Human Neurons and Pain

Sensory neurons of the dorsal root ganglia (DRG) are essential on the mechanism of pain. It detects and deliver an impulse to regions of the CNS (the central nervous system). Nerve injury and inflammation decrease threshold of pain, so pain take place for a patient. Pain, an increasing clinical problem, is a response against any problems to guard cells and tissues, and pain killers are a classification of powerful drugs to decrease or stop pain by affecting signals between neurons. Chronic inflammatory and neuropathic pains are quite critical for society. Therefore, mechanistic understanding for pain is extremely important to treat it with the help of DRG. DRG having heterogenous population of neurons studies can be highlight novel drug targets of pain. Therefore, drug screening is extremely significant to evaluate drugs and comprehend the mechanistic insight on pain.

Humankind has been suffering from several diseases for a long time. In the 1900s, especially pneumonia, influenza and tuberculosis were the most common problems all over the world. A century later, heart disease and cancer have become the most severe diseases. Even though some treatments exist to save people from terrifying disease, we have not stopped dying from them. In order to treat these diseases, the mechanism of them has to be clarified and understood with the help of several approaches. Although existing other diseases, including pain, cannot be vital like them, it is important to improve the life quality. Moreover, painkillers are a kind of supplementary drugs, which needs taking on the other treatments, including from anti-cancer to bacterial inflammatory infections. It is respectable figure that the proportion of patient having chronic pain is almost 15%. Therefore, painkillers may be the most used drugs among all other drugs, since pain affect more than 1.5 billion people worldwide.

Activation of sensory neurons by damage or disease brings about pain, an indicator to detect and protect tissue or body, and the nervous in the dorsal root ganglion (DRG) operation of encoding noxious stimuli is called as nociception. Nociceptive neurons can be used as specific markers because of their tiny or medium in diameter. There are several different signaling pathways related to pain, including the ATP-gated (P2RX) channels and the metabotropic G-protein coupled P2Y receptors. The mechanism of nociception has been understood for from several organisms to humankind; however, as for the process of pain, it becomes lesser clear. Therefore, there are a plenty of research about pain using the molecular techniques, genetic techniques, using medicinal techniques to treat pain. The continuous pain over the time, such as months, is called as chronic pain, and unfortunately about 15 % of society has been suffering of chronic pain. It can be divided into two groups: inflammatory pain and neuropathic pain. A Lesion or injury on the somatosensory nervous system results in neuropathic pain. Any tissue damage and inflammatory disease causes inflammatory nociceptive pain.

Most painkillers create an impulse on the part of brain related to pleasure. Opioids or opium-like compounds are a group of the most powerful painkillers. They are working on the nervous system, which is like a mechanism of the opium poppy, such as heroin.

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To design novel drug targets and treatment system, it is extremely critical to comprehend the mechanism of pain, including the circuitry of pain; for example, what triggers pain, how is it affecting nervous system and different kind of neurons, how nociceptors works and so on.

There are several sorts of nociceptors and sensory neurons on body related to the mechanism of pain. Once a destructive stimulus makes an ion channel on a nociceptor activated, the nociceptor producing a receptor potential is depolarized by cations. If an impulse is higher than action threshold for voltage-gated Na+ channels (NaV), it forms a pain signal to the spinal cord. In recently years, this mechanism is extremely critical to understand how nociceptor works and identify the candidate painkillers. Moreover, recently studies demonstrates that some nociceptors can be divided into myelinated Aδ-fibers and unmyelinated C-fibers. The genetically encoded Ca2+-indicator GCaMP methods provide irreplaceable technique to image the performance of painkillers. From the other studies, in vivo GCaMP studies have proved that inflammation and injury form boosted neuronal responsiveness.

The other studies with the help of single-cell RNA-sequencing of sensory neurons is indicated that their transcriptome can be essential to dive into groups. All DRG RNA-sequencing works provides knowledge about a neuronal expression picture for neuropathic pain. For example, NaV1.7 is expressed in NaV1.8-positive colonic neurons. It is obvious that the studies will play crucial role on the treatment of pain. In addition, there are seven P2RX subunit genes (P2RX1-7) expressed in DRG neurons. Also, other studies indicated that P2RX3 is key in chronic pathological pain, and selective P2RX3 drugs decrease neuropathic and inflammatory pain. The final example studies to understand the working of disease is the Nav1.7 subtype of voltage-gated sodium channels.

There are two further techniques, optogenetics and chemogenetics, to further investigate the mechanism of nociceptor. Optogenetics focus on light-activated membrane proteins, including hyperpolarization, depolarization and G protein-coupled receptor (GPCR). Designer receptors exclusively activated by designer drugs (DREADDs) is covered by chemogenetics. With the help of two approaches and tissue-specific promoters, it is possible to investigate on distinct neuronal subsets. Moreover, these are vital to control neuronal function. The other similar technique to understand mechanism of pain is an engineered chloride-channel sensitive to ivermectin (GluCl v2.0) for long-term repeatable suppression.

In conclusion, the very little current studies research demonstrates the fact that pain is currently trending topic for researches, since there are a plenty of patient needs to take safe and efficient painkiller under several conditions, including the treatment of chronic pain, cancer, diabetes, and bacterial infections.