Opioid presynaptic disinhibition of the midbrain periaqueductal grey descending analgesic pathway
Opioid presynaptic disinhibition of the midbrain periaqueductal grey descending analgesic pathway
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DOI：
10.1111/bph.14982
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发表时间：
2020-02-15
影响因子：
7.3
通讯作者：
Vaughan, Christopher W.
中科院分区：
文献类型：
--
作者：
Lau, Benjamin K.;Winters, Bryony L.;Vaughan, Christopher W.
背景与目的中脑导水管周围灰质（PAG）在疼痛调节中起核心作用，其下行通路经前腹侧内侧髓质（RVM）间接投射到脊髓。虽然阿片类药物是针对PAG的强效镇痛药，但它们对下行投射神经元的作用尚不清楚。实验方法用膜片钳在电压和电流钳模式下记录来自动物的急性制备PAG切片，这些动物在RVM中接受逆行示踪剂注射。与未标记的神经元相比，muo激动剂DAMGO在逆行标记的rvm投射神经元中更大程度地降低了gaba能诱发的抑制性突触后电流（IPSCs）。在两个神经元组中，阿片受体激动剂U69593在相似程度上减少了诱导的IPSCs，而阿片受体激动剂deltorphin-II则没有作用。DAMGO和U69593均能降低逆行标记神经元中自发微型IPSCs和异步诱发IPSCs的发生率，但不降低幅度。DAMGO和U69593也抑制了逆行标记和未标记神经元中的谷氨酸能EPSCs。然而，在反向标记的神经元中，DAMGO对诱发的EPSCs的抑制作用小于未标记的神经元。在电流箝位下，DAMGO在反向标记的神经元中产生诱发突触后电位的去极化增加，但直接抑制未标记的神经元。结论和启示这些发现表明，mu-阿片类药物通过对rvm -突起神经元的突触前解除抑制和对假定的中间神经元的突触后抑制，激活中脑PAG的下行镇痛通路。
Background and Purpose The midbrain periaqueductal grey (PAG) plays a central role in modulating pain through a descending pathway that projects indirectly to the spinal cord via the rostroventral medial medulla (RVM). While opioids are potent analgesics that target the PAG, their cellular actions on descending projection neurons are unclear.Experimental Approach Patch clamp recordings in voltage- and current-clamp mode were made from acutely prepared PAG slices from animals that received retrograde tracer injections into the RVM.Key Results The mu-agonist DAMGO reduced GABAergic evoked inhibitory postsynaptic currents (IPSCs) in retro-labelled, RVM-projecting neurons to a greater extent than in unlabelled neurons. The kappa-opioid agonist U69593 reduced evoked IPSCs to a similar extent in both neuronal groups, while the delta-opioid agonist deltorphin-II was without effect. DAMGO and U69593 both produced a reduction in the rate, but not amplitude of spontaneous miniature IPSCs and asynchronous evoked IPSCs in retro-labelled neurons. DAMGO and U69593 also suppressed glutamatergic EPSCs in retro-labelled and unlabelled neurons. The DAMGO inhibition of evoked EPSCs, however, was less than that for evoked IPSCs in retro-labelled, but not unlabelled neurons. In current clamp, DAMGO produced a depolarizing increase in evoked postsynaptic potentials in retro-labelled neurons, but directly inhibited unlabelled neurons.Conclusion and Implications These findings suggest that mu-opioids activate the descending analgesic pathway from the midbrain PAG by a combination of presynaptic disinhibition of RVM-projecting neurons and postsynaptic inhibition of presumptive interneurons.