Attempt of obstinacy pain easing by spinal cord GABA-B receptor continuation activation.

点击翻译按钮获取中文摘要

Recent reports have shown that intrathecal administration of GABA_B receptor agonist baclofen (ITB, intrathecal baclofen) is effective for intolerable pain such as neuropathic pain. Even such effective ITB therapy, prolonged application of baclofen causes tolerance and then decreases analgesic effects in patients. The main cause of the tolerance of ITB therapy arises from desensitization of GABA_B receptors due to continuous activation of the receptors. We have recently reported that G protein-coupled receptor kinase 4 (GRK4) and GRK5 are involved in the desensitization processes of GABA_B receptors (Kanaide et al., J Cell Physiol. (2007)). In the present study we sought to find drugs that inhibit GRK4 and GRK5 activity to persistently stimulate GABA_B receptors.Our findings suggest that ketamine, an anesthetic and an inhibitor of NMDA receptors, efficiently inhibited the properties of GRK4 and GRK5 to finally cause attenuation of desensitization of GABA_B receptors induced by prolonged application of baclefen in the Xenopus oocyte and baby hamster kidney cell expression systems.These results imply that co-administration of both baclofen and ketamine may inhibit desensitization of GABA_B receptors and eventually cause persistent analgesic effects without tolerance in the ITB therapy. Further studies with the whole body animals and preliminary clinical trials would be required to confirm the 'safe and effective ITB therapy' for patients suffering from severe pain.