Mechanism of melatonin in the treatment of chronic pain-depression co-morbidity

Guo-Ding Cao , Xu-Sheng Li, Jun Liu, Yu-Qi Pei, Peng Liu , Peng Li , Lan Zhang

1.Gansu University Tra-ditioal Chinese Medicine,Lanzhou 730000, China

2.The 940th Hospital Joint Logisti-cs Support Force of Peoples Liberation Army,Lanzhou730050, China 3.BeijingCentral Medical District of PLA General Hospital, Beijing 101149, China

Keywords:Melatonin Chronic pain Depression Cmorbidity Mechanism

ABSTRACT Pain and depression are the most common neural responses to many harmful or harmful stimuli. The two are risk factors for each other. The comorbid relationship between pain and depression makes clinical treatment difficult. Seeking an analgesic and antidepressant is an urgent goal of clinical management of pain and depression. Melatonin (N-acetyl-5-methoxytryptamine) secreted by the pineal gland has multiple functions, including anti-inflammatory, antioxidant, immunomodulatory, sedative and analgesic. The effectiveness, safety, and basic non-toxic side effects of melatonin as an analgesic and antidepressant have been demonstrated in various pain animal models, which makes melatonin different in pathological conditions and during surgery. It has been used clinically in patients. Melatonin-mediated analgesic and antidepressant effects may involve inflammatory factors, astrocytes, protein kinase C (PKC) / N-methyl-D-aspartate (NMDA) pathway. However, there are few reports about the mechanism of melatonin in pain syndrome and depression in China. Therefore, this article summarizes the analgesic and antidepressant mechanism of melatonin by consulting domestic and foreign literatures. Provide theoretical basis for clinical treatment of related diseases.

30% of patients with chronic pain show negative emotions such as depression and anxiety, and 50% of patients with depression have accompanying pain symptoms[1-2].Pain and depression are risk factors for each other. Depression can lead to lower pain thresholds and increased demand for analgesics. Pain can aggravate the extent and frequency of psychological and mental illnesses such as anxiety and depression[2-3].Burston et al.[1]found in a crowd survey experiment that individuals with OA and high depression had higher pain scores and pain tolerance compared with individuals with osteoarthritis (Osteoarthr-itis, OA) and normal depression levels. The degree is reduced. Wang et al [4] showed that rats with genetic susceptibility to depressive behavior exacerbated the mechanical hyperalgesia caused by unilateral temporomandibular joint (TMJ) inflammation. On the contrary, TMJ inflammation would enhance depressive behavior, so that the same In rats, a lower nociceptive threshold was associated with a higher depression behavior score. The comorbidity of pain and depression seriously affects all aspects of the patient: including increased medical expenses, decreased work efficiency, etc. In addition, the possibility of depression relief will be reduced, which may cause patients with residual symptoms to relapse and relapse It is earlier than those without residual symptoms[2-3][5]. The treatment of comorbidity of pain and depression is one of the difficulties in clinical work. Although many drugs have been developed to manage pain and depression, most drugs have multiple side effects [3]. There is an increasing need to develop new strategies to effectively manage pain and depression while reducing side effects. In recent years, melatonin (Melatonin, MLT) and its analogues have received much attention because of their protective effects on various damages to the nervous system [3]. More and more studies have shown that MLT plays a key role in many physiological processes, including circadian rhythm regulation[4], antioxidant [6], and also has powerful anti-inflammatory [7], analgesic and antidepressant effects[8-9]. Fan et al.[5]found in animal model studies that MLT can produce transient anti-nociceptive effects in mouse pain models, regulate the hyperalgesia induced by lipopolysaccharide, and interact with opioid anti-nociceptive effects. Fong et al. [10] found changes in plasma MLT levels and spinal cord MLT receptor expression in a rat model of sciatic nerve injury and depressive behavior, and administration of MLT receptor agonists was found to reverse stress-induced behavior disorders. The high efficiency and safety of MLT and its basically non-toxic side effects have aroused great interest in clinical practice [6] [11]. In clinical studies, MLT and its analogs have been reported to alleviate patients with cluster headache, irritable bowel syndrome, fibromyalgia, and seasonal depression[7] [12]. At present, there are few reports of MLT on analgesia and antidepression. The author combines domestic and foreign relevant literature to review the role and mechanism of MLT in analgesia and antidepression.

