n-arachidonylglycine and Chronic-Pain

Chronic pain constitutes a significant and expanding worldwide health crisis. Currently available analgesics poorly serve individuals suffering from chronic pain, and new therapeutic agents that are more effective, safer, and devoid of abuse liabilities are desperately needed. Among the myriad of cellular and molecular processes contributing to chronic pain, spinal disinhibition of pain signaling to higher cortical centers plays a critical role. Accumulating evidence shows that glycinergic inhibitory neurotransmission in the spinal cord dorsal horn gates nociceptive signaling, is essential in maintaining physiological pain sensitivity, and is diminished in pathological pain states. Thus, it is hypothesized that agents capable of enhancing glycinergic tone within the dorsal horn could obtund nociceptor signaling to the brain and serve as analgesics for persistent pain. This Perspective highlights the potential that pharmacotherapies capable of increasing inhibitory spinal glycinergic neurotransmission hold in providing new and transformative analgesic therapies for the treatment of chronic pain.

Topics: Analgesics; Animals; Chronic Pain; Glycine; Humans; Nociceptors; Receptors, Glycine; Spinal Cord; Synaptic Transmission

Topics: Animals; Arachidonic Acids; Chronic Pain; Glycine; Male; Neuralgia; Periaqueductal Gray; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid

Inhibitors that target the glycine transporter 2, GlyT2, show promise as analgesics, but may be limited by their toxicity through complete or irreversible binding. Acyl-glycine inhibitors, however, are selective for GlyT2 and have been shown to provide analgesia in animal models of pain with minimal side effects, but are comparatively weak GlyT2 inhibitors. Here, we modify the simple acyl-glycine by synthesizing lipid analogues with a range of amino acid head groups in both l- and d-configurations, to produce nanomolar affinity, selective GlyT2 inhibitors. The potent inhibitor oleoyl-d-lysine (33) is also resistant to degradation in both human and rat plasma and liver microsomes, and is rapidly absorbed following an intraperitoneal injection to rats and readily crosses the blood-brain barrier. We demonstrate that 33 provides greater analgesia at lower doses, and does not possess the severe side effects of the very slowly reversible GlyT2 inhibitor, ORG25543 (2).

Topics: Amino Acids; Analgesics; Animals; Blood-Brain Barrier; Chronic Pain; Disease Models, Animal; Glycine Plasma Membrane Transport Proteins; Half-Life; Humans; Microsomes, Liver; Rats; Rats, Sprague-Dawley