Endocannabinoids control vesicle release mode at midbrain periaqueductal grey inhibitory synapses

Abstract

Key pointsr The midbrain periaqueductal grey (PAG) forms part of an endogenous analgesic system which is tightly regulated by the neurotransmitter GABA.r The role of endocannabinoids in regulating GABAergic control of this system was examined in rat PAG slices.r Under basal conditions GABAergic neurotransmission onto PAG output neurons was multivesicular.r Activation of the endocannabinoid system reduced GABAergic inhibition by reducing the probability of release and by shifting release to a univesicular mode.r Blockade of endocannabinoid system unmasked a tonic control over the probability and mode of GABA release.r These findings provides a mechanistic foundation for the control of the PAG analgesic system by disinhibition. AbstractThe 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 2+ , and when release probability was reduced by lowering Ca 2+ . However, the effect of DHPG on the coefficient of variation and kinetics of evoked IPSCs differed between normal and low Ca 2+ . Lowering external Ca 2+ had a similar effect on evoked IPSCs to that observed for DHPG in normal external Ca 2+ . 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 Ca 2+ . Together these findings indicate that the normal mode of GABA release is multivesicular within the PAG, and that DHPG and lowering external Ca 2+ 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. * K.R.A. and G.M.D. contributed equally to this work.

Pain Modulation: From Conditioned Pain Modulation to Placebo and Nocebo Effects in Experimental and Clinical Pain

“…Cannabinoid receptor activation by endocannabinoids regulate the mode and the probability of g-aminobutyric acid (GABA) release within the midbrain PAG (Aubrey, Drew, Jeong, Lau, & Vaughan, 2017) and modulate GABA release in the RVM neurons (Li, Suchland, & Ingram, 2017). Cannabinoids produce antinociception in the superficial dorsal horn also by modulation of the descending noradrenergic pathways (Gutierrez et al, 2003).…”

Periaqueductal Gray Glutamatergic Transmission Governs Chronic Stress-Induced Depression

“…Alteration in GABAergic transmission leads to the pathogenesis of major depressive disorder (Luscher et al, 2011). In addition to glutamatergic excitatory transmission in the vlPAG, GABAergic-mediated inhibitory transmission also plays a critical role in controlling the excitability of vlPAG neurons (Aubrey et al, 2017;Lau and Vaughan, 2014). Hence, we investigated whether chronic stress altered GABAergic transmission in the vlPAG causing depressionlike behavior.…”

Chronic morphine reduces the readily releasable pool of GABA, a presynaptic mechanism of opioid tolerance

“…These could not be overcome because increasing release probability leads to saturation of GABAergic synaptic transmission within the PAG (Aubrey et al . ). Another potential limitation was that GABA A receptor desensitization during rapid train stimulation may have led to an underestimate of pool size (Taschenberger et al .…”

“…Evoked and miniature IPSCs are mediated by distinct Ca 2+ ‐dependent and independent processes within the PAG (Vaughan & Christie, ; Aubrey et al . ). Given the dependence of pool size on Ca 2+ influx (see above), alterations in pool size might not be equally reflected in measures of evoked and miniature IPSCs.…”