Rivera M, Gintzler A R
Department of Biochemistry, State University of New York, Health Sciences Center, Brooklyn 11203, USA.
Brain Res Mol Brain Res. 1998 Feb;54(1):165-9. doi: 10.1016/s0169-328x(97)00303-3.
In opiate naive longitudinal muscle myenteric plexus tissue, facilitation (GS-mediated) and inhibition (Gi-mediated) of adenylyl cyclase (AC) activity is observed in response to low (nM) and high (microM) concentrations of sufentanil, respectively. Following chronic in vivo exposure to morphine, previously inhibitory concentrations produce excitatory effects. The present study was undertaken to explore the potential relevance of AC isoform-specific regulation to the qualitative change in opioid responsiveness following chronic morphine. Following persistent activation of opiate receptors, levels of AC I mRNA remain unchanged but that of AC IV is significantly augmented (approximately 37%, P < 0.05). AC I and IV are differentially regulated by G alpha i and G beta gamma. The former is inhibited by G alpha i and G beta gamma whereas the latter is relatively insensitive to G alpha i and is stimulated by G beta gamma. Thus, an increase in AC IV mRNA could represent a shift from inhibitory to stimulatory opiate receptor-G protein signalling, as has been observed following chronic morphine. These results indicate that persistent activation of opiate receptors can induce selective changes in the abundance (activity) of AC isoforms. This could explain, in part, some of the adaptations that occur following chronic in vivo morphine exposure.
在阿片类药物初治的纵行肌肌间神经丛组织中，分别观察到对低浓度（纳摩尔）和高浓度（微摩尔）舒芬太尼，腺苷酸环化酶（AC）活性出现促进作用（由Gs介导）和抑制作用（由Gi介导）。在体内长期暴露于吗啡后，先前具有抑制作用的浓度会产生兴奋作用。本研究旨在探讨AC同工型特异性调节与慢性吗啡作用后阿片类药物反应性定性变化之间的潜在相关性。在阿片受体持续激活后，AC I mRNA水平保持不变，但AC IV的水平显著增加（约37%，P<0.05）。AC I和AC IV受Gαi和Gβγ的调节方式不同。前者受Gαi和Gβγ抑制，而后者对Gαi相对不敏感，并受Gβγ刺激。因此，AC IV mRNA的增加可能代表从抑制性阿片受体-G蛋白信号向刺激性信号的转变，正如在慢性吗啡作用后所观察到的那样。这些结果表明，阿片受体的持续激活可诱导AC同工型丰度（活性）的选择性变化。这可以部分解释体内长期暴露于吗啡后发生的一些适应性变化。
