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Research progress on the mechanism of Sigma‑1 receptors in pain
Research progress on the mechanism of Sigma‑1 receptors in pain. Sigma receptor is a type of receptor protein with chaperonin activity and has no homology with other mammalian proteins.
Pain is an unpleasant feeling and emotional experience related to actual or potential tissue damage, or an experience similar to it. Pain, as the fifth vital sign, affects 30% to 50% of the world’s population. According to the pathophysiology of pain, it can be divided into inflammatory pain, neuropathic pain, cancer pain, spastic pain, mental (psychological) pain and other pain.
The basis for solving pain is to clarify the pathogenesis of pain, but the study of its mechanism is still a challenge. Therefore, it is necessary to develop highly specific drugs to improve the efficacy of existing therapies and/or reduce their adverse reactions. Studies have found that Sigma‑1 receptors play a key role in multiple links in the process of nerve (pain) signal transduction and participate in the regulation of inflammatory pain, cancer pain, and neuropathic pain, which are more common in clinical pain.
Sigma-1 receptor functions as a chaperone protein and participates in the regulation of many other molecular targets, including receptors, enzymes, and ion channels involved in pain perception and transmission. However, its specific role in pain has not been fully elucidated. This article reviews the physiological characteristics of the Sigma-1 receptor, its role in different types of pain, and its relationship with ion channels (voltage-dependent ion channels such as calcium, sodium, potassium channels and NMDA receptors).
1 Introduction to Sigma‑1 Receptor
Sigma receptor is a type of receptor protein with chaperonin activity and has no homology with other mammalian proteins. Currently, the Sigma family is divided into two subtypes, Sigma-1 and Sigma-2. The Sigma-2 receptor was recently discovered to be an intact transmembrane protein 97 (TMEM97) involved in cholesterol homeostasis in cells.
Sigma‑1 receptor is a receptor protein with molecular chaperone activity. It exists in the form of a trimer and has a single transmembrane topology. It contains 223 amino acids and has a relative molecular mass of 26×103. It is mainly located in the endoplasmic reticulum. Among them, the mitochondrion-associated endoplasmic reticulum membrane (mitochondrion-associated endoplasmic reticulum membrane, MAM) exhibits an aggregated distribution, and it also dissociates to the cell membrane when activated, and also distributes on the nuclear membrane and mitochondrial membrane.
From a functional point of view, the Sigma-1 receptor can be used as a regulatory factor to regulate the intracellular signal transduction and activity of its related proteins in an allosteric manner, so it is generally considered as a regulator of other signal pathways.
In the endoplasmic reticulum, the Sigma‑1 receptor acts as a molecular chaperone for ligand operation, and regulates Ca2+ flow through the inositol 1, 4, 5‑triphosphate (IP3) receptor. On the plasma membrane, Sigma‑1 receptors interact with the signal transduction components bound to the plasma membrane to regulate the activity of ion channels and neurotransmitter receptors, including K+ channels, Ca2+ channels, NMDA receptors and opioid receptors.
In MAM, the Sigma-1 receptor forms a complex with a partner called immunoglobulin heavy chain binding protein (BIP), which controls the stability and function of specific signaling molecules in the endoplasmic reticulum. The complex is in a resting state under normal physiological conditions. When the concentration of Ca2+ in the endoplasmic reticulum membrane decreases or a specific agonist acts on the Sigma‑1 receptor, the Sigma‑1 receptor separates from BIP and activates, and acts as a signal regulator between organelles, binding conformationally unstable proteins To enhance intracellular calcium signal and increase intracellular ATP production.
If stimulated by a high concentration of agonist or the endoplasmic reticulum is affected by stress, Sigma‑1 receptors can translocate from the membrane to the plasma membrane, directly or indirectly regulating various ion channels, protein kinases and G protein coupling Receptor (G protein-coupled receptor, GPCR), etc.
Sigma‑1 receptors are widely expressed in neurons and glial cells of the central and peripheral nervous system, and regulate a variety of cellular functions, including regulating the expression and activity of various receptors and ion channels. Cell homeostasis, synapse occurrence, neuronal plasticity and nociceptivity are of great significance.
And it is highly expressed in several key pain control areas in the peripheral nervous system and central nervous system, and is highly expressed in primary sensory neurons, which are the key parts of pain initiation and maintenance after peripheral nerve injury. Studies have shown that Sigma‑1 receptors play an important role in regulating nociception, but if there is no painful stimulation, the normal sensory threshold will not be affected by Sigma‑1 receptor antagonists. Therefore, the Sigma-1 receptor can be used as one of the newest and promising pharmacological targets in the treatment of pain.
