The limited effect of current medications on neuropathic pain (NP) has initiated large
efforts to develop effective treatments. Animal studies showed that glycine transporter
(GlyT) inhibitors are promising analgesics in NP, though concerns regarding adverse
effects were raised. We aimed to study NFPS and Org-25543, GlyT-1 and GlyT-2 inhibitors,
respectively and their combination in rat mononeuropathic pain evoked by partial sciatic
nerve ligation. Cerebrospinal fluid (CSF) glycine content was also determined by capillary
electrophoresis. Subcutaneous (s.c.) 4 mg/kg NFPS or Org-25543 showed analgesia following
acute administration (30–60 min). Small doses of each compound failed to produce antiallodynia
up to 180 min after the acute administration. However, NFPS (1 mg/kg) produced antiallodynia
after four days of treatment. Co-treatment with subanalgesic doses of NFPS (1 mg/kg)
and Org-25543 (2 mg/kg) produced analgesia at 60 min and thereafter meanwhile increased
significantly the CSF glycine content. This combination alleviated NP without affecting
motor function. Test compounds failed to activate G-proteins in spinal cord. To the
best of our knowledge for the first time we demonstrated augmented analgesia by combining
GlyT-1 and 2 inhibitors. Increased CSF glycine content supports involvement of glycinergic
system. Combining selective GlyT inhibitors or developing non-selective GlyT inhibitors
might have therapeutic value in NP.
