Figure 1: Key ion channels involved in spontaneous pain. Pharmacological experiments revealed that VGSCs play an important role in spontaneous electrogenesis in neurons . The accumulation of VGSCs at sites of ectopic nerve impulse generation could be associated with the lowing of the threshold for action potential and the subsequent hyperactivity .
Several clinical genetic researches have demonstrated that deficiency of function of Nav1.
In addition, a gain-of-function Nav1. Several lines of evidence have supported that Nav1. It has also been reported that sensory neurons expressing Nav1. Furthermore, Nav1. Therefore, Nav1. A direct role of Nav1.
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It has also been demonstrated that using Nav1. In comparison with the functional roles of Nav1. However, it has been shown that an injection of a Nav1. These findings suggest a critical role of Nav1. Taken together, it is strongly suggested that Nav channels are key players in the establishment of spontaneous pain. The Kv channels subserve important roles in setting the resting membrane potentials, mediating the repolarization of action potential and controlling the subthreshold membrane potential oscillations . The Kv superfamily is known to be composed of 40 human genes .
To date, many Kv channels are known to be responsible for the inflammatory and neuropathic pain . Several Kv channels are reported to be involved in the spontaneous pain . The downregulation of Kv9. Thus, the downregulation of the Kv channel exerts an important role in spontaneous pain. To date, seven subfamilies have been identified in mammalian cells, and they are divided into four functional groups . Similar to the Kv channels, accumulating evidence suggests that Kir are responsible for neuropathic and inflammatory pain .
It is well established that the Kir channels are expressed in supporting cells such as glia. Among several Kir channels, Kir4. For example, knockdown of Kir4. In Kir4. Furthermore, it has been shown that Kir4.
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In addition, following chronic constriction injury of the infraorbital nerve, the expression level of Kir channels was decreased in the trigeminal ganglion . These observations suggest that spontaneous pain is brought about by the decreased expression of Kir4.
Thus, targeting Kir4. Among these channels, it has been reported that TREK2 channels are involved in spontaneous pain. It has also been demonstrated that TREK2 channels were selectively expressed in C-fiber nociceptors and inhibit spontaneous pain . These observations suggest that TREK2 channels hyperpolarize C-fiber nociceptive neurons and inhibits spontaneous pain. VGCCs play critical roles in diverse physiological functions.
The family of Cav1 channels is associated with synaptic transmission and integration of synaptic inputs in neurons. The family of Cav2 channels is involved in initiation of synaptic transmission. The family of Cav3 channels is involved in repetitive action potential firings in thalamic neurons . Blockade of N-type VGCCs has been shown to reduce secondary heat hyperalgesia and spontaneous pain-related behaviors associated with acute joint inflammation . Also, it has been shown that blockade of N-type VGCCs was effective on nociceptive responses in spinal dorsal horn neurons following nerve injury .
Transient receptor potential vanilloid 1 TRPV1 , known as the capsaicin receptor, is a ligand-gated ion channel.
TRPV1 channels are activated by multiple pain stimuli such as acid, heat, capsaicin, protons, lipids and spider toxins. Furthermore, the activity of TRPV1 channels is enhanced by a number of inflammatory mediators including bradykinin, prostaglandins, nerve growth factor and ATP .
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TRPV1 channels are predominately localized in small C-type fibers which mediate pain, and also present in lamina I and II of the spinal dorsal horn [46, 47]. Furthermore, TRPV1 channels are localized at the supraspinal level and contribute to descending modulation of nociceptive transmission . Both the gene deletion and pharmacological studies have shown that TRPV1 channels have central roles in inflammatory and neuropathic pain . A previous study demonstrated that a potent and selective TRPV1 antagonist, ABT, was effective in suppression of nociceptive pain in rodent various pain models: ABT depressed spontaneous pain behaviors .
Therefore, antagonist for TRPV1 channels could be effective for treatment of spontaneous pain. Transient receptor potential ankyrin 1 TRPA1 , known as a noxious cold-activated ion channel, is nonselective cation channels that are mainly expressed on nociceptive primary afferent sensory neurons . At peripheral terminals of nociceptive sensory neurons, TRPA1 channels contribute to transmitting harmful stimuli, whereas at central terminals in the spinal dorsal horn, these channels regulate excitatory synaptic transmission to interneurons in the spinal cord.
Previous findings suggested the involvement of TRPA1 in chronic and acute nociceptive processes to cold stimuli . It was reported that TRPA1 contributed to spontaneous pain-like behaviors caused by endothelin-1 in mice . It has also been demonstrated that TRPA1 was involved in postoperative pain in the rat . In their study, intrathecal treatment of a TRPA1 antagonist attenuated hypersensitivity but not spontaneous pain-like behavior, suggesting that TRPA1 channels located in the skin are involved in postoperative pain evoked by noxious mechanical stimulus while TRPA1 channels in the spinal cord contribute mainly to postoperative pain caused by innocuous mechanical stimulus.