2 Sigma‑1 receptors are involved in the regulation of pain
2.1 The role of Sigma‑1 receptors in inflammatory pain
Inflammatory pain refers to the pain that occurs when inflammation is caused by trauma, bacterial or viral infection, and peripheral tissue damage caused by surgery.
Studies have shown that Sigma‑1 receptor antagonists can reduce inflammatory pain by regulating the endogenous opioid system. Castany et al. observed that in the rat chest contusion model, repeated application of MR309 can reduce the inflammatory cytokines (such as TNF‑α, IL‑1β and IL‑6) by reducing the phosphorylation of extracellular signal-regulated kinase 1/2 at the injury site. ), but it cannot be ruled out that this treatment will also reduce the reactivity of microglia at the distal waist and the subsequent release of inflammatory cytokines.
In the carrageenan-induced inflammation model, the expression of Sigma-1 receptors in dorsal root ganglion neurons increases, which may be one of the mechanisms of peripheral sensitization. Moreover, the administration of selective Sigma-1 receptor antagonist BD-1063 can reverse the mechanical and thermal hyperalgesia in mice with acute inflammation (3 h) induced by carrageenan. It shows that the reversal of inflammatory pain depends on the blockade of Sigma‑1 receptors at the inflammation site, and the Sigma‑1 receptor agonist Pre‑084 blocks the anti-injury effect induced by selective Sigma‑1 receptor antagonists.
Carcolé et al. reported that blocking the Sigma-1 receptor can alleviate the cognitive and emotional changes associated with chronic osteoarthritis pain. Therefore, early blocking of Sigma-1 receptor may effectively prevent the occurrence and development of neuropathic pain, but the specific regulation mechanism still needs further study. At the same time, the Sigma-1 receptor is pleiotropic. When activated, it can act on the downstream of different receptors and channels to regulate the intracellular signals of various pain-causing mediators released from inflammation sites.
Therefore, these studies require us to further explore the role of Sigma-1 receptor in inflammatory pain.
2.2 The role of Sigma‑1 receptors in neuropathic pain
The International Society for Pain Research redefines neuropathic pain as pain caused by damage to the somatosensory system or disease. About 7% to 10% of the world’s population suffers from neuropathic pain, which has a negative impact on the patient’s physical and mental health and quality of life, such as mood, sleep and cognition.
Studies have confirmed that the Sigma‑1 receptor has a regulatory role in neuropathic pain. Son and Kwon found that Sigma‑1 receptors were up-regulated in the spinal cord in a rat model of chronic constrictive injury. Studies have shown that the administration of Sigma‑1 receptor agonists (Pre‑084) can promote mechanical hypersensitivity after the injection of capsaicin on the sole of the foot to induce nociceptive sensations, but hypersensitivity only occurs after the nociceptive system is activated reaction.
On the contrary, the use of Sigma-1 receptor antagonist MR309 (also reported as E-52862) can effectively reduce postoperative mechanical allodynia and thermal hyperalgesia in rats. Recently, it has been reported that after repeated MR309 treatment in patients with peripheral neuropathy caused by oxaliplatin chemotherapy, the pain intensity induced by cold pain threshold temperature and suprathreshold cold stimulation was significantly reduced. Therefore, Sigma-1 receptor can be an effective target for the treatment of neuropathic pain, and its antagonist MR309 is expected to be a suitable treatment option for the treatment and prevention of peripheral and central neuropathic pain.
Diabetic neuropathy is one of the most common complications of diabetes and a common cause of peripheral neuropathy, which has a certain impact on the quality of life of diabetic patients. Wang et al. believe that Sigma‑1 receptor may participate in streptozotocin-induced diabetic neuralgia by regulating spinal cord high mobility group protein B1, and repeated administration of E‑52862 can significantly reduce thermal hyperalgesia and mechanical pain in diabetic rats Allergy, restore the initial threshold. The above studies have shown that the activation of Sigma‑1 receptors may be an important driving factor for neuropathic pain.
2.3 The role of Sigma‑1 receptors in cancer pain
Cancer pain generally refers to the pain directly caused by the tumor, which is caused by the compression of organs and nerves. There are three main causes of cancer pain. The first is the pain directly caused by the tumor, accounting for about 88%; the second is the pain caused by cancer treatment, which accounts for 11%; the remaining 1% of the pain is not related to cancer.
The expression level of Sigma-1 receptor in lung cancer, breast cancer, prostate cancer and glioma cancer cell lines was significantly higher than that of normal control cells. Studies based on different tumor cell lines have shown that Sigma‑1 receptor antagonists reduce cellular protein synthesis in a dose- and time-dependent manner, induce endoplasmic reticulum stress, and activate unfolded protein responses.
