan S, Shen Y, Ge H, Xiong W, He L, Liu L, et al. Dihydromyricetin Alleviates Diabetic Neuropathic Pain and Depression Comorbidity Symptoms by Inhibiting P2X_⁢7 Receptor. Frontiers in Psychiatry. 2019; 10: 770. https://doi.org/10.3389/fpsyt.2019.00770.

[63] Ge H, Sun M, Wei X, Zhang M, Tu H, Hao Y, et al. Protective effects of dihydromyricetin on primary hippocampal astrocytes from cytotoxicity induced by comorbid diabetic neuropathic pain and depression. Purinergic Signalling. 2020; 16: 585–599. https://doi.org/10.1007/s11302-020-09752-9.

[64] Siuciak JA, Lewis DR, Wiegand SJ, Lindsay RM. Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacology, Biochemistry, and Behavior. 1997; 56: 131–137. https://doi.org/10.1016/S0091-3057(96)00169-4.

[65] Ren Z, Yan P, Zhu L, Yang H, Zhao Y, Kirby BP, et al. Dihydromyricetin exerts a rapid antidepressant-like effect in association with enhancement of BDNF expression and inhibition of neuroinflammation. Psychopharmacology. 2018; 235: 233–244. https://doi.org/10.1007/s00213-017-4761-z.

[66] Huang J, Chen B, Wang H, Hu S, Yu X, Reilly J, et al. Dihydromyricetin Attenuates Depressive-like Behaviors in Mice by Inhibiting the AGE-RAGE Signaling Pathway. Cells. 2022; 11: 3730. https://doi.org/10.3390/cells11233730.

[67] Ge H, Guan S, Shen Y, Sun M, Hao Y, He L, et al. Dihydromyricetin affects BDNF levels in the nervous system in rats with comorbid diabetic neuropathic pain and depression. Scientific Reports. 2019; 9: 14619. https://doi.org/10.1038/s41598-019-51124-w.

[68] Sun Y, Liu S, Yang S, Chen C, Yang Y, Lin M, et al. Mechanism of Dihydromyricetin on Inflammatory Diseases. Frontiers in Pharmacology. 2022; 12: 794563. https://doi.org/10.3389/fphar.2021.794563.

[69] Wang Z, Cao Z, Yue Z, Yang Z. Research progress of dihydromyricetin in the treatment of diabetes mellitus. Frontiers in Endocrinology. 2023; 14: 1216907. https://doi.org/10.3389/fendo.2023.1216907.

[70] Chen L, Shi M, Lv C, Song Y, Wu Y, Liu S, et al. Dihydromyricetin Acts as a Potential Redox Balance Mediator in Cancer Chemoprevention. Mediators of Inflammation. 2021; 2021: 6692579. https://doi.org/10.1155/2021/6692579.

[71] Long J, Song J, Zhong L, Liao Y, Liu L, Li X. Palmatine: A review of its pharmacology, toxicity and pharmacokinetics. Biochimie. 2019; 162: 176–184. https://doi.org/10.1016/j.biochi.2019.04.008.

[72] Ekeuku SO, Pang KL, Chin KY. Palmatine as an Agent Against Metabolic Syndrome and Its Related Complications: A Review. Drug Design, Development and Therapy. 2020; 14: 4963–4974. https://doi.org/10.2147/DDDT.S280520.

[73] Wu D, Wang P, Zhao C, Su J, Zhang J, Ma W, et al. Levo-tetrahydropalmatine ameliorates neuropathic pain by inhibiting the activation of the Clec7a-MAPK/NF-κB-NLRP3 inflammasome axis. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology. 2023; 121: 155075. https://doi.org/10.1016/j.phymed.2023.155075.

[74] Schroder K, Tschopp J. The inflammasomes. Cell. 2010; 140: 821–832. https://doi.org/10.1016/j.cell.2010.01.040.

[75] Dhingra D, Bhankher A. Behavioral and biochemical evidences for antidepressant-like activity of palmatine in mice subjected to chronic unpredictable mild stress. Pharmacological Reports: PR. 2014; 66: 1–9. https://doi.org/10.1016/j.pharep.2013.06.001.

[76] Shen Y, Guan S, Ge H, Xiong W, He L, Liu L, et al. Effects of palmatine on rats with comorbidity of diabetic neuropathic pain and depression. Brain Research Bulletin. 2018; 139: 56–66. https://doi.org/10.1016/j.brainresbull.2018.02.005.

[77] Zhang X, Qiu F, Jiang J, Gao C, Tan Y. Intestinal absorption mechanisms of berberine, palmatine, jateorhizine, and coptisine: involvement of P-glycoprotein. Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 2011; 41: 290–296. https://doi.org/10.3109/00498254.2010.529180.

[78] Yu CP, Huang CY, Lin SP, Hou YC. Activation of P-glycoprotein and CYP 3A by Coptidis Rhizoma in vivo: Using cyclosporine as a probe substrate in rats. Journal of Food and Drug Analysis. 2018; 26: S125–S132. https://doi.org/10.1016/j.jfda.2017.11.005.

