Publications by authors named "Kensuke Saeki"

5 Publications

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Mirogabalin, a novel ligand for αδ subunit of voltage-gated calcium channels, improves cognitive impairments in repeated intramuscular acidic saline injection model rats, an experimental model of fibromyalgia.

Biomed Pharmacother 2021 Jul 30;139:111647. Epub 2021 Apr 30.

Specialty Medicine Research Laboratories I, Daiichi-Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address:

Mirogabalin is a novel potent and selective ligand for the αδ subunit of voltage-gated calcium channels, and shows potent and sustained analgesic effects in neuropathic pain and fibromyalgia models. Fibromyalgia is often associated with multiple comorbid symptoms, such as anxiety, depression and cognitive impairment. In the present study, we investigated the effects of mirogabalin on cognitive impairments in an experimental animal model for fibromyalgia, repeated intramuscular acidic saline injection model (Sluka model) rats. Male rats received two repeated intramuscular injections of pH 4 acidic saline into their gastrocnemius muscle. After developing mechanical hypersensitivity as identified in the von Frey test, the animals received the test substance orally once daily for 13 days and were subjected to four cognitive function tests, (Y-maze, novel object recognition, Morris water maze and step-through passive avoidance). Sluka model rats showed cognitive impairments in all four tests. Oral administration of mirogabalin (3 and 10 mg/kg) improved the cognitive impairments in these rats. In conclusion, mirogabalin improved the impaired cognitive function in Sluka model rats. It may thus also alleviate cognitive impairments as well as painful symptoms in fibromyalgia patients.
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http://dx.doi.org/10.1016/j.biopha.2021.111647DOI Listing
July 2021

Anxiolytic-like effects of mirogabalin, a novel ligand for αδ ligand of voltage-gated calcium channels, in rats repeatedly injected with acidic saline intramuscularly, as an experimental model of fibromyalgia.

Pharmacol Rep 2020 Jun 8;72(3):571-579. Epub 2020 Apr 8.

Specialty Medicine Research Laboratories I, Daiichi-Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.

Background: Mental disorders including anxiety and depression are common comorbidities in fibromyalgia patients, and exert a profound impact on their quality of life. Mirogabalin, a novel ligand for the αδ-subunit of voltage-gated calcium channels, shows analgesic effects in fibromyalgia and neuropathic pain models. To provide additional information regarding its potential utility for treating chronic pain, we examined its anxiolytic-like effects in rats repeatedly injected with acidic saline intramuscularly (Sluka model), as an experimental fibromyalgia model.

Methods: Male Sprague-Dawley rats received two intramuscular injections of acidic saline (pH 4.0) into the gastrocnemius muscle. After the development of tactile allodynia demonstrated by decreased paw withdrawal threshold to von Frey filaments, anxiety-like behaviours were evaluated using the open field test and the elevated plus maze test.

Results: Sluka model rats exhibited anxiety-like behaviours in the open field test (significant decreases in distance travelled and time spent in the central area, and significant increases in time spent in the wall area) and the elevated plus maze test (significant decreases in time spent in the open arms and significant increases in time spent in the closed arms). A single oral dose of mirogabalin (3 or 10 mg/kg) significantly alleviated and normalised these anxiety-like behaviours.

Conclusions: Sluka model rats exhibited anxiety-like behaviours in the open field test and the elevated plus maze test, but mirogabalin alleviated these behaviours. Mirogabalin might thus have the potential to relieve anxiety in fibromyalgia patients.
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http://dx.doi.org/10.1007/s43440-020-00103-4DOI Listing
June 2020

Anxiolytic effects of the novel αδ ligand mirogabalin in a rat model of chronic constriction injury, an experimental model of neuropathic pain.

Psychopharmacology (Berl) 2020 Jan 12;237(1):189-197. Epub 2019 Sep 12.

Pain & Neuroscience Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.

Rationale: Psychiatric disorders such as anxiety and depression are frequently observed in neuropathic pain patients, and negatively impact their quality of life. Mirogabalin is a novel ligand for the αδ subunit of voltage-gated calcium channels and has unique binding characteristics to αδ subunits and potent and long-lasting analgesic effects in neuropathic pain models.

Objectives: To provide further information on the pharmacological profile of mirogabalin and its utility for chronic pain therapy, we investigated its anxiolytic effects in an experimental animal model for neuropathic pain.

Methods: In chronic constriction injury (CCI) model rats, mechanical hypersensitivity was determined by the von Frey test. Anxiety- and depression-related behaviours were evaluated using the elevated plus maze test and forced swimming test, respectively.

Results: CCI model rats showed sustained tactile allodynia followed by anxiety-related behaviours, not depression-related behaviours. The tactile allodynia (significant decreases in paw withdrawal threshold) developed within 2 weeks after model preparation, whereas the anxiety-related behaviours (significant decreases in the number of entries and time spent in open arms and significant increases in time spent in closed arms) were observed at 5 weeks but not 4 weeks after model preparation. Single oral administration of mirogabalin (3 or 10 mg/kg) dose-dependently alleviated the above-mentioned anxiety-related behaviours and tactile allodynia.