Studies have shown that compounds with affinity for the Sigma-1 receptor can inhibit the proliferation and survival of cancer cells, tumor growth, cell adhesion and migration, reduce cancer-related pain, and have immunomodulatory properties. In the rat model of bone cancer pain, the expression of Sigma‑1 receptor and phosphorylated extracellular signal-regulated kinase protein in the spinal cord was significantly increased.
After intrathecal injection of the Sigma‑1 receptor antagonist BD‑1047, the rat bone cancer pain symptoms At the same time, it reduces and inhibits the phosphorylation of extracellular signal-regulated kinase in the spinal cord, suggesting that the spinal cord Sigma-1 receptor may be involved in the maintenance of bone cancer pain in rats by promoting the phosphorylation of extracellular signal-regulated kinase. The occurrence of cancer pain.
3 Sigma‑1 receptors and pain-related ion channels
3.1 Sigma-1 receptor and voltage-gated calcium channel (VGCC)
VGCC Cav3.1~3.3 constitute the T subfamily, and its dysfunction is related to epilepsy, mental disorders and chronic pain. VGCC controls neuronal functions, including development, excitability, and synaptic transmission. When activated, Ca2+ flows into the cell and acts as a second messenger to activate different cell signaling pathways, leading to different physiological responses. In the dorsal horn of the spinal cord, calcium channel activity controls the release of neurotransmitters.
Blocking calcium channels can reduce neurotransmission and relieve pain. Peripheral neuralgia can reduce Ca2+ current (ICa) through VGCC in sensory neurons and increase neuronal excitability. Studies have shown that Sigma-1 receptor can directly interact with L-type VGCC to inhibit ICa. Pan et al. found that in the rat model of spinal nerve ligation injury, the Sigma-1 receptor antagonist BD1047 can prevent the decrease in voltage-gated calcium current of rat dorsal root ganglion neurons, but the dorsal root ganglion in the control group was not damaged.
Therefore, there is no change in ICa, which is considered to be an anti-injury mechanism, indicating that Sigma‑1 receptors regulate Ca2+ influx and participate in neuropathic pain during sensory neuron activity. In contrast, pregnenolone sulfate activates the Sigma-1 receptor and increases the L-type calcium current in the hippocampal CA1 area. These findings indicate that the role of Sigma‑1 receptor ligands varies from region to region of the nervous system.
In addition to VGCC, Sigma-1 receptors also regulate non-VGCC through protein-protein interactions, such as the IP3 receptor at the endoplasmic reticulum level that regulates calcium signals. Sigma-1 aggregates in MAM. The physical membrane contact between the endoplasmic reticulum and mitochondria enables the endoplasmic reticulum to directly provide Ca2+ to the mitochondria through the IP3 receptor at the MAM, thereby regulating bioenergetics and the formation of free radicals in the mitochondria.
This Ca2+ provided by MAM can activate the enzymes involved in the tricarboxylic acid cycle (TCA), thereby enhancing the production of ATP. The MAM where the Sigma-1 receptor is located can ensure the proper flow of Ca2+ from the endoplasmic reticulum into the mitochondria through the IP3 receptor or the transport of phospholipids. Other studies have shown that the Sigma-1 receptor is indirectly coupled with the GPCR of the phospholipase C (phospholipase C, PLC)-inositol triphosphate-calcium signaling cascade. The activation of the Sigma-1 receptor can stimulate the PLC to produce diacyl Glycerin and IP3.
Its downstream channel represents another link in pain modulation-protein kinase C (PKC). PKC and its phosphorylated form have been shown to be involved in the regulation of neuropathic pain. Diacylglycerol and IP3 are the two main secondary messengers required to stimulate PKC. The latest research shows that the administration of Sigma‑1 receptor agonist (PRE084) can mediate susceptibility, and the effect mediated by PRE084 is related to the increase of intracellular Ca2+ concentration through the PLC‑IP3‑PKC signaling pathway.
The above findings indicate that Sigma-1 receptor can directly or indirectly bind to calcium channels to mediate pain, but its mechanisms are complex and diverse, providing more ideas for exploring the mechanism of pain mediated by calcium channels.
3.2 “Sigma‑1 receptors and voltage-gated sodium channels
Voltage-gated sodium channels initiate and propagate action potentials in excitable cells. Nociceptors detect nociceptive stimuli and transmit this sensation to the central nervous system through action potentials. The generation of action potentials involves rapid inward sodium currents. The voltage-gated sodium channel is composed of α subunit and β subunit, and is divided into 9 different channels (Nav1.1~1.9). Nav1.8 is a voltage-gated sodium channel resistant to tetrodotoxin, specifically expressed in the dorsal root ganglia of small-diameter unmyelinated sensory neurons, and is involved in nociceptive perception.