1. Physical and chemical properties of MLT

MLT is considered to be a dark hormone because it secretes most from the pineal gland during the dark period of the night, and it is also known as the "dark chemical code"[7]. MLT biosynthesis begins with the conversion of tryptophan to serotonin, which is then acetylated by arylalkylamine-N-acetyltransferase to form N-acetyl-5-hydroxytryptamine, and then at the 5-hydroxyl Methylation to form N-acetyl-5-methoxytryptamine[13]. After the synthesis is complete, MLT is released into the cerebrospinal fluid and circulation with a half-life of 20-30 minutes, and most of its metabolism occurs in the liver through cytochrome P450-mediated oxygenation[14]. The biosynthesis and secretion of MLT are low during the day and high at night. This mode is regulated by the suprachiasmatic nuclei (SCN) of the hypothalamus[15]. At night, due to the decreased activity of SCN electrical signals, sympathetic nerve fibers release more norepinephrine after SCN. Norepinephrine activates the β-adrenergic receptors present on the pineal gland cells, leading to the activation of the adenylate cyclase-CAMP system and the biosynthesis of MLT. During the day, the increased electrical signal in SCN inhibits the release of norepinephrine from sympathetic nerve fibers after the ganglion, thereby reducing the activation of MLT synthesis and the release of pineal gland cells[16]. The physiological function of MLT is achieved by activating specific receptors present on the surface of the cell membrane and on the nucleus. MLT has at least two receptors on the cell membrane, namely MT1 and MT2 of the G protein receptor family, and MT3 receptor [14]. MLT also activates MLT nuclear receptors belonging to the RZR / ROR orphan receptor type, including three subtypes (α, β, γ) and four splice variants of the subtype MLT receptor [17]. In addition to membrane and nuclear receptors, MLT also interacts with some cytoplasmic proteins and enzymes to exert antioxidant effects [18].

2. Inflammatory factors

The latest research indicates that the inflammatory pathway may interact between pain and depression[8]. Lin et al [6] found tumor necrosis factor-α(TNF-α), interleukin-1β (IL-1β) and monocyte chemoattractant protein-1 (MCP) in astrocytes in a rat pain model -1) and monocyte inflammatory protein-1 (MIP-1 ) mRNA levels were higher than the control group. TNF-α, IL-1β, and MCP-1 can enhance excitatory synaptic transmission and inhibitory transmission in the dorsal horn of the spinal cord, while TNF-αand IL-1βcan further activate spinal cord astrocytes [8][19]. Several clinical studies have found that the concentration of pro-inflammatory factors TNF-a and IL-6 in the peripheral blood of patients with pain and depression is significantly higher than that of non-pain and depression patients [1-2]. Inhibition of inflammatory factors such as TNF-α, IL-1β, MCP-1 or MIP-1 may be an effective target for relieving chronic pain and depression [20].

Studies have confirmed that MLT has anti-inflammatory effects [4][6]. Wang et al.[8] therefore studied the effect of systemic application of MLT on oxaliplatin-induced pain, and found that after intraperitoneal injection of oxaliplatin in rats caused obvious mechanical hyperalgesia and thermal hyperalgesia, however, MLT can Significantly reduces hyperalgesia in rats, and the reduction in nociceptive response lasts for 3 days. The possible mechanism of oxaliplatin-induced pain is known to enhance interleukin-1β, tumor necrosis factor- , and monocyte chemotaxis MRNA expression of Cytokines-1 and other cytokines. The effect of MLT on inflammatory factors is mainly through the following factors: (1) In a dose-related manner, it greatly inhibits the synthesis of inflammatory mediators[8]. (2) The ability to directly remove toxic free radicals such as nitric oxide (NO), singlet oxygen, hydroxyl radicals, peroxide, hydrogen peroxide, and peroxynitrite to protect tissues during inflammation [3]. Nitrate is considered to play a key role in the occurrence and development of neuropathic pain. NO may directly affect the damaged axon or indirectly affect the pain through Waller's degeneration, thereby sending a signal to the dorsal horn of the spinal cord [3][21]. (3) Prevent nuclear transcription factors (nuclear factor-kappa B, NF-κB) from transferring to the nucleus and bind to DNA, thereby reducing the upregulation of proinflammatory cytokines such as IL-1 and TNF-α[9]. (4) Inhibit the activation of NF-κB and inhibit the production of adhesion promoting molecules, which can promote the adhesion of leukocytes to endothelial cells and prevent migration across the endothelial cells[22]. (5) Inhibit the expression of IL-1β and TNF-α[8]. (6) Inhibit the activation of inflammatory cells [23].

