Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, The University of Sydney and Royal North Shore Hospital, St Leonards, New South Wales, 2065, Australia.
J Physiol. 2017 Oct 15;595(20):6541-6555. doi: 10.1113/JP274157. Epub 2017 Sep 7.
Chronic treatment with opioids, such as morphine, leads to analgesic tolerance. While postsynaptic opioid tolerance is well documented, the involvement of presynaptic mechanisms remains unclear. We show that chronic morphine reduces the ability of periaqueductal grey (PAG) neurons to maintain GABAergic transmission. This depression of GABAergic transmission was due to a reduction in the effective size of the readily releasable pool. This also led to a reduction in opioid presynaptic inhibition; these presynaptic adaptations need to be considered in the development of strategies to reduce opioid tolerance.
The midbrain periaqueductal grey (PAG) plays a critical role in tolerance to the analgesic actions of opioids such as morphine. While numerous studies have identified the postsynaptic adaptations induced by chronic morphine treatment in this and other brain regions, the presence of presynaptic adaptations remains uncertain. We examined GABAergic synaptic transmission within rat PAG brain slices from animals which underwent a low dose morphine treatment protocol which produces tolerance, but not withdrawal. Evoked GABAergic IPSCs (inhibitory postsynaptic currents) were less in morphine compared to control saline treated animals. Postsynaptic GABA receptor mediated currents and desensitization, presynaptic release probability (P ), and inhibition by endogenous neurotransmitters were similar in morphine and saline treated animals. By contrast, the effective size of the readily releasable pool (RRP) was smaller in morphine treated animals. While the μ-opioid agonist DAMGO produced a reduction in P and RRP size in saline treated animals, it only reduced P in morphine treated animals. Consequently, DAMGO-induced inhibition of evoked IPSCs during short burst stimulation was less in morphine, compared to saline treated animals. These results indicate that low dose chronic morphine treatment reduces presynaptic μ-opioid inhibition by reducing the size of the pool of vesicles available for action potential dependent release. This novel presynaptic adaptation may provide important insights into the development of efficacious pain therapies that can circumvent the development of opioid tolerance.
慢性使用阿片类药物（如吗啡）会导致镇痛耐受。虽然突触后阿片类药物耐受已得到充分证实，但突触前机制的参与仍不清楚。我们发现，慢性吗啡降低了导水管周围灰质（PAG）神经元维持 GABA 能传递的能力。这种 GABA 能传递的抑制是由于易释放池的有效大小减少所致。这也导致了阿片类药物突触前抑制的减少；在制定减少阿片类药物耐受的策略时，需要考虑这些突触前适应性。
中脑导水管周围灰质（PAG）在吗啡等阿片类药物镇痛作用的耐受中起着关键作用。虽然许多研究已经确定了慢性吗啡处理后在该区域和其他脑区诱导的突触后适应性，但突触前适应性的存在仍然不确定。我们检查了经历低剂量吗啡处理方案（产生耐受但不产生戒断）的动物的 PAG 脑切片中的 GABA 能突触传递。与对照组生理盐水处理的动物相比，吗啡处理的动物中的诱发 GABA 能 IPSC（抑制性突触后电流）较少。吗啡和生理盐水处理的动物中的突触后 GABA 受体介导的电流和脱敏、突触前释放概率（P ）以及内源性神经递质的抑制作用相似。相比之下，吗啡处理的动物中的易释放池的有效大小较小。虽然 μ 阿片类激动剂 DAMGO 降低了生理盐水处理的动物中的 P 和 RRP 大小，但它仅降低了吗啡处理的动物中的 P 。因此，在短爆发刺激期间，DAMGO 诱导的诱发 IPSC 抑制作用在吗啡处理的动物中，与生理盐水处理的动物相比减少了。这些结果表明，低剂量慢性吗啡处理通过减少可用于动作电位依赖性释放的囊泡池的大小，减少了突触前 μ 阿片类抑制。这种新的突触前适应性可能为开发有效的疼痛治疗方法提供重要的见解，这些方法可以避免阿片类药物耐受的发展。
