Wu Zhen-Yu, Lu Ya-Cheng, Feng Ban, Chen Ying-Biao, Bai Yang, Zhang Ting, Zhang Hua, Chen Tao, Dong Yu-Ling, Li Hui, Li Yun-Qing
Department of Anatomy and K. K. Leung Brain Research Centre, The Fourth Military Medical UniversityXi'an, China.
Department of Anatomy, Fujian Health CollegeMinhou, China.
Front Neural Circuits. 2017 Aug 8;11:55. doi: 10.3389/fncir.2017.00055. eCollection 2017.
Motor impairment is one of the serious side-effects of morphine, which is an exogenous agonist of the μ-opioid receptor (MOR) as well as a widely used analgesic drug in clinical practice for chronic pain treatment. Endomorphins (EMs, including EM-1 and EM-2), the most effective and specific endogenous agonists of the MOR, exert more potent analgesia in acute and neuropathic pain than other opiates, such as morphine. Although EMs had fewer side-effects comparing to other opiates, motor impairment was still one unwanted reaction which limited its clinical application. In order to prevent and treat the motor impairment, it is critical to reveal the neural mechanisms underlying such locomotion disorder. The purpose of the present study was to reveal the neural mechanisms underlying the effects of EM-2 on the activity of motoneurons in the spinal ventral horn. First, we examine the distribution of EM-2-immunoreactive (IR) primary afferent fibers and their synaptic connections with the motoneurons innervating the skeletal muscles of the lower limb revealed by sciatic nerve retrograde tracing. The results showed that EM-2-IR fibers and terminals were sparsely observed in lamina IX and they formed symmetric synaptic connections with the motoneurons within lamina IX of the spinal ventral horn. Then, whole-cell patch-clamp technique was used to observe the effects of EM-2 on the spontaneous excitatory postsynaptic current (sEPSC) of motoneurons in lamina IX. The results showed that EM-2 could decrease both the frequency and amplitude of the sEPSC of the motoneurons in lamina IX, which was reversed by the MOR antagonist CTOP. These results indicate that EM-2-IR fibers originated from primary afferent fibers form symmetric synaptic connections with motoneurons innervating skeletal muscles of the lower limbs in lamina IX of the spinal ventral horn and EM-2 might exert inhibitory effects on the activities of these motoneurons through both presynaptic and postsynaptic mechanisms.
运动功能障碍是吗啡的严重副作用之一，吗啡是μ-阿片受体（MOR）的外源性激动剂，也是临床实践中广泛用于治疗慢性疼痛的镇痛药。内吗啡肽（EMs，包括EM-1和EM-2）是MOR最有效和特异的内源性激动剂，在急性和神经性疼痛中比吗啡等其他阿片类药物发挥更强效的镇痛作用。尽管与其他阿片类药物相比，EMs的副作用较少，但运动功能障碍仍然是限制其临床应用的一种不良反应。为了预防和治疗运动功能障碍，揭示这种运动障碍背后的神经机制至关重要。本研究的目的是揭示EM-2对脊髓腹角运动神经元活动影响的神经机制。首先，我们通过坐骨神经逆行追踪，研究了EM-2免疫反应性（IR）初级传入纤维的分布及其与支配下肢骨骼肌的运动神经元的突触连接。结果显示，在脊髓灰质第IX层中稀疏观察到EM-2-IR纤维和终末，它们与脊髓腹角第IX层内的运动神经元形成对称突触连接。然后，采用全细胞膜片钳技术观察EM-2对第IX层运动神经元自发性兴奋性突触后电流（sEPSC）的影响。结果表明，EM-2可降低第IX层运动神经元sEPSC的频率和幅度，而MOR拮抗剂CTOP可逆转这种作用。这些结果表明，源自初级传入纤维的EM-2-IR纤维与脊髓腹角第IX层中支配下肢骨骼肌的运动神经元形成对称突触连接，并且EM-2可能通过突触前和突触后机制对这些运动神经元的活动发挥抑制作用。
