Novel therapeutics for chronic pain

Wood, Paul

Abstract

The N-methyl-D-aspartate receptor (NMDAR) is an excellent target for the development of therapeutic agents for the treatment of chronic pain: of the many targets on this receptor, the glycine co-agonist site appears especially attractive. Previously, a monoclonal antibody, B6B21, was created that acts as a partial agonist at the glycine site of the NMDAR. The hypervariable region of the light chain of B6B21 was cloned and sequenced. Peptides were then synthesized based on this sequence information and screened using rat hippocampal membrane preparations to measure [3H]-MK-801 binding in the presence of 7-chlorokynurenic acid, a glycine site-specific competitive inhibitor of the NMDAR. Peptides that were able to increase [3H]- MK801 binding in a dose-dependent manner under these conditions were named Glyxins. GLYX-13, a tetrapeptide, was found to readily cross the blood-brain barrier and act as a partial agonist when examined pharmacologically and electrophysiologically. Additionaly, GLYX-13 has been shown to possess antinociceptive activity in the chronic constriction injury model of neuropathic pain in the rat. We propose to further characterize the antinociceptive actions of GLYX-13. The rat formalin assay, a model sensitive to NMDA modulators, will be used as a model of persistent pain. Efficacy and side-effect profiles will be compared with gabapentin in this behavioral model of persistent pain. Additionally, we will evaluate the efficacy of GLYX-13 in a rat model of incisional pain. Efficacy and side-effect profiles will also be compared with gabapentin in this behavioral model of post-operative pain. While the data obtained to date indicate that the Glyxins are a new class of NMDA-receptor modulators that have therapeutic potential, the studies proposed here are crucial to define the optimal patient population for evaluating the analgesic efficacy of GLYX-13 in humans. ? ?