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      Mechanisms of Dexmedetomidine in Neuropathic Pain

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          Abstract

          Dexmedetomidin is a new-generation, highly selective α2 adrenergic receptor agonist with a large number of advantages, including its sedative and analgesic properties, its ability to inhibit sympathetic nerves, its reduced anesthetic dosage, its hemodynamic stability, its mild respiratory depression abilities, and its ability to improve postoperative recognition. Its safety and effectiveness, as well as its ability to provide a certain degree of comfort to patients, make it a useful anesthetic adjuvant for a wide range of clinical applications. For example, dexmedetomidine is commonly used in patients undergoing general anesthesia, and it also exerts sedative effects during tracheal intubation or mechanical ventilation in intensive care unit patients. In recent years, with the deepening of clinical research on dexmedetomidine, the drug is still applied in the treatment of spastic pain, myofascial pain, neuropathic pain, complex pain syndrome, and chronic headache, as well as for multimodal analgesia. However, we must note that the appropriateness of patient and dose selection should be given attention when using this drug; furthermore, patients should be observed for adverse reactions such as hypotension and bradycardia. Therefore, the safety and effectiveness of this drug for long-term use remain to be studied. In addition, basic experimental studies have also found that dexmedetomidine can protect important organs, such as the brain, heart, kidney, liver, and lung, through various mechanisms, such as antisympathetic effects, the inhibition of apoptosis and oxidative stress, and a reduction in the inflammatory response. Moreover, the neuroprotective properties of dexmedetomidine have received the most attention from scholars. Hence, in this review, we mainly focus on the characteristics and clinical applications of dexmedetomidine, especially the role of dexmedetomidine in the nervous system and the use of dexmedetomidine in the relief of neuropathic pain.

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          Most cited references104

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          Neuropathic pain

          Neuropathic pain is caused by a lesion or disease of the somatosensory system, including peripheral fibres (Aβ, Aδ and C fibres) and central neurons, and affects 7-10% of the general population. Multiple causes of neuropathic pain have been described and its incidence is likely to increase owing to the ageing global population, increased incidence of diabetes mellitus and improved survival from cancer after chemotherapy. Indeed, imbalances between excitatory and inhibitory somatosensory signalling, alterations in ion channels and variability in the way that pain messages are modulated in the central nervous system all have been implicated in neuropathic pain. The burden of chronic neuropathic pain seems to be related to the complexity of neuropathic symptoms, poor outcomes and difficult treatment decisions. Importantly, quality of life is impaired in patients with neuropathic pain owing to increased drug prescriptions and visits to health care providers, as well as the morbidity from the pain itself and the inciting disease. Despite challenges, progress in the understanding of the pathophysiology of neuropathic pain is spurring the development of new diagnostic procedures and personalized interventions, which emphasize the need for a multidisciplinary approach to the management of neuropathic pain.
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            Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine

            Dexmedetomidine is an α2-adrenoceptor agonist with sedative, anxiolytic, sympatholytic, and analgesic-sparing effects, and minimal depression of respiratory function. It is potent and highly selective for α2-receptors with an α2:α1 ratio of 1620:1. Hemodynamic effects, which include transient hypertension, bradycardia, and hypotension, result from the drug’s peripheral vasoconstrictive and sympatholytic properties. Dexmedetomidine exerts its hypnotic action through activation of central pre- and postsynaptic α2-receptors in the locus coeruleus, thereby inducting a state of unconsciousness similar to natural sleep, with the unique aspect that patients remain easily rousable and cooperative. Dexmedetomidine is rapidly distributed and is mainly hepatically metabolized into inactive metabolites by glucuronidation and hydroxylation. A high inter-individual variability in dexmedetomidine pharmacokinetics has been described, especially in the intensive care unit population. In recent years, multiple pharmacokinetic non-compartmental analyses as well as population pharmacokinetic studies have been performed. Body size, hepatic impairment, and presumably plasma albumin and cardiac output have a significant impact on dexmedetomidine pharmacokinetics. Results regarding other covariates remain inconclusive and warrant further research. Although initially approved for intravenous use for up to 24 h in the adult intensive care unit population only, applications of dexmedetomidine in clinical practice have been widened over the past few years. Procedural sedation with dexmedetomidine was additionally approved by the US Food and Drug Administration in 2003 and dexmedetomidine has appeared useful in multiple off-label applications such as pediatric sedation, intranasal or buccal administration, and use as an adjuvant to local analgesia techniques.
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              Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift.

              Traumatic brain injury (TBI) is a leading cause of morbidity and disability, with a considerable socioeconomic burden. Heterogeneity of pathoanatomical subtypes and diversity in the pathogenesis and extent of injury contribute to differences in the course and outcome of TBI. Following the primary injury, extensive and lasting damage is sustained through a complex cascade of events referred to as "secondary injury." Neuroinflammation is proposed as an important manipulable aspect of secondary injury in animal and human studies. Because neuroinflammation can be detrimental or beneficial, before developing immunomodulatory therapies, it is necessary to better understand the timing and complexity of the immune responses that follow TBI. With a rapidly increasing body of literature, there is a need for a clear summary of TBI neuroimmunology. This review presents our current understanding of the immune response to TBI in a chronological and compartment-based manner, highlighting early changes in gene expression and initial signaling pathways that lead to activation of innate and adaptive immunity. Based on recent advances in our understanding of innate immune cell activation, we propose a new paradigm to study innate immune cells following TBI that moves away from the existing M1/M2 classification of activation states toward a stimulus- and disease-specific understanding of polarization state based on transcriptomic and proteomic profiling.
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                Author and article information

                Contributors
                Journal
                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                1662-4548
                1662-453X
                05 May 2020
                2020
                : 14
                : 330
                Affiliations
                Department of Anesthesiology, The Affiliated Hospital of Qingdao University , Qingdao, China
                Author notes

                Edited by: Nick Andrews, Harvard Medical School, United States

                Reviewed by: Dara Bree, Cygnal Therapeutics, United States; Alan Kaye, Louisiana State University Health Sciences Center Shreveport, United States

                *Correspondence: Yang Zhao, zhaoy1979@ 123456163.com

                This article was submitted to Neuropharmacology, a section of the journal Frontiers in Neuroscience

                Article
                10.3389/fnins.2020.00330
                7214625
                32431587
                2c0c1df4-aad9-4a77-bba5-3c249b94922d
                Copyright © 2020 Zhao, He, Yu, Jia and Wang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 10 December 2019
                : 20 March 2020
                Page count
                Figures: 1, Tables: 2, Equations: 0, References: 111, Pages: 11, Words: 0
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Categories
                Neuroscience
                Review

                Neurosciences
                neuropathic pain,dexmedetomidine,adrenergic receptor,neuroprotective effect,α2 adrenergic receptor

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