Our pets have CB-1 receptors in the brain and CB-2 receptors in the body, their natural messenger cannabinoids are anandamide and 2-AG, anandamide's. Let's talk about the endocannabinoid system in cats and dogs and how CBD oil works with this system to keep dogs and cats — and humans. Just like their human companions, animals like dogs, cats, and horses have an endocannabinoid system responsible for maintaining balance.
Have Endocannabinoid Systems Dogs
B Prominent intracytoplasmic staining of large foamy macrophages gitter cells with CB2 antibody. C Severe diffuse infiltration of the subarachnoidal space with strongly CB2 labeled inflammatory cells. D The CB2 positive leukocyte population mainly consists of macrophages and fewer lymphocytes and plasma cells.
In the present study, it could be proven that the endocannabinoid system is involved in two different canine inflammatory CNS diseases. In the last decades, evidence has shown that the functions of the endocannabinoid system are not limited to the CNS but are involved in the whole organism of mammals [ 42 ].
Although the endocannabinoid system has been widely studied for its involvement in regulation of neurotransmission [ 6 , 43 , 44 ], increasing evidence supports its involvement in immunomodulation [ 5 , 15 , 18 , 19 , 23 , 25 ] and neuroprotection [ 45 — 47 ]. CB receptors are expressed by leukocytes [ 14 , 20 ], mice with deficient CB receptors display an altered, usually more severe, inflammatory phenotype [ 18 ].
Therefore, the enhancement of the endocannabinoids or the activation of cannabinoid receptors may have valuable therapeutic effects [ 48 ]. In accordance with previous studies in other species [ 39 , 49 , 50 ] and in dogs [ 34 ], overall CSF levels of AEA were in the picomolar range pM and of total AG in nanomolar range nM.
Levels of 2-AG in unstimulated tissues and cells are usually much higher than those of AEA, and are in principle sufficient to permanently activate both cannabinoid receptors [ 11 , 51 ]. Interestingly, 2-AG spontaneously isomerizes to its biologically inactive form 1-AG, by acyl migration [ 39 ]. This phenomenon is of particular importance for quantification of 2-AG. Therefore, both 1-AG and 2-AG were measured and summarized to total AG, since such calculation has been proven to be more accurate [ 39 ].
Spirocercosis in dogs has been mostly associated with the presence of esophageal granulomas [ 52 ], and although the disease is frequently subclinical, esophageal dysphagia is considered the clinical hallmark [ 52 ]. Aberrant migration of the worm to unusual anatomical structures results in atypical clinical signs [ 28 ]. Neurological deficits presented in the IS group are similar to previous findings of extradural and intraspinal Spirocerca lupi migration [ 30 , 53 ].
Although the reason for aberrant migration is still unclear [ 28 ], it possibly occurs via the intercostal arteries, originating from the thoracic aorta, through their spinal branches and into the extradural space [ 53 ]. The worm possibly penetrates the dura and pia mater to enter the spinal cord parenchyma [ 29 ]. Eosinophils play a major role in dealing with elimination of parasites [ 54 ]. CSF samples from the IS group showed mixed neutrophilic pleocytosis with moderate to severe eosinophilia and foamy macrophages.
CSF findings agree with previous CSF analysis in single cases of dogs with intraspinal migration [ 29 , 55 ]. This disease was chosen for the current study, to include a canine population with inflammatory CNS disease and eospinophilia in CSF samples to compare with SRMA dogs and a clear neutrophilic pleocytosis. ECs are lipids that are able to modulate cell migration through specific receptors [ 1 ]. Both in vitro and in vivo studies have shown CB2 receptor involvement in eosinophil migration [ 1 ], which is supported by the current study.
Interestingly, another study showed that 2-AG induces migration of eosinophils in a dose-dependent manner and that the concentration required appears to be pathophysiologically relevant [ 59 ]. Since 2-AG is a fully effective CB2 agonist [ 60 ], several studies have focused on the immunomodulatory effects of 2-AG, while information of AEA in this aspect is lacking.
Moreover, 2-AG has been proven to be produced and released from platelets [ 61 ], macrophages [ 61 , 62 ], endothelial cells [ 63 , 64 ], glial cells [ 65 ], macrophages [ 62 ] and adipocytes [ 66 ].
The main 2-AG effects on neutrophils seem to be independent of CB activation in humans [ 67 ]. Although 2-AG does not seem to have a chemotactive effect on neutrophils, it has been proven to activate them [ 67 ]. Increased levels of AEA have been found in CSF in dogs with epilepsy and correlated with disease severity and duration [ 34 ]. AEA seems to regulate seizure threshold in epilepsy [ 34 ]. Moreover, dogs suffering from SRMA in the acute phase and those with Intraspinal Spirocercosis showed significantly higher concentrations of total AG than healthy controls in serum.
