This review examines the role glycerophospholipids (PL) in dairy cow health, with specific focus on phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI) and phosphatidylserine (PS). Increasing parity of cows is associated with lower concentrations of plasma PL that contain very long-chain omega-3 fatty acids, including docosahexaenoic acid and eicosapentaenoic acid, which are precursors for prostaglandin synthesis, and have anti-inflammatory roles. Low concentrations of these PL could plausibly contribute to the increased risk of disease, reproductive failure and mortality in older cows. The bioavailability and metabolism of fatty acids may differ among supplements that are predominately neutral lipids, such as triacylglycerol-rich oils, and those bound to PL including pasture, whole or ground oilseeds and fish meal. Hepatic lipidosis can occur during the transition period if there is insufficient very-low density lipoproteins (VLDL) production in the liver to transport lipids into blood circulation. The PC are the primary PL of VLDL and are produced by two main pathways in the liver, the cytidine diphosphate-choline pathway that uses choline as a substrate, and the PE N-methyltransferase pathway that uses PE and methyl-donors as substrates. Co-supplementation strategies that target both pathways may increase PC production over a one-pathway supplementation strategy. The PIs are phosphoinositides precursors, which have broad physiological roles including regulating inflammatory processes and may offer targets for novel treatment and management of disease. Both the PI and PE are precursors to endocannabinoids, important regulators of energy metabolism, immune function and reproduction in mammals. Early findings on the endocannabinoid system in transition dairy cows yielded results that diverge from non-ruminant models. The PS expression on cytoplasmic membranes signals apoptosis, coagulation and contributes to sperm–oocyte recognition. As lipidomic diagnostics become increasingly available, understanding the metabolism of PL will continue to develop and promises to offer novel strategies for optimising cattle health and longevity.

The endocannabinoid (EC) system in the central and peripheral nerves plays a crucial role in various physiological processes, including feeding behaviour and energy metabolism. In particular, gut ECs stimulate appetite, and excessive activation of the system can induce hedonic eating, leading to obesity. Previous studies have indicated elevation of gut EC levels in high-fat diet-induced or genetically obese rodents. The present study aimed to expand our understanding of gut ECs involved in feeding behaviour during obesity by characterising the profiles of arachidonic metabolites, including ECs, in the gut and by examining their impact on feeding behaviour in KK-Ay mice, an obesity model established by crossing diabetic KK mice with lethal yellow (Ay) mice. KK-Ay mice exhibit hyperphagia compared with lean mice under either free-feeding condition or refeeding condition after 24 h of food deprivation. Meal pattern analyses revealed that hyperphagia in KK-Ay mice was primarily due to higher meal frequency rather than meal size or interval, suggesting a defect in hunger control. In addition, levels of EC and other arachidonic acid metabolites such as prostaglandin E2 and F2α were elevated in KK-Ay mice. Pharmacological blockade of the peripheral cannabinoid receptor 1 (CB1) and diacylglycerol lipase, but not N-acyl phosphatidylethanolamine phospholipase D, reduced food intake, as did treatment with cyclo-oxygenase-2 inhibitors. These findings suggest that intestinal 2-arachidonoyl glycerol-dependent CB1 activation contributes to hyperphagic behaviour in KK-Ay mice and PGs are involved in feeding control.

Cannabis has a long history as a medicine and was a part of medical practice until the late 19th century. The discovery of cannabidiol (CBD) and ∆9-tetrahydrocannabinol (THC) in the mid-20th century, and then the various components of the endocannabinoid system (ECS) over the following decades has again brought cannabis back into the public eye as a potential therapeutic agent. At present, cannabis is being used in the community across the world for both recreational and medical purposes. In the case of medical usage, it may be prescribed by a medical doctor or purchased either legally or illicitly for medical purposes such as symptom relief. Evidence for cannabis as a medicine is still an emerging field, and while potential mechanisms of action for a variety of conditions have been elucidated, including cancer, epilepsy, and chronic pain, high-quality randomized controlled trials in humans are still lacking. Despite popular beliefs, cannabis, like all other medicines, has potential benefits and harms, and long-term consumption of cannabis, even for medical reasons, may not be risk-free. In addition, consumption via modes of administration such as smoking or using a bong may increase the risk of negative health outcomes.