[79] Kim JW, Suzuki K, Kavalali ET, Monteggia LM. Ketamine: Mechanisms and Relevance to Treatment of Depression. Annual Review of Medicine. 2024; 75: 129–143. https://doi.org/10.1146/annurev-med-051322-120608.

[80] Crisp T, Perrotti JM, Smith DL, Stafinsky JL, Smith DJ. The local monoaminergic dependency of spinal ketamine. European Journal of Pharmacology. 1991; 194: 167–172. https://doi.org/10.1016/0014-2999(91)90101-u.

[81] Durieux ME. Inhibition by ketamine of muscarinic acetylcholine receptor function. Anesthesia and Analgesia. 1995; 81: 57–62. https://doi.org/10.1097/00000539-199507000-00012.

[82] Mihaljević S, Pavlović M, Reiner K, Ćaćić M. Therapeutic Mechanisms of Ketamine. Psychiatria Danubina. 2020; 32: 325–333. https://doi.org/10.24869/psyd.2020.325.

[83] Culp C, Kim HK, Abdi S. Ketamine Use for Cancer and Chronic Pain Management. Frontiers in Pharmacology. 2021; 11: 599721. https://doi.org/10.3389/fphar.2020.599721.

[84] Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. British Journal of Clinical Pharmacology. 2014; 77: 357–367. https://doi.org/10.1111/bcp.12094.

[85] Dominguini D, Steckert AV, Michels M, Spies MB, Ritter C, Barichello T, et al. The effects of anaesthetics and sedatives on brain inflammation. Neuroscience and Biobehavioral Reviews. 2021; 127: 504–513. https://doi.org/10.1016/j.neubiorev.2021.05.009.

[86] Yavi M, Lee H, Henter ID, Park LT, Zarate CA, Jr. Ketamine treatment for depression: a review. Discover Mental Health. 2022; 2: 9. https://doi.org/10.1007/s44192-022-00012-3.

[87] Jelen LA, Stone JM. Ketamine for depression. International Review of Psychiatry (Abingdon, England). 2021; 33: 207–228. https://doi.org/10.1080/09540261.2020.1854194.

[88] Górska N, Słupski J, Szałach ŁP, Włodarczyk A, Szarmach J, Jakuszkowiak-Wojten K, et al. Magnesium and ketamine in the treatment of depression. Psychiatria Danubina. 2019; 31: 549–553.

[89] Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. 2018; 554: 317–322. https://doi.org/10.1038/nature25509.

[90] Dong Y, Li Y, Xiang X, Xiao ZC, Hu J, Li Y, et al. Stress relief as a natural resilience mechanism against depression-like behaviors. Neuron. 2023; 111: 3789–3801.e6. https://doi.org/10.1016/j.neuron.2023.09.004.

[91] Wang J, Goffer Y, Xu D, Tukey DS, Shamir DB, Eberle SE, et al. A single subanesthetic dose of ketamine relieves depression-like behaviors induced by neuropathic pain in rats. Anesthesiology. 2011; 115: 812–821. https://doi.org/10.1097/ALN.0b013e31822f16ae.

[92] Sassano-Higgins S, Baron D, Juarez G, Esmaili N, Gold M. A REVIEW OF KETAMINE ABUSE AND DIVERSION. Depress Anxiety. 2016; 33: 718–727. https://doi.org/10.1002/da.22536.

[93] Zanos P, Moaddel R, Morris PJ, Riggs LM, Highland JN, Georgiou P, et al. Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms. Pharmacological Reviews. 2018; 70: 621–660. https://doi.org/10.1124/pr.117.015198.

[94] Qian X, Zhao X, Yu L, Yin Y, Zhang XD, Wang L, et al. Current status of GABA receptor subtypes in analgesia. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 2023; 168: 115800. https://doi.org/10.1016/j.biopha.2023.115800.

[95] Mathieson S, Lin CWC, Underwood M, Eldabe S. Pregabalin and gabapentin for pain. BMJ (Clinical Research Ed.). 2020; 369: m1315. https://doi.org/10.1136/bmj.m1315.

[96] Martin JC, Gainer D. Psychiatric Uses of Gabapentin. Innovations in Clinical Neuroscience. 2022; 19: 55–60.

[97] Senderovich H, Jeyapragasan G. Is there a role for combined use of gabapentin and pregabalin in pain control? Too good to be true? Current Medical Research and Opinion. 2018; 34: 677–682. https://doi.org/10.1080/03007995.2017.1391756.

[98] Chen J, Li L, Chen SR, Chen H, Xie JD, Sirrieh RE, et al. The α2δ-1-NMDA Receptor Complex Is Critically Involved in Neuropathic Pain Development and Gabapentin Therapeutic Actions. Cell Reports. 2018; 22: 2307–2321. https://doi.org/10.1016/j.celrep.2018.02.021.

