Prefrontal cortex and spinal cord mediated anti-neuropathy and analgesia induced by sarcosine, a glycine-T1 transporter inhibitor.

Sarcosine is a competitive inhibitor of glycine type 1 transporter. We hypothesized that it may have analgesic and anti-neuropathic efficacy by a dual action: affecting neurotransmission in the prefrontal cortex as well as within the spinal cord. In rats with spared nerve injury (SNI) oral sarcosine reduced mechanical sensitivity for the injured limb (anti-neuropathy or anti-allodynia) as well as for the uninjured limb (analgesia), showing better dose efficacy for the injured limb. Intrathecal administration of sarcosine was more effective in reducing mechanical sensitivity for the uninjured paw. In contrast, prefrontal cortex infusions of sarcosine acutely reduced mechanical sensitivity for the injured paw. Repeated daily oral sarcosine induced anti-neuropathy, observed only after days of repeated treatment; this long-term effect disappeared a few days after treatment cessation. The findings indicate that manipulating glycine-T1 transporter at multiple central sites can induce acute analgesia, as well as acute and long-term reduction in neuropathic pain behavior. Analgesic effects seem primarily mediated through spinal cord circuitry while anti-neuropathic effects seem mediated through prefrontal cortex circuitry, most likely through distinct molecular pathways. The results suggest that such an approach may provide a novel venue for treating clinical pain conditions.