Cannabis is well established to impact affective states, emotion and perceptual processing, primarily through its interactions with the endocannabinoid system. While cannabis use is quite prevalent in many individuals afflicted with psychiatric illnesses, there is considerable controversy as to whether cannabis may worsen these conditions or provide some form of therapeutic benefit. The development of pharmacological agents which interact with components of the endocannabinoid system in more localized and discrete ways then via phytocannabinoids found in cannabis, has allowed the investigation if direct targeting of the endocannabinoid system itself may represent a novel approach to treat psychiatric illness without the potential untoward side effects associated with cannabis. Herein we review the current body of literature regarding the various pharmacological tools that have been developed to target the endocannabinoid system, their impact in preclinical models of psychiatric illness and the recent data emerging of their utilization in clinical trials for psychiatric illnesses, with a specific focus on substance use disorders, trauma-related disorders, and autism. We highlight several candidate drugs which target endocannabinoid function, particularly inhibitors of endocannabinoid metabolism or modulators of cannabinoid receptor signaling, which have emerged as potential candidates for the treatment of psychiatric conditions, particularly substance use disorder, anxiety and trauma-related disorders and autism spectrum disorders. Although there needs to be ongoing clinical work to establish the potential utility of endocannabinoid-based drugs for the treatment of psychiatric illnesses, the current data available is quite promising and shows indications of several potential candidate diseases which may benefit from this approach.

Cannabidiol (CBD) has been generating increasing interest in medicine due to its therapeutic properties and an apparent lack of negative side effects. Research has suggested that high dosages of CBD can be taken acutely and chronically with little to no risk. This review focuses on the neuroprotective effects of a CBD, with an emphasis on its implications for recovering from a mild traumatic brain injury (TBI) or concussion. CBD has been shown to influence the endocannabinoid system, both by affecting cannabinoid receptors and other receptors involved in the endocannabinoid system such as vanilloid receptor 1, adenosine receptors, and 5-hydroxytryptamine via cannabinoid receptor-independent mechanisms. Concussions can result in many physiological consequences, potentially resulting in post-concussion syndrome. While impairments in cerebrovascular and cardiovascular physiology following concussion have been shown, there is unfortunately still no single treatment available to enhance recovery. CBD has been shown to influence the blood brain barrier, brain-derived neurotrophic factors, cognitive capacity, the cerebrovasculature, cardiovascular physiology, and neurogenesis, all of which have been shown to be altered by concussion. CBD can therefore potentially provide treatment to enhance neuroprotection by reducing inflammation, regulating cerebral blood flow, enhancing neurogenesis, and protecting the brain against reactive oxygen species. Double-blind randomized controlled trials are still required to validate the use of CBD as medication following mild TBIs, such as concussion.

The endocannabinoid (EC) system consists of two main receptors: cannabinoid type 1 receptor cannabinoid receptors are found in both the central nervous system (CNS) and periphery, whereas the cannabinoid type 2 receptor cannabinoid receptor is found principally in the immune system and to a lesser extent in the CNS. The EC family consists of two classes of well characterised ligands; the N-acyl ethanolamines, such as N-arachidonoyl ethanolamide or anandamide (AEA), and the monoacylglycerols, such as 2-arachidonoyl glycerol. The various synthetic and catabolic pathways for these enzymes have been (with the exception of AEA synthesis) elucidated. To date, much work has examined the role of EC in nociceptive processing and the potential of targeting the EC system to produce analgesia. Cannabinoid receptors and ligands are found at almost every level of the pain pathway from peripheral sites, such as peripheral nerves and immune cells, to central integration sites such as the spinal cord, and higher brain regions such as the periaqueductal grey and the rostral ventrolateral medulla associated with descending control of pain. EC have been shown to induce analgesia in preclinical models of acute nociception and chronic pain states. The purpose of this review is to critically evaluate the evidence for the role of EC in the pain pathway and the therapeutic potential of EC to produce analgesia. We also review the present clinical work conducted with EC, and examine whether targeting the EC system might offer a novel target for analgesics, and also potentially disease-modifying interventions for pathophysiological pain states.

