Endocannabinoids control vesicle release mode at midbrain periaqueductal grey inhibitory synapses

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• 作者：Karin R. Aubrey ; Geoffrey M. Drew ; Hyo‐Jin Jeong ; Benjamin K. Lau ; Christopher W. Vaughan
• 刊名：The Journal of Physiology
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：595
• 期：1
• 页码：165-178
• 全文大小：981.6KB
• ISSN：1469-7793

文摘

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 Ca²⁺, and when release probability was reduced by lowering Ca²⁺. However, the effect of DHPG on the coefficient of variation and kinetics of evoked IPSCs differed between normal and low Ca²⁺. Lowering external Ca²⁺ had a similar effect on evoked IPSCs to that observed for DHPG in normal external Ca²⁺. The low affinity GABA_A receptor antagonist TPMPA ((1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid) inhibited evoked IPSCs to a greater extent in low than in normal Ca²⁺. Together these findings indicate that the normal mode of GABA release is multivesicular within the PAG, and that DHPG and lowering external Ca²⁺ 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.