Correspondence Address:
Dr. Pallavi Ahluwalia
Department of Anaesthesia, Rohilkhand Medical College and Hospital, Bareilly, Uttar Pradesh
India

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The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with real or potential tissue damage.”[1] Chronic pain is a common, complicated, and distressing disorder that has a significant impact on both individuals and society. It is more than just a troubling symptom; it is a separate clinical illness with its own medical diagnosis and taxonomic classification. Chronic pain is terrible and impacts every aspect of a patient's life. Approximately 30% of the world population suffers from pain. One global chronic pain prevalence survey found that 19.3% of the Indian adult population suffers from chronic pain.[2]

Lower employment, higher sick leave, disability retirement, lower household income, poor global recovery after surgery, deteriorated mental health, increased use of health-care resources, and increased mortality, are attributed to pain and has also been linked to an increase in suicide ideation, planning, and attempts in patients suffering from chronic pain.[3]

Because of the big breakthrough, i.e., finding of novel receptors, recent Nobel Prize winners this year, 2021, were David Julius and Ardem Patapoutian (for their discoveries of temperature and touch receptors).[3] To study how heat and pain signals can be transmitted to the brain, Julius in the University of California, San Francisco laboratory used a variety of noxious substances from animals and plants, including toxicants from tarantulas and coral snakes; capsaicin, the chemical compound that creates the “heat” in chili peppers; and the chemical products underlying the characteristic odor of horseradish and wasabi.[4] In mammals, up to 28 (transient receptor potential channel [TRP channel]) superfamily isoforms are involved in a wide range of physiological and pathological processes, including pain. These proteins are required for touch sensation and the ability to sense pain. The TRP superfamily has up to 28 isoforms in mammals. They mediate a myriad of physiological and pathophysiological processes, including pain. TRP channel activation, such as TRP1 and (transient receptor potential cation channel, subfamily A, member 1 [TRPA1]), has been shown to activate the trigeminal calcitonin gene-related peptide pathway, which mediates neurogenic inflammation and consequently causes migraine attacks. (transient receptor potential vanilloid 1 [TRPV1]) is the most important TRP channel found so far in terms of inflammatory pain. TRPV1 antagonists have been found in TRPV1-deficient animal models to be efficient at reducing thermal hyperalgesia and increasing the unpleasant heat threshold in inflammatory conditions. According to research, electroacupuncture (stimulates TRPV1) can provide analgesia in a small diameter mouse model of inflammation.[5] Mechanical forces can evoke many different types of sensation initiating in the peripheral nervous system and includes discriminative touch, proprioception, and mechanonociception. Recent studies have suggested strong evidence that PIEZO2 are mechanically gated channel. They mediate discriminative touch and proprioception, but not mechanonociception.[6],[7] TRPA1 is linked to cutaneous edema, leukocyte infiltration at the location, and antihistamine-resistant scratching in mice treated with oxazolone. Chronic pain is a multifaceted complication in patients with cancer or those undergoing therapy for it. Extensive research has been conducted to determine the role of TRPV1 in the pain of bone cancer. TRPV1 has been associated with bone cancer pain, as indicated by experimental/pharmacological inactivation of TRPV1 and gene disruption. SB366791, a TRPV1 antagonist, has also been found to improve the analgesic effect of intraperitoneal morphine administration in a mouse model of bone cancer pain.[8] TRP1 has been shown to play a function in neuropathic pain caused by diabetes or the use of chemotherapeutics such as oxaliplatin and 5-fluorouracil.

Patapoutian also identified PIEZO1 and PIEZO2[6] receptor proteins that function as mechanoreceptors and Merkel cells, respectively, and are open to mechanical pressure and touch. Touch and temperature senses may play a role in pain perception. PIEZO1 is a mechanosensitive ion channel protein that in humans is encoded by the gene PIEZO1. Treatments aimed at targeting touch receptors, according to Patapoutian, will have to focus on specific organs, such as utilizing skin patches or providing medication directly to the affected area. Piezo channels may also play a role in the management of migraine pain, which is thought to be caused by the trigeminovascular nociceptive system within the meninges.[9] These mechanosensitive systems may be responsible for some of the most severe migraine symptoms, such as mechanical hyperalgesia and pain. Piezo channels have been proposed as unique molecular receptors in the meningeal trigeminovascular nociceptive system, presenting a potential approach to treating this severe neurological condition.

Mechanotransduction refers to the processes that convert mechanical forces into biological responses. The molecular mechanisms underlying mechanotransduction are unknown, but mechanically activated cation channels are thought to be important.[10] For mechanically activated cation channel activity, PIEZO1 and PIEZO2 are proposed. Mechanical stimuli activate both vertebrate and invertebrate PIEZO channels, implying an evolutionarily conserved gating mechanism geared to transmit mechanical force.[6] Indeed, mechanical stimuli are currently the only way to activate PIEZO ion channels. The discovery of a chemical agonist of PIEZO channels has enormous potential and can benefit the study of mechanotransduction.

Many studies and clinical trials have resulted in the identification and characterization of new nociceptive TRP and PIEZO antagonists with the ability to reduce pain transmission at nociceptors in situ. These receptors, on the other hand, may one day provide an alternative to opioids and other pain therapies, which would be a blessing to the majority of pain sufferers and a useful guide for future analgesic drug discovery. Many clinical trials are currently underway in an attempt to identify new antagonists of nociceptive TRPs and characterize their effects in the in vivo attenuation of pain transduction transmitted by nociceptive receptors. Treatments based on these receptors may be able to replace opioid-like medications and there can be a major breakthrough of newer analgesic agents.

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