The presence of an active and functioning endocannabinoid (EC) system within cardiovascular tissues implies that this system has either a physiological or pathophysiological role (or both), and there is a substantial literature to support the notion that, in the main, they are protective in the setting of various CVD states. Moreover, there is an equally extensive literature to demonstrate the cardio- and vasculo-protective effects of n-3 long-chain (LC)-PUFA. It is now becoming evident that there appears to be a close relationship between dietary intervention with n-3 LC-PUFA and changes in tissue levels of EC, raising the question as to whether or not EC may, at least in part, play a role in mediating the cardio-and vasculo-protective effects of n-3 LC-PUFA. This brief review summarises the current understanding of how both EC and n-3 LC-PUFA exert their protective effects in three major cardiovascular disorders (hypertension, atherosclerosis and acute myocardial infarction) and attempts to identify the similarities and differences that may indicate common or integrated mechanisms. From the data available, it is unlikely that in hypertension EC mediate any beneficial effects of n-3 LC-PUFA, since they do not share common mechanisms of blood pressure reduction. However, inhibition of inflammation is an effect shared by EC and n-3 LC-PUFA in the setting of both atherosclerosis and myocardial reperfusion injury, while blockade of L-type Ca2+ channels is one of the possible common mechanisms for their antiarrhythmic effects. Although both EC and n-3 LC-PUFA demonstrate vasculo- and cardio-protection, the literature overwhelmingly shows that n-3 LC-PUFA decrease tissue levels of EC through formation of EC–n-3 LC-PUFA conjugates, which is counter-intuitive to an argument that EC may mediate the effects of n-3 LC-PUFA. However, the discovery that these conjugates have a greater affinity for cannabinoid receptors than the native EC provides a fascinating avenue for further research into novel approaches for the treatment and prevention of atherosclerosis and myocardial injury following ischaemia/reperfusion.

Fatty acid amide hydrolase (FAAH) is the degradative enzyme for anandamide (AEA), an endogenous ligand for the vanilloid receptor (TRPV1) and cannabinoid receptor 1. As FAAH and TRPV1 are integral membrane proteins, FAAH activity could modulate the availability of AEA for TRPV1 activation. Previous studies in this laboratory reported an extensive endocannabinoid system in goldfish retina. Immunocytochemistry was used to determine the relative distributions of FAAH-immunoreactivity (IR) and TRPV1-IR in goldfish retina. Here, we show the first example in an intact neural system in which TRPV1-IR co-localizes in subpopulations of FAAH-immunoreactive neurons, in this case amacrine cells. These cells are rare and consist of three subtypes: 1. ovoid cell with granular-type dendrites restricted to sublamina a, 2. pyriform cell with smooth processes in sublamina b, and 3. fusiform cell with smooth processes that project to sublaminae a and b. The varied appearances of reaction product in the dendrites suggest different subcellular localization of TRPV1, and hence function of FAAH activity regarding TRPV1 stimulation among the cell types. Ovoid and pyriform amacrine cells, but not fusiform cells, labeled with GAD-IR and constituted subsets of GABAergic amacrine cells. TRPV1 amacrine cells, though rare, are represented in the ON, OFF and ON/OFF pathways of the retina. As TRPV1 stimulation increases intracellular calcium with numerous downstream effects, co-localization of TRPV1 and FAAH suggests an autoregulatory function for anandamide. Due to the rarity of these cells, the three vanilloid amacrine cell types may be involved in global effects rather than feature extraction, for example: sampling of ambient light or maintaining homeostasis.

GABAergic amacrine cells, cultured from embryonic chick retina, display spontaneous mini frequencies ranging from 0–4.6 Hz as a result of the release of quanta of transmitter from both synapses and autapses. We show here that at least part of this variation originates from differences in the degree to which endocannabinoids, endogenously generated within the culture, are present at terminals presynaptic to individual cells. Though all cells examined scored positive for cannabinoid receptor type I (CB1R), only those showing a low initial rate of spontaneous minis responded to CB1R agonists with an increase in mini frequency, caused by a Gi/o-mediated reduction in [cAMP]. Cells displaying a high initial rate of spontaneous minis, on the other hand, were unaffected by CB1R agonists, but they did show a rate decrease with CB1R antagonists. Such a regulation of spontaneous transmitter release by endocannabinoids might be important in network maintenance in amacrine cells and other inhibitory interneurons.