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      A K Ca3.1 Channel Opener, ASP0819, Modulates Nociceptive Signal Processing from Peripheral Nerves in Fibromyalgia-Like Pain in Rats

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          Abstract

          Purpose

          Although abnormal peripheral and central pain processing has been observed in fibromyalgia (FM) patients, the biomechanics and pathophysiology, surrounding the peripheral mechanism are not well understood. An intermediate conductance channel, K Ca3.1, is expressed in peripheral sensory nerve fibers where it maintains the resting membrane potential and controls nerve firing, making it a plausible target for peripheral therapeutic interventions. ASP0819, a K Ca3.1 channel opener, is an orally available molecular entity and is used in this investigation to elucidate the role of K Ca3.1 in signal processing of pain in FM.

          Methods

          Human or rat K Ca3.1 channel-expressing cells were used for evaluating the main action of the compound. Effects of the compound on withdrawal behavior by mechanical stimulation were examined in reserpine-induced myalgia (RIM) and vagotomy-induced myalgia (VIM) models of rats. In addition, in vivo electrophysiological analysis was performed to examine the peripheral mechanisms of action of the compound. Other pain models were also examined.

          Results

          ASP0819 increased the negative membrane potential in a concentration-dependent manner. Oral administration of ASP0819 significantly recovered the decrease in muscle pressure threshold in rat FM models of RIM and VIM. The in vivo electrophysiological experiments showed that Aδ- and C-fibers innervating the leg muscles in the RIM model demonstrated increased spontaneous and mechanically evoked firing compared with normal rats. Intravenous infusion of ASP0819 significantly reduced both the spontaneous activity and mechanically evoked responses in Aδ-fibers in the rat RIM model. ASP0819 significantly reduced the number of abdominal contractions as an indicator of abdominal pain behaviors in the rat visceral extension model and withdrawal responses in the osteoarthritis model, respectively.

          Conclusion

          These findings suggest that ASP0819 may be a promising analgesic agent with the ability to modulate peripheral pain signal transmission. Its use in the treatment of several pain conditions should be explored, chief amongst these being FM pain.

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          Most cited references 31

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          Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis.

          To describe an in vivo model in the rat in which change in weight distribution is used as a measure of disease progression and efficacy of acetaminophen and two nonsteroidal anti-inflammatory drugs (NSAIDs) in a model of monosodium iodoacetate (MIA)-induced osteoarthritis (OA). Intra-articular injections of MIA and saline were administered to male Wistar rats (175-200 g) into the right and left knee joints, respectively. Changes in hind paw weight distribution between the right (osteoarthritic) and left (contralateral control) limbs were utilized as an index of joint discomfort. Acetaminophen and two archetypal, orally administered NSAIDs, naproxen and rofecoxib, were examined for their ability to decrease MIA-induced change in weight distribution. A concentration-dependent increase in change in hind paw weight distribution was noted after intra-articular injection of MIA. Both naproxen and rofecoxib demonstrated the capacity to significantly (P<0.05) decrease hind paw weight distribution in a dose-dependent fashion, indicating that the change in weight distribution associated with MIA injection is susceptible to pharmacological intervention. The determination of differences in hind paw weight distribution in the rat MIA model of OA is a technically straightforward, reproducible method that is predictive of the effects of anti-inflammatory and analgesic agents. This system may be useful for the discovery of novel pharmacologic agents in human OA.
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            Central sensitization: implications for the diagnosis and treatment of pain.

            Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and post-surgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk in both developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity. Copyright © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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              Role of central dopamine in pain and analgesia.

               Harvey Wood (2008)
              Recent insights have demonstrated a central role for dopaminergic neurotransmission in modulating pain perception and natural analgesia within supraspinal regions, including the basal ganglia, insula, anterior cingulate cortex, thalamus and periaqueductal gray. In addition, while the participation of serotonin and norepinephrine in spinal descending inhibition of pain is well known, a critical role for dopamine in descending inhibition has also been demonstrated. Decreased levels of dopamine likely contribute to the painful symptoms that frequently occur in Parkinson's disease. Moreover, abnormalities in dopaminergic neurotransmission have been objectively demonstrated in painful clinical conditions, including burning mouth syndrome, fibromyalgia and restless legs syndrome. Evidence from animal models and indirect evidence from pharmaceutical trials also suggest a role for dopamine in chronic regional pain syndrome and painful diabetic neuropathy. Several novel classes of medication with analgesic properties have bearing on dopaminergic activity as evident in the capacity of dopamine antagonists to attenuate their analgesic capacity. An expanded appreciation for the role of dopamine in natural analgesia provides the impetus for further study involving preclinical models and advanced neuroimaging techniques in humans, which may lead to the development of novel therapeutic strategies.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                jpr
                jpainres
                Journal of Pain Research
                Dove
                1178-7090
                12 January 2021
                2021
                : 14
                : 23-34
                Affiliations
                [1 ]Drug Discovery Research, Astellas Pharma Inc , Ibaraki, Japan
                Author notes
                Correspondence: Nobuaki Takeshita Drug Discovery Research , Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki305-8585, JapanTel +81-29-852-1111Fax +81-29-850-5120 Email nobuaki.takeshita@astellas.com
                Article
                274563
                10.2147/JPR.S274563
                7811477
                33469353
                © 2021 Takeshita et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 7, Tables: 2, References: 31, Pages: 12
                Categories
                Original Research

                Anesthesiology & Pain management

                pain, fibromyalgia, potassium channel

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