Thus, it is likely that peripheral TRPA1 channels play essential roles in spontaneous pain-like behaviors. The ASIC subunits can form functional homomultimers as well as heteromultimers. Although the exact subunit combinations of functional native ASICs have not been identified, the composition of ASIC subunits determines the pH-sensitivity, ionic selectivity and kinetics of activation and desensitization.
Thus, the extracellular acidification activates ASICs under the physiological and pathophysiological states. Several studies demonstrated that inflammation and nerve injury induce acidosis, and acidic low pH can cause pain [58, 59]. This suggests that ASICs have a critical role in nociception. A previous study demonstrated that ASIC3 display a biphasic current in response to acidosis in extracellular pH when these channels were expressed in heterologous cells . In addition to a transient inward current that was rapidly inactivated, ASIC3 showed a non-desensitizing sustained current that lasts as long as the acidic extracellular pH is maintained .
Therefore, it is conceivable that ASIC3 exert a critical role in nociception by acting as an indicator of tissue acidosis. It has previously been reported that after injection of acetic acid, spontaneous pain behaviors were significantly increased in neuropathic rats induced by the spinal nerve ligation SNL of the L5 spinal nerves, compared to the sham-treated group . Although it is thought that ASIC3 are involved in acute pain states, it also contributes to spontaneous pain.
The antagonists for ASICs may provide a new option for suppressing spontaneous pain. Among four HCN isoforms, HCN1, 2 and 4 channels are responsible for the generation of neuronal activity, whereas the functional role of HCN3 channels remains largely unclear. Several studies have showed that the hyperpolarization-activated currents regulate the neuronal membrane excitability by regulating basic membrane properties in both the physiological and pathological states .
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HCN channels are known as the pacemaker channels since they help to generate rhythmic activities of cells both in the brain and heart . Furthermore, it has been reported that HCN channels contribute to generation of neuropathic pain, and thus, these channels are pharmacological targets to treat neuropathic pain . It has been proposed that ectopic discharges are associated with the development of spontaneous pain and mechanical allodynia .
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Such spontaneous activities were generated in axons and soma of injured DRG neurons. There is evidence supporting the role of the hyperpolarization-activated current in ectopic discharges. The ectopic discharges are primarily generated from large- and medium-diameter DRG neurons in chronic neuropathic pain rats of the SNL, the chronic constriction injury for the sciatic nerve and the chronic compression for the DRG .
These findings strongly suggest that the hyperpolarization-activated currents are produced predominantly in these large-diameter and medium-diameter cells. It is generally known that activation time constants for HCN channels ten to hundreds of milliseconds near the resting potential are slower compared with the rapid activation rate for ectopic discharges about Hz . Thus, it is unlikely that the hyperpolarization-activated current participates in generation of ectopic discharges.
However, in the dissociated DRG cells from rats subjected to chronic compression of the DRG, the time constant of fast activation of the hyperpolarization-activated current was significantly upregulated . Therefore, it is conceivable that the hyperpolarization-activated currents are associated with the rapid ectopic discharges. It has been evident that many ion channels contribute to generation of spontaneous pain.
In addition, treatments for spontaneous pain targeting ion channels have grown rapidly. However, the molecular mechanisms by which drugs targeting ion channels relieve spontaneous pain remain largely unknown. Understanding these mechanisms will help to develop new therapeutic strategies for spontaneous pain. The author declares that he has no competing interests.
Optobow method makes functional connections between individual neurons visible. Using light alone, scientists from the Max Planck Institute of Neurobiology in Martinsried are now able to reveal pairs or chains of functionally connected neurons under the microscope. The new optogenetic method, named Optobow, allows probing the pathways along which information flows by targeted activation of individual neurons and monitoring the responses of neighboring cells.
The shape of the cells and their contact points are also revealed — even in dense tissue in which the thin fibers of thousands of cells are interwoven. With Optobow, it is thus possible to discover individual components of functional circuits in the living brain. Researchers can activate individual neurons in the zebrafish brain with light magenta and observe which neighboring cells are connected to the neuron in the same circuit yellow. Modern methods provide increasingly detailed insights into the structure and functions of the brain. It is now possible to observe under the microscope when and where neurons are active during a particular task, such as sensory perception or behavior.
However, it is still largely impossible to establish whether the active cells are connected to each other and to identify the sequence in which they exchange information. To date, such information could only be obtained, in part and with considerable effort, using electrophysiology and electron microscopy methods.
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With electrophysiology, the activity of neighboring cells is measured using very thin, hollow needles, which serve as electrodes. These are inserted into the brain through holes in the skin and the skull of the animal. However, it is almost impossible to record activity from very small, densely clustered or deep-lying neurons, and it is also difficult to trace long connection pathways between neurons. Moreover, impulses from only one, or few cells, can be recorded at a time. With modern electron microscopy processes connectomics , all neurons and their connections in a fixed brain are recorded, layer by layer, by a scanning electron microscope and then reconstructed on a computer.