[99] Fu B, Wen SN, Wang B, Wang K, Zhang JY, Weng XC, et al. Gabapentin regulates dopaminergic neuron firing and theta oscillation in the ventral tegmental area to reverse depression-like behavior in chronic neuropathic pain state. Journal of Pain Research. 2018; 11: 2247–2256. https://doi.org/10.2147/JPR.S170167.

[100] Quintero GC. Review about gabapentin misuse, interactions, contraindications and side effects. Journal of Experimental Pharmacology. 2017; 9: 13–21. https://doi.org/10.2147/JEP.S124391.

[101] Meaadi J, Obara I, Eldabe S, Nazar H. The safety and efficacy of gabapentinoids in the management of neuropathic pain: a systematic review with meta-analysis of randomised controlled trials. International Journal of Clinical Pharmacy. 2023; 45: 556–565. https://doi.org/10.1007/s11096-022-01528-y.

[102] Bonnet U, Scherbaum N. How addictive are gabapentin and pregabalin? A systematic review. European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology. 2017; 27: 1185–1215. https://doi.org/10.1016/j.euroneuro.2017.08.430.

[103] Jonas M, Cunha BA. Minocycline. Therapeutic Drug Monitoring. 1982; 4: 137–145.

[104] Onge ES, Mobley WC. Minocycline Topical Foam: A New Drug for the Treatment of Acne. The Annals of Pharmacotherapy. 2021; 55: 105–110. https://doi.org/10.1177/1060028020939926.

[105] Li J, Qin Y, Zhao C, Zhang Z, Zhou Z. Tetracycline antibiotics: Potential anticancer drugs. European Journal of Pharmacology. 2023; 956: 175949. https://doi.org/10.1016/j.ejphar.2023.175949.

[106] Lee JY, Park CS, Seo KJ, Kim IY, Han S, Youn I, et al. IL-6/JAK2/STAT3 axis mediates neuropathic pain by regulating astrocyte and microglia activation after spinal cord injury. Experimental Neurology. 2023; 370: 114576. https://doi.org/10.1016/j.expneurol.2023.114576.

[107] Qiao L, Tang Q, An Z, Qi J. Minocycline relieves neuropathic pain in rats with spinal cord injury via activation of autophagy and suppression of PI3K/Akt/mTOR pathway. Journal of Pharmacological Sciences. 2023; 153: 12–21. https://doi.org/10.1016/j.jphs.2023.06.002.

[108] Zhang C, Zhang YP, Li YY, Liu BP, Wang HY, Li KW, et al. Minocycline ameliorates depressive behaviors and neuro-immune dysfunction induced by chronic unpredictable mild stress in the rat. Behavioural Brain Research. 2019; 356: 348–357. https://doi.org/10.1016/j.bbr.2018.07.001.

[109] Kacal MJ. Is minocycline effective for treating depression? JAAPA: Official Journal of the American Academy of Physician Assistants. 2022; 35: 13–14. https://doi.org/10.1097/01.JAA.0000824988.46634.1d.

[110] Al Jumaili W, Vora D, Trivedi C, Jain S. Role of Minocycline as an Adjunct Neuroinflammatory Modulator in Treatment-Resistant Depression: A Systematic Review of Randomized Controlled Trials. The Primary Care Companion for CNS Disorders. 2023; 25: 22r03467. https://doi.org/10.4088/PCC.22r03467.

[111] Wang B, Huang X, Pan X, Zhang T, Hou C, Su WJ, et al. Minocycline prevents the depressive-like behavior through inhibiting the release of HMGB1 from microglia and neurons. Brain, Behavior, and Immunity. 2020; 88: 132–143. https://doi.org/10.1016/j.bbi.2020.06.019.

[112] Burke NN, Kerr DM, Moriarty O, Finn DP, Roche M. Minocycline modulates neuropathic pain behaviour and cortical M1-M2 microglial gene expression in a rat model of depression. Brain, Behavior, and Immunity. 2014; 42: 147–156. https://doi.org/10.1016/j.bbi.2014.06.015.

[113] Fanning WL, Gump DW. Distressing side-effects of minocycline hydrochloride. Archives of Internal Medicine. 1976; 136: 761–762.

[114] Williams DN, Laughlin LW, Lee YH. Minocycline: Possible vestibular side-effects. Lancet (London, England). 1974; 2: 744–746. https://doi.org/10.1016/s0140-6736(74)90941-6.

[115] Acharya S, Thakurathi P, Plocharczyk E, Arbach A, Gupta SS. Minocycline-Associated Fatal Liver Injury. American Journal of Therapeutics. 2024; 31: e195–e197. https://doi.org/10.1097/MJT.0000000000001585.

Funding

Young Scholarship Program of the National Natural Science Foundation of China(82201366)

Jiangsu Provincial Research Hospital(YJXYY202204-YSB33)