Abstract
Background and Aims: Several types of analgesics are currently used in treatment for neuropathic pain (NP). These analgesics, however, often fail to achieve beneficial therapeutic outcome due to increased incidence of the CNS adverse effects such as dizziness and somnolence, resulting in poorer adherence and treatment discontinuation. We had explored and found a series of compounds that show analgesic but not sedative effects at all. Here, we describe an orally-available and central-penetrating analgesic, TRK-700, now being developed.
Methods: We evaluated the anti-allodynic effects in various animal models of NP. In addition, we recorded electrophysiological response of wide dynamic range (WDR) neurons in spinal cord during mechanical stimulation with a von Frey filament, and examined the effect by spinal superfusion in the rat spinal nerve ligation model to reveal the site of action.
Results: TRK-700 had anti-allodynic effects with a similar potency to that of pregabalin in the mouse partial sciatic nerve ligation model. Meanwhile, TRK-700 showed no effect on motor functions at supra-effective doses. TRK-700, additionally had anti-allodynic effects in rat models of diabetic neuropathy and fibromyalgia, demonstrating that TRK-700 is an orally-available and broad-spectrum analgesic without affecting CNS. In electrophysiological studies, spinal superfusion of TRK-700 suppressed the frequency of firing in WDR neurons evoked by mechanical stimulation, suggesting that TRK-700 acts to at least partly spinal cord and suppresses the activation of WDR neurons.
Conclusion: TRK-700 could be a new type of analgesic for the treatment of chronic pain such as diabetic neuropathy and fibromyalgia.
