Aubrey Karin R, Drew Geoffrey M, Jeong Hyo-Jin, Lau Benjamin K, Vaughan Christopher W
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, Australia.
J Physiol. 2017 Jan 1;595(1):165-178. doi: 10.1113/JP272292. Epub 2016 Sep 15.
The midbrain periaqueductal grey (PAG) forms part of an endogenous analgesic system which is tightly regulated by the neurotransmitter GABA. The role of endocannabinoids in regulating GABAergic control of this system was examined in rat PAG slices. Under basal conditions GABAergic neurotransmission onto PAG output neurons was multivesicular. Activation of the endocannabinoid system reduced GABAergic inhibition by reducing the probability of release and by shifting release to a univesicular mode. Blockade of endocannabinoid system unmasked a tonic control over the probability and mode of GABA release. These findings provides a mechanistic foundation for the control of the PAG analgesic system by disinhibition.
The midbrain periaqueductal grey (PAG) has a crucial role in coordinating endogenous analgesic responses to physiological and psychological stressors. Endocannabinoids are thought to mediate a form of stress-induced analgesia within the PAG by relieving GABAergic inhibition of output neurons, a process known as disinhibition. This disinhibition is thought to be achieved by a presynaptic reduction in GABA release probability. We examined whether other mechanisms have a role in endocannabinoid modulation of GABAergic synaptic transmission within the rat PAG. The group I mGluR agonist DHPG ((R,S)-3,5-dihydroxyphenylglycine) inhibited evoked IPSCs and increased their paired pulse ratio in normal external Ca , and when release probability was reduced by lowering Ca . However, the effect of DHPG on the coefficient of variation and kinetics of evoked IPSCs differed between normal and low Ca . Lowering external Ca had a similar effect on evoked IPSCs to that observed for DHPG in normal external Ca . The low affinity GABA receptor antagonist TPMPA ((1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid) inhibited evoked IPSCs to a greater extent in low than in normal Ca . Together these findings indicate that the normal mode of GABA release is multivesicular within the PAG, and that DHPG and lowering external Ca switch this to a univesicular mode. The effects of DHPG were mediated by mGlu5 receptor engagement of the retrograde endocannabinoid system. Blockade of endocannabinoid breakdown produced a similar shift in the mode of release. We conclude that endocannabinoids control both the mode and the probability of GABA release within the PAG.
中脑导水管周围灰质（PAG）是内源性镇痛系统的一部分，该系统受神经递质γ-氨基丁酸（GABA）的严格调控。我们在大鼠PAG切片中研究了内源性大麻素在调节该系统的GABA能控制中的作用。在基础条件下，PAG输出神经元上的GABA能神经传递是多泡的。内源性大麻素系统的激活通过降低释放概率并将释放转变为单泡模式来减少GABA能抑制。内源性大麻素系统的阻断揭示了对GABA释放概率和模式的紧张性控制。这些发现为通过去抑制控制PAG镇痛系统提供了机制基础。
中脑导水管周围灰质（PAG）在协调对生理和心理应激源的内源性镇痛反应中起关键作用。内源性大麻素被认为通过减轻输出神经元的GABA能抑制（一种称为去抑制的过程）来介导PAG内一种形式的应激诱导镇痛。这种去抑制被认为是通过突触前降低GABA释放概率来实现的。我们研究了其他机制是否在大鼠PAG内GABA能突触传递的内源性大麻素调节中起作用。I组代谢型谷氨酸受体（mGluR）激动剂DHPG（（R，S）-3,5-二羟基苯甘氨酸）在正常细胞外钙浓度下抑制诱发的抑制性突触后电流（IPSCs）并增加其配对脉冲比率，以及当通过降低钙浓度来降低释放概率时也是如此。然而，DHPG对诱发的IPSCs的变异系数和动力学的影响在正常钙浓度和低钙浓度下有所不同。降低细胞外钙对诱发的IPSCs的影响与在正常细胞外钙浓度下观察到的DHPG的影响相似。低亲和力GABA受体拮抗剂TPMPA（（1,2,5,6-四氢吡啶-4-基）甲基次膦酸）在低钙浓度下比在正常钙浓度下更能抑制诱发的IPSCs。这些发现共同表明，PAG内GABA释放的正常模式是多泡的，并且DHPG和降低细胞外钙将其转变为单泡模式。DHPG 的作用是通过逆行性内源性大麻素系统的mGlu5受体参与介导的。内源性大麻素分解的阻断在释放模式上产生了类似的转变。我们得出结论，内源性大麻素控制PAG内GABA释放的模式和概率。
