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A novel GABAB receptor positive allosteric modulator, ASP8062, exerts analgesic effects in a rat model of fibromyalgia.
Eur J Pharmacol. 2019 Dec 15; 865:172750.EJ

Abstract

The gamma-aminobutyric acid type B (GABAB) receptor agonist, the sodium salt of gamma-hydroxybutyrate (GHB), significantly improved pain, sleep disturbance and fatigue in fibromyalgia (FM) patients. However, the use of GABAB receptor agonists is limited by their undesirable side-effects. To clarify whether GABAB receptor positive allosteric modulator (PAM) approach would achieve analgesia with less side-effects than GABAB receptor agonist in FM, we investigated the potential of a novel GABAB receptor PAM, ASP8062, for FM treatment. We examined the in vitro profiles of ASP8062, the effects of a GABAB receptor PAM and an agonist on pain in a rat model of FM, and the sleep/wake cycle, EEG during sleep stages and motor coordination in rats. ASP8062 showed PAM activity on human and rat GABAB receptors. Oral administration of ASP8062 significantly reversed the decrease in muscle pressure threshold in reserpine-induced myalgia rats. The analgesic effects of ASP8062 were significantly blocked by a GABAB receptor antagonist. ASP8062 had a significant effect on motor coordination at a 1000-fold higher dose than the analgesic dose in rats. ASP8062 significantly decreased total REM sleep time and frequency of sleep interruptions, and increased the power in delta waves frequency during non-REM sleep in rats. ASP8062, a novel GABAB receptor PAM, has therapeutic potential to exert analgesic effects with less side-effects compared to GABAB receptor agonists in patients with FM.

Authors+Show Affiliations

Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan. Electronic address: nobuhito.murai@astellas.com.Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan.Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan.Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan.Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan.Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan.Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31647906

Citation

Murai, Nobuhito, et al. "A Novel GABAB Receptor Positive Allosteric Modulator, ASP8062, Exerts Analgesic Effects in a Rat Model of Fibromyalgia." European Journal of Pharmacology, vol. 865, 2019, p. 172750.
Murai N, Kondo Y, Akuzawa S, et al. A novel GABAB receptor positive allosteric modulator, ASP8062, exerts analgesic effects in a rat model of fibromyalgia. Eur J Pharmacol. 2019;865:172750.
Murai, N., Kondo, Y., Akuzawa, S., Mihara, T., Shiraishi, N., Kakimoto, S., & Matsumoto, M. (2019). A novel GABAB receptor positive allosteric modulator, ASP8062, exerts analgesic effects in a rat model of fibromyalgia. European Journal of Pharmacology, 865, 172750. https://doi.org/10.1016/j.ejphar.2019.172750
Murai N, et al. A Novel GABAB Receptor Positive Allosteric Modulator, ASP8062, Exerts Analgesic Effects in a Rat Model of Fibromyalgia. Eur J Pharmacol. 2019 Dec 15;865:172750. PubMed PMID: 31647906.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel GABAB receptor positive allosteric modulator, ASP8062, exerts analgesic effects in a rat model of fibromyalgia. AU - Murai,Nobuhito, AU - Kondo,Yuji, AU - Akuzawa,Shinobu, AU - Mihara,Takuma, AU - Shiraishi,Nobuyuki, AU - Kakimoto,Shuichiro, AU - Matsumoto,Mitsuyuki, Y1 - 2019/10/21/ PY - 2019/03/09/received PY - 2019/10/11/revised PY - 2019/10/18/accepted PY - 2019/10/28/pubmed PY - 2020/5/21/medline PY - 2019/10/25/entrez KW - Fibromyalgia KW - GABA(B) receptor KW - Pain KW - Positive allosteric modulator KW - Sleep SP - 172750 EP - 172750 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 865 N2 - The gamma-aminobutyric acid type B (GABAB) receptor agonist, the sodium salt of gamma-hydroxybutyrate (GHB), significantly improved pain, sleep disturbance and fatigue in fibromyalgia (FM) patients. However, the use of GABAB receptor agonists is limited by their undesirable side-effects. To clarify whether GABAB receptor positive allosteric modulator (PAM) approach would achieve analgesia with less side-effects than GABAB receptor agonist in FM, we investigated the potential of a novel GABAB receptor PAM, ASP8062, for FM treatment. We examined the in vitro profiles of ASP8062, the effects of a GABAB receptor PAM and an agonist on pain in a rat model of FM, and the sleep/wake cycle, EEG during sleep stages and motor coordination in rats. ASP8062 showed PAM activity on human and rat GABAB receptors. Oral administration of ASP8062 significantly reversed the decrease in muscle pressure threshold in reserpine-induced myalgia rats. The analgesic effects of ASP8062 were significantly blocked by a GABAB receptor antagonist. ASP8062 had a significant effect on motor coordination at a 1000-fold higher dose than the analgesic dose in rats. ASP8062 significantly decreased total REM sleep time and frequency of sleep interruptions, and increased the power in delta waves frequency during non-REM sleep in rats. ASP8062, a novel GABAB receptor PAM, has therapeutic potential to exert analgesic effects with less side-effects compared to GABAB receptor agonists in patients with FM. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/31647906/A_novel_GABAB_receptor_positive_allosteric_modulator_ASP8062_exerts_analgesic_effects_in_a_rat_model_of_fibromyalgia_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(19)30702-2 DB - PRIME DP - Unbound Medicine ER -