Transient receptor potential vanilloid 1 (TRPV1) is primarily expressed in central and peripheral terminals of non-myelinated primary afferent neurons. We previously showed that
AS1928370, a novel TRPV1 antagonist that can prevent
ligand-induced activation but not
proton-induced activation, ameliorates
neuropathic pain in rats without hyperthermic effect. In this study, we investigated its
analgesic profile in mice.
AS1928370 showed good oral bioavailability and high penetration into the brain and spinal cord in mice. The mean plasma-to-brain and plasma-to-spinal cord ratios were 4.3 and 3.5, respectively. Pretreatment with
AS1928370 significantly suppressed both
capsaicin-induced
acute pain and withdrawal response in hot plate test
at 10-30 mg/kg per os (p.o.). At lower oral doses (0.3-1.0 mg/kg),
AS1928370 improved
mechanical allodynia in mice undergoing spinal nerve
ligation. Intrathecal administration of
AS1928370 (30 µg/body) also significantly suppressed
mechanical allodynia. In addition,
AS1928370 showed no effect on locomotor activity up to 30 mg/kg p.o. These results suggest that spinal TRPV1 has an important role in the transmission of
neuropathic pain and that the central nervous system (CNS) penetrant
TRPV1 receptor antagonist
AS1928370 is a promising candidate for treating
neuropathic pain.