Endocannabinoid and nitric oxide interactions in the brain

 Of course your competent? doctor has been working on understanding these individually in getting you recovered, right? NO? So, you DON'T have a functioning stroke doctor, do you?

Endocannabinoid (13 posts to November 2013)

nitric oxide (116 posts to March 2011)

Endocannabinoid and nitric oxide interactions in the brain

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https://doi.org/10.1016/j.neuroscience.2025.02.006

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Highlights

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  Endocannabinoids modulate nitric oxide synthesis and signaling.
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  Nitric oxide influences endocannabinoid production, metabolism, and signaling.
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  Targeting both eCB and NO pathways could lead to new therapeutic interventions.

Abstract

Endogenous cannabinoids (eCBs) and nitric oxide (NO) are classical retrograde transmitters that modulate synaptic function throughout the brain. Although much is known about how these signals individually control synaptic activity and behavior, accumulating evidence suggests that they can also interact in a multitude of ways in the brain and beyond. Here, we present evidence for interactions between endogenous cannabinoids and nitric oxide in the brain. Specifically, we describe the effects of eCBs on NO synthesis and downstream signaling and in turn, we discuss how NO alters eCB levels and signaling pathways. We also provide an overview on how these transmitters work together or in opposition at the same synapses. This information will further our understanding of how two important, ubiquitous signals interact in the brain to ultimately affect neural function and behavior. Because eCBs and NO are involved in many physiological and pathological phenomena, understanding how these transmitters interact in non-human animals could lead to important therapeutic interventions in humans that potentially target both systems.

Introduction

Synaptic function is regulated by a multitude of neurotransmitters including presynaptic amino acids and peptides, gliotransmitters from neighboring astrocytes, and postsynaptic retrograde signals such as gaseous nitric oxide (NO) and the lipid-based endogenous cannabinoids (eCBs). Retrograde signals have received a lot of attention in recent years due to their ability to modulate synaptic transmission and ultimately regulate the strength of the inputs they receive (Regehr et al., 2009). These signals are made on demand in response to a stimulus, freely diffuse across the membrane, and travel relatively short distances to act on presynaptic axon terminals to modulate synaptic transmission. Of the retrograde transmitters, eCBs and NO are nearly ubiquitous signals that regulate neuronal function throughout the brain. These signals can also act in non-classical (ex. anterograde, via glial cells, etc.) ways and have been reported to interact with each other to modulate physiological and behavioral phenomena.

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Section snippets

Endocannabinoids

Endocannabinoids are lipid-based transmitters that are synthesized de novo, largely in response to a rise in intracellular calcium. The two main eCBs, N-arachidonoylethanolamine (anandamide) and 2-arachidonyl glycerol (2-AG) are synthesized from membrane lipids: anandamide is derived from N-acyl-phosphatidylethanolamine (NAPE) via a reaction catalyzed by phospholipase D (Petrocellis et al., 2004). The formation of NAPE from phosphatidylethanolamine and phospholipids is dependent on Ca²⁺ and is

Nitric oxide

NO is a gaseous neuromodulator that is synthesized from the precursor molecule L-arginine via a reaction catalyzed by nitric oxide synthase (NOS), a calcium/calmodulin-dependent enzyme that is expressed in three isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS). nNOS is the predominant source of NO in the brain (Alderton et al., 2001, Feil and Kleppisch, 2008, Förstermann and Sessa, 2012). This isoform is physically coupled to N-methyl-D-aspartic acid receptors

Endocannabinoids and nitric oxide

Both eCBs and NO are nearly ubiquitous signals and therefore are often synthesized in, and capable of modulating, the same neurons (Azad et al., 2001). Thus, NO and eCBs not only individually control neurotransmitter release, but they also interact with one another to modulate synaptic function. Because these signals are implicated in numerous physiological processes such as food intake (Flier and Maratos-Flier, 1998, Jo et al., 2005, Pagotto et al., 2006, Bellocchio et al., 2010), pain

Endocannabinoids modulate NO synthesis

There is compelling evidence that the eCB system can modulate NO signaling in the nervous system, either through direct production of NO or via downstream signaling pathways. Early invertebrate studies reported that eCBs could trigger the synthesis of NO in a CB1R-dependent manner. In the leech, Hirudo medicinalis and mussel, Mytilus edulis, anandamide regulates dopamine neurotransmission via a process that requires CB1R activation and NO synthesis (Stefano et al., 1997). Another study showed

Endocannabinoids modulate the downstream NO signaling pathway

Accumulating evidence suggests that eCBs not only control NO synthesis, but they are also capable of modulating the signaling pathway downstream of NO production. Following synthesis, NO typically activates soluble guanylate cyclase (sGC), leading to an increase in cGMP, activation of protein kinase G, and phosphorylation of an array of downstream targets. Support for eCB-induced modulation of the NO signaling pathway stems from work illustrating that eCBs can prevent the effects of NO donors

NO modulates eCB levels

The evidence we have presented thus far suggests that eCBs modulate nitric oxide synthesis and signaling, but the opposite also appears to be true; NO can affect the synthesis and breakdown of eCBs, and their signaling pathways. There are limited reports that NO can affect eCB synthesis in the brain. Borgquist et al. found that activation of nNOS in the hypothalamic arcuate nucleus in guinea pigs blocked eCB-mediated short-term plasticity (Borgquist et al., 2015). The authors proposed that nNOS

NO modulates the downstream eCB signaling pathway

NO can modulate the expression of cannabinoid receptors or downstream signaling in the brain. Evidence from knockout studies indicates that nNOS knockout mice had increased CB1R levels in the cerebellum early in development (post-natal day 7) but CB1R levels were subsequently lower in nNOS knockout mice later in development compared to wild type mice (Tellios et al., 2022). When nNOS knockout cell cultures were treated with an NO-donor, CB1R expression was lower after 7 days, mirroring the

More complex interactions between eCBs and NO

Synergistic effects of eCBs and NO.

It is well established that eCBs can alter NO synthesis and signaling and that NO can in turn modulate eCB production, signaling, and breakdown. In addition to these effects, there appear to be synergistic actions of eCBs and NO that cannot be explained by one signal simply influencing the other. Indeed, these retrograde signals can be synthesized in the same neurons (Crosby et al., 2011, Zou et al., 2015) by the same stimulus (a rise in intracellular calcium)

Future directions

Although our understanding of eCB and NO signaling has greatly advanced in the last three decades, less is known about how these two signals interact in the brain to modulate synaptic function and behavior. One major challenge is deciphering whether one transmitter influences the other via changes in synthesis or downstream signaling. A better understanding of the exact localization of the eCB and NO machinery (i.e. membrane vs intracellular, pre vs postsynaptic, neuronal vs astrocytic, etc.)