3. Regulation of astrocytes

Glial cells, such as microglia and astrocytes, have been shown to play an important role in promoting chronic pain and depression. It is generally believed that glial cells activate and sensitize spinal nociceptive neurons by producing pro-inflammatory and proinflammatory mediators (such as pro-inflammatory cytokines, chemokines, and growth factors), thereby promoting pain and depression [1] [19-20]. Astrocytes mediate TLR4 / NF-κB, ROSTXNIP-NLRP3 and other signaling pathways through pain and depression in their own activation. Studies have found that MLT can alleviate the onset of pain and depression by inhibiting the above pathways.

3.1 Inhibition of astrocyte activation

After spinal cord injury or peripheral nerve injury, the glia of reactive astrocytes change to release specific cytokines, chemokines and growth factors and cause neuropathic pain[20][22], neural circuit dysfunction, abnormal Poor adaptation[8]. Burston et al.[1]found that in OA pain-depression rat histopathology, spinal neurons were overexcited and glial cells were activated. Lin et al [6] found that the activation of astrocytes in the formation of morphine tolerance is also involved, causing the body to produce hyperalgesia.

Inhibiting reactive astrocyte activation may be an effective target for relieving chronic pain and enhancing morphine tolerance [8]. Studies have reported that MLT can reduce the hyperalgesia induced by opioids, oxaliplatin and other drugs and inhibit the activation of astrocytes in the spinal dorsal horn [6] [24] In the OA pain model, Wang et al [8] observed by immunohistochemistry and Western blot analysis that MLT significantly inhibited the activation of astrocytes. However, the mechanism underlying the inhibition of astrocyte activation is still unclear. Hu et al. [23]believed that MLT binds to Toll-like receptors on astrocytes, thereby inhibiting astrocyte activation. Lehnardt et al.[25] believed that MLT inhibited the activation of astrocytes by inhibiting the sensitive ligand lipopolysaccharide of Toll-like receptors. Inflammatory mediators can activate astrocyte activation[20], and MLT inhibits astrocyte activation by inhibiting the production, release, and chemotaxis of inflammatory mediators [8] [22].

3.2 Inhibition of TLR4 / NF-κB signaling pathway in astrocytes

TLR4 (toll-like receptors, TLRs) -mediated NF-κB signaling pathway plays a vital role in the initiation of brain inflammation in central nervous system diseases, such as increasing the permeability of the blood-brain barrier [22-23]. The blood-brain barrier is composed of basement membrane, peripheral cells, and astrocytes. The structural integrity of the blood-brain barrier is essential to ensure normal neuronal function and protect the central nervous system from damage[26]. The destruction of the blood-brain barrier can lead to the occurrence of neurodegenerative diseases such as neurotrauma and related neuropathological diseases such as multiple sclerosis, depression, brain injury, neuropathic pain, ischemia and reperfusion, bleeding and infarction [23][27].

Toll-like receptors are pathogen-related molecular pattern recognition receptors for innate immunity. They play an important role in innate immunity and its secondary acquired immunity. They are mainly expressed in innate immune cells, such as astrocytes [28]. NF-κB is a classic glutamate mediator and is involved in the inflammatory response of the nervous system after activation [19]. After activating NF-κB, TLRs induce an antimicrobial defense system. The combination of NF-κB and deoxyribonucleic acid significantly enhances the production of pro-inflammatory factors and regulates the expression of many important cytokines, adhesion molecules and chemokines. The body's immune response, inflammation and tissue repair play important roles [29]. The role of TLR2, TLR3 and TLR4 in neuropathic pain has been extensively studied [28][30]. Among all TLRs, TLR4 is considered to be a sensitive receptor for endotoxin (LPS) and is involved in tissue damage in infectious and non-infectious central nervous system diseases [31].