According to reports, the interaction between Sigma-1 receptor and Nav1.8 can regulate the continuous sodium current in the neuron region, which plays a part in nociceptive perception. Sigma-1 receptor and Nav1.5 channel can also interact. Aydar et al. found that Sigma-1 receptor and Nav1.5 are structurally expressed in some breast cancer cell lines (such as MDA-MB-231), and protein complexes are formed. Down-regulation of Sigma-1 receptor expression reduces the surface level of Nav1.5 channels in this cancer breast cell line. The physiological result is reduced cell adhesion, which indicates that the Sigma-1 receptor/Nav1.5 protein complex is regulating these cancers. It plays an important role in cell transfer behavior.
3.3 Sigma‑1 receptor and voltage-gated potassium channel
Potassium channels play a role in nociceptive pain. In central nervous system neurons, Kv1.2 channels are mainly distributed in the initial segment of axons. Action potential thresholds, firing frequency, and nerve endings that control the release of neurotransmitters play an important role in pain. In the peripheral nervous system, Kv1.2 exists in the large dorsal root ganglia. The decrease in Kv1.2 activity leads to mechanical and cold neuropathic pain by depolarizing the resting membrane potential, lowering the threshold current, and increasing the firing rate of myelinated neurons.
The immunoprecipitated cell lysate of the medial accumbens nuclear tissue showed that Kv1.2 co-precipitated with the Sigma‑1 receptor. This interaction was further confirmed in double-transfected NG108-15 cells. Studies have found that the Kv1.4 channel is the only Kv1α subtype expressed in the small-diameter dorsal root ganglion nerve, which means that this channel subtype is responsible for the potassium conductance of the Aδ and C nociceptor fibers. In this particular type of nociceptor In Sigma-1, the regulation of this subtype of potassium channel is consistent with its role in pain regulation.
3.4 “Sigma-1 receptor and other ion channels
Transient receptor potential vanilloid type-1 (TRPV1) ion channel is a non-selective cation channel, expressed in nociceptors (Aδ and C fibers), when activated by chemical or thermal stimulation , Plays an important role in nociceptive signal transduction. Studies have shown that TRPV1 and Sigma‑1 receptors have a direct interaction in pain. Injection of Sigma‑1 receptor antagonists BD‑1063 or P4 can down-regulate the TRPV1 protein level in the plasma membrane of sensory neurons, thereby reducing pepper Nociceptive response induced by venom.
Acid-sensing ion channels (ASICs) are cation channels activated by extracellular protons. They are not only involved in nociception, but also in pathological conditions such as learning, memory and ischemic stroke. Kwon et al. reported that peripheral Sigma‑1 receptors promote ASICs and purinergic P2X receptors. In the thrombus-induced ischemic pain model, the expression of Sigma‑1 receptors in the skin, sciatic nerve and dorsal root ganglion was significantly increased. Plantar injection of the Sigma‑1 receptor antagonist BD‑1047 can significantly enhance ASICs blockers The analgesic effect of amiloride or P2X receptor antagonist TNP‑ATP reduces mechanical hypersensitivity.
NMDA receptor is a subtype of ionotropic glutamate receptor, which can be divided into NR1, NR2 and NR3. The NR1 subunit is located in the posterior horn of the spinal cord and plays an important role in pain transmission. Studies have shown that Sigma‑1 receptors can play a role in central sensitization by activating NMDA receptors. In addition, intrathecal injection of Sigma-1 receptor agonists significantly increased the NR1 expression of spinal cord phosphorylation induced by NMDA receptors and the nociceptive behaviors induced by NMDA receptors. This suggests that the spinal cord Sigma-1 receptor plays a crucial role in the regulation of NMDA-induced pain.
In summary, the Sigma-1 receptor regulates peripheral and central sensitization by interacting with different molecular targets (such as various pain-related ion channels, receptors, etc.).
Pain is a ubiquitous problem, which has adverse effects on physical function, social function and mental health. Therefore, new drugs are urgently needed to improve pain. As a chaperone protein, the Sigma-1 receptor regulates a variety of ion channels related to nociceptivity and participates in the occurrence and development of pain. However, the specific regulation mechanism has not yet been elucidated and we need to further study. At present, the Sigma-1 receptor antagonist E-52862 developed by Esteve of Spain has been proven effective for different types of pain in the preclinical phase and the second phase of clinical trials. Obviously, the results of these clinical trials have great significance in the field of pain. The Sigma‑1 receptor is expected to become a new target for pain treatment, improving the insufficiency of existing pain treatments and reducing drug-related side effects, bringing new hope to patients.
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