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The endogenous cannabinoid transmitter system regulates synaptic transmission throughout the nervous system. Unlike conventional transmitters, specific stimuli induce synthesis of endocannabinoids (eCBs) in the postsynaptic neuron, and these travel backwards to modulate presynaptic inputs. In doing so, eCBs can induce short-term changes in synaptic strength and longer-term plasticity. While this eCB regulation is near ubiquitous, it displays major regional and synapse specific variations with different synapse specific forms of short-versus long-term plasticity throughout the brain. These differences are due to the plethora of pre- and postsynaptic mechanisms which have been implicated in eCB signalling, the intricacies of which are only just being realised. In this review, we shall describe the current understanding and highlight new advances in this area, with a focus on the retrograde action of eCBs at CB1 receptors (CB 1 Rs). This article is part of the special Issue on 'Cannabinoids'., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background and Purpose: Pain is a subjective experience involving sensory discriminative and emotionally aversive components. Consistent with its role in pain processing and emotions, the amygdala modulates the aversive component of pain. The laterocapsular region of the central nucleus of the amygdala (CeLC) receives nociceptive information from the parabrachial nucleus (PB) and polymodal, including nociceptive, inputs from the basolateral nucleus of the amygdala (BLA). Opioids are strong analgesics and reduce both the sensory discriminative and the affective component of pain. However, it is unknown whether opioids regulate activity at the two nociceptive inputs to the amygdala., Experimental Approach: Using whole-cell electrophysiology, optogenetics, and immunohistochemistry, we investigated whether opioids inhibit the rat PB-CeLC and BLA-CeLC synapses., Key Results: Opioids inhibited glutamate release at the PB-CeLC and BLA-CeLC synapses. Opioid inhibition is via the μ-receptor at the PB-CeLC synapse, while at the BLA-CeLC synapse, inhibition is via μ-receptors in all neurons and via δ-receptors and κ-receptors in a subset of neurons., Conclusions and Implications: Agonists of μ-receptors inhibited two of the synaptic inputs carrying nociceptive information into the laterocapsular amygdala. Therefore, μ-receptor agonists, such as morphine, will inhibit glutamate release from PB and BLA in the CeLC, and this could serve as a mechanism through which opioids reduce the affective component of pain and pain-induced associative learning. The lower than expected regulation of BLA synaptic outputs by δ-receptors does not support the proposal that opioid receptor subtypes segregate into subnuclei of brain regions., (© 2019 The British Pharmacological Society.)

Background and Purpose: Inhibitory neurotransmission plays an important role in controlling excitability within nociceptive circuits of the spinal cord dorsal horn. Loss of inhibitory signalling is thought to contribute to the development of pathological pain. Preclinical studies suggest that increasing inhibitory glycinergic signalling is a good therapeutic strategy for treating pain. One approach to increase synaptic glycine is to inhibit the activity of the glycine transporter 2 (GlyT2) on inhibitory nerve terminals. These transporters are involved in regulating glycine concentrations and recycling glycine into presynaptic terminals. Inhibiting activity of GlyT2 increases synaptic glycine, which decreases excitability in nociceptive circuits and provides analgesia in neuropathic and inflammatory pain models., Experimental Approach: We investigated the effects of reversible and irreversible GlyT2 inhibitors on inhibitory glycinergic and NMDA receptor-mediated excitatory neurotransmission in the rat dorsal horn. The effect of these drugs on synaptic signalling was determined using patch-clamp electrophysiology techniques to measure glycine- and NMDA-mediated postsynaptic currents in spinal cord slices in vitro., Key Results: We compared activity of four compounds that increase glycinergic tone with a corresponding increase in evoked glycinergic postsynaptic currents. These compounds did not deplete synaptic glycine release over time. Interestingly, none of these compounds increased glycine-mediated excitatory signalling through NMDA receptors. The results suggest that these compounds preferentially inhibit GlyT2 over G1yT1 with no potentiation of the glycine receptor and without inducing spillover from inhibitory to excitatory synapses., Conclusions and Implications: GlyT2 inhibitors increase inhibitory neurotransmission in the dorsal horn and have potential as pain therapeutics., Linked Articles: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc., (© 2018 The British Pharmacological Society.)

Although muscarinic acetylcholine receptors (mAChRs) and NMDA receptors (NMDARs) are important for synaptic plasticity, learning and memory, the manner in which they interact is poorly understood. We found that stimulation of muscarinic receptors, either by an agonist or by the synaptic release of acetylcholine, led to long-term depression (LTD) of NMDAR-mediated synaptic transmission. This form of LTD involved the release of Ca2+ from IP₃-sensitive intracellular stores and was expressed via the internalization of NMDARs. Our results suggest that the molecular mechanism involves a dynamic interaction between the neuronal calcium sensor protein hippocalcin, the clathrin adaptor molecule AP2, the postsynaptic density enriched protein PSD-95 and NMDARs. We propose that hippocalcin binds to the SH3 region of PSD-95 under basal conditions, but it translocates to the plasma membrane on sensing Ca2+; in doing so, it causes PSD-95 to dissociate from NMDARs, permitting AP2 to bind and initiate their dynamin-dependent endocytosis.