A calcitonin gene-related peptide receptor antagonist prevents the development of tolerance to spinal morphine analgesia
A calcitonin gene-related peptide receptor antagonist prevents the development of tolerance to spinal morphine analgesia
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DOI：
10.1523/jneurosci.16-07-02342.1996
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发表时间：
1996-04
期刊：
影响因子：
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通讯作者：
Daniel P M6nard;Denise Van Rossurn;S Kar;S. St;Pierre;M. Sutak;K. Jhamandas;R6mi Quirionl
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文献类型：
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作者：
Daniel P M6nard;Denise Van Rossurn;S Kar;S. St;Pierre;M. Sutak;K. Jhamandas;R6mi Quirionl
对吗啡镇痛的耐受性被认为是由连续给药产生的神经适应引起的，尽管所涉及的确切机制尚未建立。最近，我们报道了选择性改变大鼠脊髓降钙素基因相关肽（CGRP）标记物在吗啡耐受动物。事实上，CGRP样免疫染色的增加和背角浅层特异性[125]hCGRP结合的减少与吗啡脊髓抗伤害作用耐受性的发展相关。其他位于脊髓的肽，如P物质，甘丙肽和神经肽Y不受影响。因此，本研究的主要目的是研究是否可以通过使用有效的CGRP拮抗剂hCGRP（8-37）阻断背角CGRP受体来调节对脊髓输注吗啡的耐受性的发展。事实上，与hCGRP（8-37）的共处理以剂量依赖性方式防止了在大鼠甩尾/尾巴浸没和爪压试验中对吗啡诱导的镇痛的耐受性的发展。此外，在吗啡耐受动物中观察到的脊髓CGRP标记物的改变在吗啡和hCGRP共同施用后未观察到（8-37）。这些结果表明，存在特定的相互作用之间的CGRP和发展的耐受性脊髓镇痛效应的吗啡。他们还表明，CGRP受体拮抗剂可能成为治疗疼痛和耐受吗啡的抗伤害性作用的有用的药物。
Tolerance to morphine analgesia is believed to result from a neuronal adaptation produced by continuous drug administration, although the precise mechanisms involved have yet to be established. Recently, we reported selective alterations in rat spinal calcitonin gene-related peptide (CGRP) markers in morphine-tolerant animals. In fact, increases in CGRP-like immunostaining and decrements in specific [125]hCGRP binding in the superficial laminae of the dorsal horn were correlated with the development of tolerance to the spinal antinociceptive action of morphine. Other spinally located peptides such as substance P, galanin, and neuropeptide Y were unaffected. Thus, the major goal of the present study was to investigate whether the development of tolerance to spinally infused morphine could be modulated by the blockade of dorsal horn CGRP receptors using the potent CGRP antagonist hCGRP(8–37). Indeed, cotreatments with hCGRP(8–37) prevented, in a dose- dependent manner, the development of tolerance to morphine-induced analgesia in both the rat tail-flick/tail-immersion and paw-pressure tests. Moreover, alterations in spinal CGRP markers seen in morphine- tolerant animals were not observed after a coadministration of morphine and hCGRP(8–37). These results demonstrate the existence of specific interaction between CGRP and the development of tolerance to the spinal antinociceptive effects of morphine. They also suggest that CGRP receptor antagonists could become useful adjuncts in the treatment of pain and tolerance to the antinociceptive effects of morphine.