吗啡作为疼痛治疗的常用药物，在临床应用广泛，但耐受阻碍了其有效应用，机制不明。我们预实验提示，吗啡可经μ受体诱导Immediately Early Gene-Homer1a的表达，且Homer1a基因敲除可损伤吗啡的镇痛效力。Homer1a作为短链Homer蛋白，可竞争性结合在mGluR5胞内段解聚mGluR5-Homer复合体，影响mGluR5对离子通道的调节及胞内游离钙水平。过表达Homer1a被证明可有效对抗炎性痛的进展，而我们在前期预实验研究中也得到类似的结果，过表达Homer1a可有效增强吗啡的镇痛效力。为此，我们提出如下假说：吗啡经μ受体诱导的Homer1a表达可有效协同吗啡对胞内外钙离子及钾离子电流的调节，增强吗啡的急性镇痛效应，反复吗啡处理所致的μ受体脱敏失活将降低吗啡诱导的Homer1a的表达，导致吗啡的镇痛效力丧失，引发耐受。申报课题的完成将有助于形成吗啡耐受的新理论。

As an effective analgesic, morphine was widely used in clinical practice. But the tolerance damages its efficacy and the mechanism remains unknown. Our preliminary data suggest that morphine may induce the expression of Homer1a, an immediately early gene, through μ opioid receptor. The induced Homer1a could potentiate acute morphine efficacy and knockout of Homer1a may lead to decreased antinociception by acute morphine. As a short chain Homer protein, which just includes an EVH1 domain, Homer1a could compete with Homer1 to bind with the TPPSPF at the C-terminal of mGluR5 and lead to the dissociation of mGluR5-Homer crosslinking, and affect the mGluR5-mediated modulation of ion channels. These may have effect on the intracellular calcium level. Overexpression of Homer1a has been proved to have protective effect on inflammatory pain. We also got the similar results in our preliminary tests: overexpression of Homer1a by MECS could potentiate acute morphine efficacy. So we hypothesize that acute morphine-induced Homer1a through μ opioid receptor may potentiate morphine-mediated modulation of transmembrane N-type calcium and M-type potassium currents, and then strengthen acute morphine-induced antinociception; Repeated morphine treatments lead to desensitization of μ opioid receptor, which may result in decreased expression of morphine-induce Homer1a. Decreased expression of Homer1a may hurt morphine-induced antinociception, and then tolerance appears. The current project is helpful in building new mechanism of morphine antinociceptive tolerance and also it has a potential value in peptide synthesis to treat morphine analgesic tolerance in future.