Department of Cellular, Molecular, and Developmental Neurobiology, Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain.
Endocrinology. 2010 Oct;151(10):4908-15. doi: 10.1210/en.2010-0121.
Adrenomedullin (AM) is a regulatory peptide, coded by the adm gene, which is involved in numerous physiological processes, including pain sensitivity. Previous studies have shown that intrathecal injection of AM induced hyperalgesia in the rat. Here, we explore pain sensitivity in a mouse conditional knockout for adm in neurons of the central nervous system, including the spinal cord and dorsal root ganglia. Double immunofluorescence in wild-type (WT) animals shows that AM immunoreactivity is found in calcitonin gene-related peptide-positive neurons of the dorsal root ganglia but not in neurons that bind isolectin B4. Mice lacking adm had modified expression of canonical sensorial neuropeptides, having significantly more calcitonin gene-related peptide and less substance P and enkephalin than their WT littermates. Furthermore, the spinal cord of adm knockout mice expressed higher levels of the AM receptor components, suggesting a compensation attempt to deal with the lack of afferent AM signaling. Behavioral nociceptive tests also found differences between genotypes. In the tail-flick test, which measures mostly spinal reflexes, the adm-null animals had a longer latency than their WT counterparts. On the other hand, in the hotplate test, which requires encephalic processing, mice lacking adm had shorter latencies than normal littermates. These results suggest that AM acts as a nociceptive modulator in spinal reflexes, whereas it may have an analgesic function at higher cognitive levels. This study confirms the important role of AM in pain sensitivity processing but unveils a more complex scenario than previously surmised.
肾上腺髓质素 (AM) 是一种调节肽，由 adm 基因编码，参与许多生理过程，包括疼痛敏感性。先前的研究表明，鞘内注射 AM 会在大鼠中引起痛觉过敏。在这里，我们探索了中枢神经系统神经元条件性缺失 adm 的小鼠的疼痛敏感性，包括脊髓和背根神经节。野生型 (WT) 动物的双重免疫荧光显示，AM 免疫反应性存在于背根神经节中的降钙素基因相关肽阳性神经元中，但不存在与异硫氰酸荧光素 B4 结合的神经元中。缺乏 adm 的小鼠具有改变的经典感觉神经肽表达，其降钙素基因相关肽明显多于 WT 同窝仔鼠，而 P 物质和脑啡肽则明显少于 WT 同窝仔鼠。此外，adm 敲除小鼠的脊髓表达更高水平的 AM 受体成分，表明这是一种补偿尝试，以应对缺乏传入 AM 信号的情况。行为性疼痛测试也发现了基因型之间的差异。在尾巴闪烁测试中，主要测量脊髓反射，adm 缺失的动物的潜伏期比 WT 对照动物长。另一方面，在热板测试中，需要大脑处理，缺乏 adm 的小鼠的潜伏期比正常同窝仔鼠短。这些结果表明，AM 在脊髓反射中作为一种伤害性调制物起作用，而在更高的认知水平上可能具有镇痛作用。本研究证实了 AM 在疼痛敏感性处理中的重要作用，但揭示了比以前推测的更复杂的情况。
