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

Abstract

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 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.

Chronic pain: The role of learning and brain plasticity

“…This is the first time that a specific brain circuit in humans pinpoints the transition from acute to chronic back pain. The identified circuit is fully consistent with our earlier human brain imaging studies, our earlier studies in rodents (Centeno et al, 2009; Metz et al, 2009; Millecamps et al, 2007), our proposed model, our preliminary brain imaging data in rodents, and recent studies of rodents in other labs (Gear and Levine, 2011; Johansen and Fields, 2004; Qu et al, 2011; Sarkis et al, 2011). This subacute propensity result complements our proposed model, as it identifies the more critical elements that mediate transition to chronicity.…”

Antinociceptive effect of intracerebroventricular administration of glycine transporter-2 inhibitor ALX1393 in rat models of inflammatory and neuropathic pain

“…A GlyT1 inhibitor in the specific regions of the brain also produced analgesic actions. Centeno et al (2009) showed that the GlyT1 inhibitor, sarcosine, injected into the prefrontal cortex reduced mechanical sensitivity for the injured paw in rat neuropathic pain model. Several brain areas, including the prefrontal cortex and hypothalamus, project to the brainstem, which elicits facilitation or inhibition of the descending inhibitory system (Tracey and Mantyh, 2007).…”

Lidocaine Metabolites Inhibit Glycine Transporter 1

“…The authors of this study concluded that inhibition of GlyT1 at multiple central sites induces acute analgesia, as well as acute and long-term reduction in neuropathic pain behavior. 11 In addition to that, Tanabe et al found that an increase of endogenous glycine concentration following GlyT1 inhibition not only leads to inhibition of pain transmission at the spinal level but also to protection against impairment of hippocampal long-term potentiation. Therefore, the authors concluded that GlyT1 inhibition might also be capable of ameliorating the cognitive disturbances often observed in patients with chronic pain.…”