Previous studies have found that MLT has pharmacological properties such as antioxidant, anti-inflammatory, and anti-apoptosis. More and more evidence supports that MLT can reduce the bloodbrain barrier permeability of rodents, protect and improve nerve function [7]. Hu et al. [23] found that MLT improves the blood-brain barrier damage caused by astrocyte hyperplasia and inflammatory response after ischemia and hypoxia in animals by inhibiting TPS4-NF-κB signaling pathway induced by LPS Induced hyperalgesia. Fu et al [32] found that MLT pretreatment can also disrupt TLR4 signaling and prevent tetrachloro-p-benzoquinone-induced neuroinflammation and neurological dysfunction. After MLT interacts with TLRs, it can inhibit the activation of NF-κB, and NFκB plays a vital role in the synthesis of pro-inflammatory cytokines [33].

3.3 Regulate ROS-TXNIP-NLRP3 signaling pathway of astrocytes

Oxidative / nitrosative stress in peripheral nerves and dorsal root ganglia may be an important basis for mitochondrial dysfunction, inflammation and apoptosis leading to neurodegeneration and interrelated pathological mechanisms [3][11][34-35]. In the brain, astrocytes are the most numerous and diverse of all types of glial cells. They are responsible for the production of reactive oxygen species (ROS) and inflammatory mediators, for example, IL-1β[20][34][36]. The expression level of IL-1βcontinues to increase in the blood or brain of patients with depression, and is positively correlated with the severity of the disease; exogenous IL-1βdirectly enters the brain and will produce depression-like symptoms, while the IL-1 receptor blocks Break will inhibit the effects of these similar stresses[36-37]. The production of IL-1β is controlled by an inflammatory body, which is an intracellular multi-protein complex composed of nod-like re-ceptor protein (NLRP), adaptor proteins ASC and preaspartic ammonia Acid protease-1 (procaspase-1) composition[38]. The inflammasome can regulate the activation of caspase-1 and then promote the maturation and secretion of pro-IL-1βand pro-IL-18, the proinflammatory cytokine precursors during the immune defense process, and regulate the caspase-1 dependent form of programmed cell pyrolysis , Induces cell death under inflammatory and stressful pathological conditions [39]. In the NLR family, the NLRP3 inflammasome is the most widely studied member [40]. The NLRP3 inflammatory body can be activated by a variety of danger signals, such as pathogen-related molecular patterns and risk-related molecular patterns [39]. It has been shown that the generation of ROS can be used as a common cellular signal upstream of NLRP3 activation[38]. ROS promotes the dissociation of thioredoxin interacting protein (TXNIP) from thioredoxin, and allows TXNIP to bind to NLRP3, and subsequently stimulates NLRP3 activation in mouse beta cells[41]. Activated NLRP3 activates caspase-1, inducing its self-cleavage and activation. Caspase-1 can cleave and promote the maturation of cellular interleukins and other cytokines [40]. It is now well recognized that the NLRP3 inflammatory body is involved in the pathophysiology of many diseases, including depression and osteoarthritis [34].

The main source of ROS is the mitochondria. Among the uncoupling proteins (UCP) in the mitochondrial inner membrane, UCP2 is commonly expressed and plays a key role in controlling the production of ROS by cells [34]. UCP2 is associated with neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease and depression, and its neuroprotective function may be achieved by limiting the production of ROS and inhibiting inflammation and cell death [42]. Du et al. [34] confirmed that UCP2 knockout mice showed severe depression-like behavior in the chronic mild stress-induced depression-deficient model, impaired neurogenesis, and caused the loss of astrocytes, And confirmed that UCP2 knockout significantly enhanced the activation of NLRP3 inflammatory bodies in hippocampus and astrocytes. Since UCP2 plays a crucial role in the development of depression and chronic pain, and is a key protein controlling the production and release of ROS [36], improving UCP2 activity in astrocytes can reduce the production of reactive oxygen species Weakening the reaction of superoxide anion mediated by reactive oxygen species with peroxynitrite produced by NO [34].

