A novel GABAB receptor positive allosteric modulator, ASP8062, exerts analgesic effects in a rat model of fibromyalgia.

The gamma-aminobutyric acid type B (GABA_B) receptor agonist, the sodium salt of gamma-hydroxybutyrate (GHB), significantly improved pain, sleep disturbance and fatigue in fibromyalgia (FM) patients. However, the use of GABA_B receptor agonists is limited by their undesirable side-effects. To clarify whether GABA_B receptor positive allosteric modulator (PAM) approach would achieve analgesia with less side-effects than GABA_B receptor agonist in FM, we investigated the potential of a novel GABA_B receptor PAM, ASP8062, for FM treatment. We examined the in vitro profiles of ASP8062, the effects of a GABA_B 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 GABA_B 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 GABA_B 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 GABA_B receptor PAM, has therapeutic potential to exert analgesic effects with less side-effects compared to GABA_B receptor agonists in patients with FM.