Conclusions: CCI model rats showed anxiety-related behaviours in a time-dependent manner in the elevated plus maze test. Mirogabalin alleviated both the anxiety-related behaviours and tactile allodynia in CCI model rats. Mirogabalin may provide effective anxiety relief as well as pain relief in patients with neuropathic pain.
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http://dx.doi.org/10.1007/s00213-019-05356-3DOI Listing
January 2020

Analgesic effects of mirogabalin, a novel ligand for αδ subunit of voltage-gated calcium channels, in experimental animal models of fibromyalgia.

Naunyn Schmiedebergs Arch Pharmacol 2019 06 15;392(6):723-728. Epub 2019 Feb 15.

Pain & Neuroscience Laboratories, Daiichi-Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.

Mirogabalin, a novel ligand for the αδ subunit of voltage-gated calcium channels, is under the development for the treatment of neuropathic pain. Mirogabalin specifically and potently binds to αδ subunits, and it shows analgesic effects in both peripheral and central neuropathic pain models in rats. To expand pharmacological findings on mirogabalin and provide additional information of its potential for chronic pain therapy, we examined the effects of mirogabalin in 2 experimental models of fibromyalgia, namely, the intermittent cold stress model (ICS model) and the unilateral intramuscular acidic saline injection model (Sluka model). To induce chronic mechanical hypersensitivity, mice were placed under ICS conditions for 3 days, whereas rats were injected twice with acidic saline (pH 4) into the gastrocnemius muscle in a 4-day interval. The pain sensitivity was evaluated by the von Frey test. Long-lasting increases in pain response score or decreases in pain threshold to the von Frey stimulation were observed in both the ICS and Sluka models. Mirogabalin (1, 3, or 10 mg/kg, p.o.) dose-dependently alleviated the mechanical hypersensitivity, with significant effects persisting at 6 or 8 h following administration. The standard αδ ligand, pregabalin (30 mg/kg, p.o.), also significantly reduced the mechanical hypersensitivity. In summary, mirogabalin showed analgesic effects in the ICS model mice and in the Sluka model rats. Therefore, mirogabalin may have the potential to provide effective pain relief in patients with fibromyalgia.
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http://dx.doi.org/10.1007/s00210-019-01628-zDOI Listing
June 2019

Spinal cord stimulation modulates supraspinal centers of the descending antinociceptive system in rats with unilateral spinal nerve injury.

Mol Pain 2015 Jun 24;11:36. Epub 2015 Jun 24.

Department of Anesthesiology, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Background: The descending antinociceptive system (DAS) is thought to play crucial roles in the antinociceptive effect of spinal cord stimulation (SCS), especially through its serotonergic pathway. The nucleus raphe magnus (NRM) in the rostral ventromedial medulla is a major source of serotonin [5-hydroxytryptamine (5-HT)] to the DAS, but the role of the dorsal raphe nucleus (DRN) in the ventral periaqueductal gray matter is still unclear. Moreover, the influence of the noradrenergic pathway is largely unknown. In this study, we evaluated the involvement of these serotonergic and noradrenergic pathways in SCS-induced antinociception by behavioral analysis of spinal nerve-ligated (SNL) rats. We also investigated immunohistochemical changes in the DRN and locus coeruleus (LC), regarded as the adrenergic center of the DAS, and expression changes of synthetic enzymes of 5-HT [tryptophan hydroxylase (TPH)] and norepinephrine [dopamine β-hydroxylase (DβH)] in the spinal dorsal horn.

Results: Intrathecally administered methysergide, a 5-HT1- and 5-HT2-receptor antagonist, and idazoxan, an α2-adrenergic receptor antagonist, equally abolished the antinociceptive effect of SCS. The numbers of TPH-positive serotonergic and phosphorylated cyclic AMP response element binding protein (pCREB)-positive neurons and percentage of pCREB-positive serotonergic neurons in the DRN significantly increased after 3-h SCS. Further, the ipsilateral-to-contralateral immunoreactivity ratio of DβH increased in the LC of SNL rats and reached the level seen in naïve rats, even though the number of pCREB-positive neurons in the LC was unchanged by SNL and SCS. Moreover, 3-h SCS did not increase the expression levels of TPH and DβH in the spinal dorsal horn.

Conclusions: The serotonergic and noradrenergic pathways of the DAS are involved in the antinociceptive effect of SCS, but activation of the DRN might primarily be responsible for this effect, and the LC may have a smaller contribution. SCS does not potentiate the synthetic enzymes of 5HT and norepinephrine in the neuropathic spinal cord.
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http://dx.doi.org/10.1186/s12990-015-0039-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479321PMC
June 2015