Reducing oxidative stress in mitochondria may be one of the targets for relieving pain and depression episodes. MLT has antioxidant properties and has been proven to be very effective in reducing oxidative damage to the central nervous system. The central nervous system has a high utilization rate of oxygen and contains a large amount of fatty acids that are easily oxidized [21]. Because MLT is mainly produced in the pineal gland and released into the cerebrospinal fluid[43], its concentration in human serum and cerebrospinal fluid is sufficient to protect the central nervous system. A recent report by Gley et al.[11]found that MLT can effectively improve mitochondrial dysfunction in vitro and protect paclitaxel-induced neuropathic pain. Areti et al[35]found that MLT treatment significantly reduced oxaliplatin-induced pain behavior and neuropathy defects in rats. The mechanism may be that MLT improves oxaliplatin-mediated nitrooxidative stress, thereby preventing protein The loss of nitrosation and antioxidant enzymes, and by increasing ATP levels, improve the function of the mitochondrial electron transport chain and maintain the bioenergetics of the cell. And in further investigation, it was found that the protective effect of MLT may be to prevent mitochondrial dysfunction and promote neuroprotection by increasing the autophagy pathway of peripheral nerves and dorsal root ganglia. MLT is considered to be an effective antioxidant, and many of its reaction products and metabolites (such as 6-hydroxymelatonin) also have antioxidant activity [7][21]. MLT synthesis is carried out in the mitochondria of eukaryotic cells, so it must have a strong ability to protect organelles from toxic oxygen derivatives [44]. MLT can pass through the cell membrane, concentrate in the mitochondria, and interact with its receptors in the mitochondria to regulate mitochondrial function [11]. The antioxidant effect of MLT is achieved by directly removing free radicals such as NO and peroxynitrite, stimulating antioxidant enzymes, improving the efficiency of mitochondrial oxidative phosphorylation and electron transport chain, and enhancing the efficiency of other antioxidants [3] [35] [44-45].

4. Mediate protein kinase C (PKC) / N-methyl-Daspartate (NMDA) pathway

Activation of protein kinase C (PKC) and N-methyl-D-aspartic acid receptor (NMDA) in the spinal cord plays a key role in pain and depression[5][46]. NMDA receptors participate in many important physiological functions, including synaptic plasticity and neuroendocrine regulation, but also control various pathological states, including neurological disorders and neuroendocrine disorders caused by excitatory neuronal damage[21]. The activation of NMDA receptors leads to the formation of Ca2+influx, Ca2 + -calmodulin (CaM), and the activation of neuronal NOS, which ultimately produces free radical NO, which produces a positive feedback effect. Oxidative damage mediates the occurrence and development of diseases such as depression and pain[47-48].

Patients with severe depression have high levels of glutamate in plasma and the structure of the central nervous system. High concentrations of glutamate in the central nervous system induce receptor hyperactivation, especially ionic NMDA receptors. Intracellular calcium ion increases neuronal excitotoxicity and cell death[46][48]. In addition, glutamate inhibits brain-derived neurotrophic factor (BDNF) signals, inhibits neurogenesis, and leads to depression[49]. Using drugs to activate NMDA receptors in rats can cause hyperalgesia, and blocking NMDA receptors can relieve pain[4].

PKC and other intracellular second messenger systems have been shown to regulate the activation of NMDA receptors and play a key role in the molecular mechanisms of morphine-induced hyperalgesia and morphine tolerance[47]. Studies have shown that the activation of μ-opioid receptors induced by morphine treatment may initiate G protein-mediated PKC translocation and activation, resulting in the clearance of Mg2+from NMDA receptors, thereby allowing increased calcium influx[50]. Intrathecal administration of intracellular PKC translocation inhibitors can effectively attenuate the development of tolerance to morphine analgesia in rats[51]. Similarly, intrathecal administration of NMDA receptor antagonists can also effectively prevent nerve injury or no nerve injury Development of animal morphine tolerance[52]. Song et al.[47] demonstrated in the experiment that the expression of PKCγand NR1 co-localized in the superficial layersⅠand Ⅱof the dorsal horn of the spinal cord was significantly increased in the dorsal horn of morphine exposed rats. Therefore, inhibiting PKC / or NMDA receptor activity in the spinal cord may be effective in relieving hyperalgesia and depression [4-5].

