Activation of spinal GABAB receptors normalizes N-methyl-D-aspartate receptor in diabetic neuropathy

Abstract N-methyl-D-aspartate receptor (NMDAR) activity is increased, while GABA B receptor is downregulated in the spinal cord dorsal horn in diabetic neuropathy. In this study, we determined the interaction of NMDARs and GABA B receptors in streptozotocin (STZ)-induced diabetic neuropathy. The paw withdrawal threshold (PWT) was significantly lower in STZ-treated rats than in vehicle-treated rats. Intrathecal injection of baclofen, a GABA B receptor agonist, significantly increased the PWT in STZ-treated rats, an effect that was abolished by pre-administration of the GABA B receptor specific antagonist CGP55845. Spinal NR2B, an NMDA receptor subunit, protein and mRNA expression levels were significantly higher in STZ-treated rats than in vehicle-treated rats. Intrathecal baclofen significantly reduced the NR2B protein and mRNA expression levels in STZ-treated rats. Intrathecal administration of CGP55845 eliminated baclofen-induced reduction of NR2B protein and mRNA levels in STZ-treated rats. In addition, the phosphorylated cAMP response element-binding (CREB) protein level was significantly higher in the spinal cord dorsal horn in STZ-treated rats compared with vehicle-treated rats. Intrathecal injection of baclofen significantly decreased phosphorylated CREB protein level in STZ-treated rats; an effect was blocked by CGP55845. These data suggest that activation of GABA B receptors in the spinal cord dorsal horn normalizes NMDAR expression level in diabetic neuropathic pain.