key: cord-0946806-cw34kvma
authors: Scuteri, Damiana; Sakurada, Tsukasa; Tonin, Paolo; Corasaniti, Maria Tiziana; Bagetta, Giacinto
title: Editorial: “Novel Pain Therapeutics: From Basic Research to Clinical Translation and Rehabilitation”
date: 2021-04-14
journal: Front Pharmacol
DOI: 10.3389/fphar.2021.681422
sha: 2c586a36988382caf2f865c5a46cc1a2498dd9a4
doc_id: 946806
cord_uid: cw34kvma

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glutamate (Morrone et al., 2007) and this contributes to its analgesic activity (Scuteri et al., 2019c) , which is enriched by anxiolytic properties devoid of sedation (Rombola et al., 2019) . Interestingly, the analgesic effect occurs also when it is administered via the inhalatory route (Scuteri et al., 2018a) , though it is independent on olfactory stimulation and mediated by systemic absorption of active principles (Hamamura et al.) . Trazodone has been demonstrated to restore acutely the aberrant plasticity to which mGlu autoreceptors are subjected after spinal nerve ligation (Cisani et al.) . Furthermore, glutamate is involved in the antinociceptive effect of apelin, the endogenous ligand for the putative receptor protein related to the type 1 angiotensin receptor (APJ) orphan G-protein-coupled receptor (Lv et al.) . Opioid receptors occurring on nociceptor terminals play a pivotal role in pain modulation. For instance, in neuropathic pain deltorphin II can inhibit the response of C fibers in a concentration-dependent and delta opioid receptors-mediated manner (Joukal et al.) . Moreover, methadone has been found to be effective in morphine-resistant hyperalgesia and to restore morphine antinociception in the inflammatory model of the complete Freund's adjuvant (CFA) (Watanabe et al.). The latter is interesting also in view of the lack of efficacy and the onset of serious side effects for chronic administration of opioids in the treatment of osteoarthritis. The role of the inflammasome in pain is fundamental and the interaction between immune and nervous system contributes to the development of chronic pain. Also, the modulation of microglia can reduce allodynia in a sexdependent manner (Saika et al.) . Oxidative stress and nuclear factor erythroid derived-2-related factor 2 (Nrf2) pathway is notably implicated in neuropathic pain (Zhao et al.) . Other targets for pain treatment are the small-conductance Ca 2+activated K + channels for visceral hypersensitivity (Ji et al.) . In particular, the study of visceral hypersensitivity is of the utmost importance since it can predispose to visceral chronic pain and it can be caused by maternal separation responsible for elevated firing frequency of corticotropin-releasing factor neurons (Huang et al.). Among the non pharmacologic approaches, acupuncture has been studied in primary dysmenorrhea and its efficacy can be predicted by painrelated functional connectivity patterns through machine learning multivariate pattern analysis (Yu et al.); the endocannabinoid system seems to be implicated in electroacupuncture-induced analgesia (MacDonald and Chen). Hence, the use of novel technological tools, e.g., machine learning, can improve the comprehension of the machinery of chronic pain. A better understanding of the above mechanisms can lead to discover the properties of already known and widely used analgesics, like acetaminophen, which still holds some surprises, e.g., the action of its metabolite N-acylphenolamine on brain TRPV1 and cannabinoid 1 receptors with consequent central analgesia (Ohashi and Kohno). These findings highlight the need for more basic as well as clinical studies on commonly used painkillers. One of the most remarkable is the case of opioids, often inappropriately used in fragile populations of the elderly commonly suffering from diseases that impair their communication skills. The treatment of chronic pain per se represents an area of strong therapeutic inappropriateness resulting in real-world limited access to care for fragile patients, e.g., demented aged people (Scuteri et al., 2017; Scuteri et al., 2018b; Scuteri et al., 2021) . This is mirrored by the scarce use of the existing adequate observational pain scales and by the lack of standardization and guidelines for clinical practice in dementia (Gimenez-Llort et al.) . This issue is very serious also for patients suffering from post-stroke pain. In fact, what emerges from the systematic review and meta-analysis of current literature is that the use of opioids in these patients is not specifically studied in the latter population with clinical trials designed for this purpose and using suitable pain assessment tools (Scuteri et al.) . The assessment and the treatment of pain after spinal cord injury is still an unmet need (Finnerup, 2013; Yasko and Mains, 2018) . The correct management of pain in patients who have been subjected to a severe brain injury with disorders of consciousness is fundamental to allow the best therapeutic approach and the planning of the most effective rehabilitation strategy (Riganello et al.).

All the datasets generated/analyzed for this study are included in the article.

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

DS is a post-doc recipient of a research grant salary in the frame of a research project (Tutor: GB) on "Pharmacoepidemiology of drugs used in the treatment of neuropsychiatric symptoms and pain in aged (over 65) people with dementia" funded by Calabria Region (POR Calabria FESR-FSE 2014/2020-Linea B) Azione 10.5.12.

Frontiers in Pharmacology | www.frontiersin.org April 2021 | Volume 12 | Article 681422

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