Studies have found that MLT can significantly inhibit NMDAinduced activities in several brain regions, including the striatum[21][45]. Song et al[47]found that MLT can reduce the hyperalgesia and tolerance caused by repeated morphine by inhibiting the activity of PKCγ and NR1 in the spinal cord. Wang et al [4] found in the rat model of pain and depression that the NR1 subunit of the NMDA receptor in the ipsilateral trigeminal nucleus of the experimental group was up-regulated, and intracranial injection of 6-chloromelatonin was found The mechanical hyperalgesia and depressive behavior were alleviated, and the expression of NR1 in Sp5C on the same side was down-regulated. Fan et al [5] found that the possible mechanism by which MLT inhibits morphineinduced hyperalgesia and tolerance is by inhibiting the prolongation of PKCγ activity and the increase of NR1 activity induced byμ opioid receptors, thereby reducing the influx of Ca2+and lowering the level of spinal cord nerves Excitability and activity of glial cells. It has also been found that MLT exerts a neuroprotective effect against NMDA-mediated excitotoxic effects of glutamate, including impaired BDNF signaling and cell death [49].

However, the current research does not clarify how MLT inhibits the PKC / NMDA pathway [49]. Wu et al. [24] believe that MLT reduces intracellular cyclic adenosine phosphate (CAMP) levels by inhibiting the activity of adenylate cyclase. Noseda et al. [53]believed that MLT can interfere with NMDA-mediated glutamatergic components of rat spinal cord pain transmission by acting on MT2 receptors. Escames et al [48] reported that MLT inhibits NMDA by inhibiting neuronal nitric oxide synthase and regulating redox sites, regardless of the known melatonin receptor. To date, little is known about the exact mechanism by which MLT inhibits NMDA and the role of melatonin receptors in this effect.

5. Regulate GABAA receptors in the spinal cord region

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter responsible for overall control and fine-tuning excitatory transmission in the brain. Decreased GABA content and GABAergic activity in the central nervous system can cause anxiety, depression, and insomnia And other mental illnesses[46]. Noronha et al [54]found that the occurrence and development of depression in rats is related to the GABAergic neurotransmission disorder in the dorsal medial nucleus of hypothalamus. It is known that the dorsal medial hypothalamic nucleus participates in physiological functions and behavioral responses, and its neural activity is essential in regulating depression. Microinjection of GABA antagonist directly into the dorsal medial hypothalamic nucleus has anxiety effect on animals tested in elevated plus maze[55].

GABAA receptors are GABA ion channel receptors that mediate the role of GABA in pain and anxiety-related behaviors[45]. The BZ site on the GABAA receptor is the target of benzodiazepine classic anti-anxiety drugs [21]. Golombek et al [56]confirmed in the study that the sedative effect of MLT on mice can be blocked by the benzodiazepine antagonists flumazenil and amphetamine, which suggests that the sedative effect of MLT may be through the regulation of the spinal cord The GABAA receptor. This regulatory effect is specifically manifested in MLT strengthened GABA response [10]. The enhancement of MLT's response to GABA is mediated by increasing the effectiveness of GABA rather than its effectiveness[46]. Papp et al.[55]believe that long-term treatment of MLT can increase the synthesis capacity of GABA. In addition, MLT actively regulates the effect of GABA also contributes to the neuroprotective effect of MLT. However, MLT cannot function through redox regulatory sites on the gamma-aminobutyric acid receptor. In addition to MLT, γ-aminobutyric acid receptors are also actively regulated by benzodiazepines, barbiturates and steroids [3]. Does MLT act through benzodiazepine or barbiturate sites Enhance the response of GABA needs further study [10]. MLT regulates GABAA receptor function on the one hand directly interacts with GABAA receptors, on the other hand it may be achieved by directly interacting with MT2 type receptors[3].

6. Conclusion and outlook

The clinic is challenging to deal with the co-morbid state of pain and depression. In recent years, a large number of studies have confirmed that MLT has analgesic and antidepressant effects. At present, many MLT analogs and agonists are approved for the treatment of sleep and depression. Their activities are similar to those of currently available analgesics and antidepressants, and they have good pharmacological characteristics. However, the physiological mechanism of MLT in analgesia and antidepression is still unclear, and the specific intracellular signal transduction pathway is still unknown. In addition, many molecular factors involved in the regulation of pain-depression and their interactions under physiological and pathological conditions are unclear, which is why the further application of MLT is limited. Future research should focus on not only focusing on the molecular mechanism of MLT exerting analgesia and antidepression, but also continuing to explore the mechanism of the interaction between pain and depression. It is believed that with the deepening of research, the molecular mechanism of MLT analgesia and antidepression will be specifically elaborated to better guide the clinical treatment of patients with pain and depression.