A novel GABAB receptor positive allosteric modulator, ASP8062, exerts analgesic effects in a rat model of fibromyalgia
| Autor: | Yuji Kondo, Shuichiro Kakimoto, Nobuhito Murai, Mitsuyuki Matsumoto, Shinobu Akuzawa, Takuma Mihara, Nobuyuki Shiraishi |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Pharmacology Agonist Sleep Stages Allosteric modulator business.industry medicine.drug_class Analgesic Antagonist GABAB receptor Motor coordination 03 medical and health sciences 030104 developmental biology 0302 clinical medicine nervous system Medicine Receptor business 030217 neurology & neurosurgery |
| Zdroj: | European Journal of Pharmacology. 865:172750 |
| ISSN: | 0014-2999 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect