Overcoming refractory pain : prevention of tolerance of pain by simultaneous activation of G_<i/o>-coupled receptors

在晚期癌症患者中观察到的难治性疼痛的管理难以控制，在这种情况下，目前使用鞘内吗啡（ITM）或鞘内巴氯芬治疗（ITB）。然而，长期使用ITM或ITB常因μ-阿片受体（μOR）或GABA_B受体（GBR）的脱敏而导致耐受。为了克服这一问题，我们用体外实验系统证明：1）巴氯芬与氯胺酮联合治疗可抑制GBR的脱敏; 2）GBR因与受体脱敏的关键蛋白β-arrestins结合失败而不能内化，3）在μOR和GBR共表达的细胞中，低浓度的吗啡和巴氯芬联合作用几乎不引起受体脱敏。这些结果表明，上述一些新的治疗方法将有助于通过预防受体脱敏来控制难治性疼痛。

Management of refractory pain seen in advanced cancer patients is hard to control, and in such cases intrathecal morphine(ITM) or intrathecal baclofen treatment(ITB) is currently used. However, persistent use of either ITM or ITB often causes tolerance due to desensitization ofμ-opioid(μOR) or GABA_B receptors(GBR).To overcome such issue, we demonstrated by using in vitro experimental system that 1) treatment of baclofen with ketamine suppressed GBR desensitization, 2) GBR did not internalize because of failure of association withβ-arrestins, key proteins for receptor desensitization, 3) in cells coexpressingμOR and GBR, combination of low concentrations of morphine and baclofen hardly caused receptor desensitization. These results suggest that some of newer treatments described above would be useful for the control of refractory pain by prevention of receptor desensitization.