SRMA is a systemic immune-mediated disorder [ 32 ]. Even when the main lesions are found in the cervical leptomeninges, SRMA causes systemic inflammatory lesions of the vessels of the heart and intestine [ 70 , 71 ]. Albeit migration and persistence of larvae or adult worms are responsible for intraspinal lesions in Spirocercosis [ 72 ], the tissue damage is not restricted to the spinal cord in these dogs.
The systemic nature of both diseases might explain the increased levels of both ECs in serum. Strong CB2 immunoreaction was found in leukocytes within the marginal zone of splenic follicles and hepatocytes and Kupffer cells as previously described [ 20 , 73 , 74 ].
Previous studies performed in healthy dog tissues have shown strong CB2 immunoreaction in B cell zones of lymphoid follicles, and diffuse immunoreaction in cells in the dermis, including perivascular cells with mast cell morphology, fibroblasts, and endothelial cells [ 75 ]. Moreover, slight to moderate immunoreaction was found in the neurons in the ventral and dorsal horns. CB2 receptor expression, was initially thought to occur only in peripheral tissues mostly immune organs and cells [ 1 , 3 , 14 , 20 ].
However, several studies have demonstrated CB2 expression in microglia [ 76 — 79 ], oligodendrocytes, astrocytes and endothelial cells in the healthy CNS [ 80 — 83 ]. The expression of CB2 receptors in neurons remains controversial [ 84 ]. Nonetheless, functional CB2 receptors have been found in neuronal subpopulations in cerebellum, brainstem, cerebral cortex [ 85 — 88 ], although less concentrated than CB1 receptors [ 85 ].
However, CB2 expression depended on lesion severity and was even downregulated in glial cells in regions with severe necrosis and cell loss. Interestingly, CB2 positive glial cells underwent changes in the morphology in SRMA and IS toward a round morphology showing less and shorter cytoplasmic extensions.
In other studies, upregulation of CB2 receptor expression in microglia, macrophages, neurons and astrocytes upon activation has been demonstrated [ 5 , 86 , 89 , 90 ]. The understanding of the role of AEA in inflammation is particularly important regarding its interaction with microglia [ 93 ]. Depending on the relative quantities of 2-AG and AEA that accumulate in certain CNS areas, their competition at CB2 receptors may determine the extent to which CB2 receptors will regulate microglial cell behavior and phenotype, towards a M1 pro-inflammatory phenotype or a M2 anti-inflammatory phenotype [ 93 ].
Indeed, CB2 can be induced on demand during early inflammatory events and it has been linked to attenuation of pro-inflammatory cytokine production by microglia, counteracting neuronal damage [ 1 , 42 ]. On the other hand, upon CB2 activation microglia have also been shown to cause pro-inflammatory actions by eliciting cell migration [ 65 ].
CB2 was strongly expressed on infiltrating leukocytes i. Interestingly, arachnoid mesothelial-like cells and cells in the pia matter near the lesions expressed also CB2. The level of expression, however, is dependent on the activation state of the cell and the type of stimuli [ 20 ]. CB2 receptor expression in macrophages has been proven to be modulated upon activation. CB2 is detected at low levels in resting cells, while it is present at high levels in activated macrophages [ 5 , 89 ].
Endocannabinoids have been shown to downregulate inflammation in numerous experimental models [ 20 — 26 ]. Activation of the cannabinoid system has been linked to decreased inflammatory cell recruitment and enhanced anti-inflammatory cytokine production [ 18 ]. Evidence shows that exogenous application of AEA and 2-AG exerts anti-inflammatory effects by decreasing the production of inflammatory mediators [ 19 ].
The rapid activation of cannabinoid receptors by endocannabinoids after SCI is thought to be an endogenous protective response [ 48 ]. In another study, Arevalo-Martin and colleagues showed that one single injection of 2-AG 30 minutes after the induction of the lesion, protects the white matter from secondary damage, reducing the lesion expansion and myelin loss [ 46 ], while CB1 and CB2 antagonists increased myelin damage [ 48 ].
Although several studies support endocannabinoids as anti-inflammatory mediators, several in vitro and in vivo experiments have reported a pro-inflammatory role of the endocannabinoid system in the development of inflammation [ 18 ]. These pro-inflammatory effects have been associated with enhanced leukocyte recruitment and activation, production of reactive oxygen species and release of pro-inflammatory cytokines [ 1 , 58 , 59 , 65 , 95 , 96 ]. Nonetheless, most of these pro-inflammatory effects attributed to endocannabinoids involve 2-AG, but not AEA [ 18 ].
Indeed, AEA is a potent anti-inflammatory endocannabinoid and acts practically on all cell subsets except natural killer cells and B cells, while 2-AG exerts both pro- and anti-inflammatory effects which seem to be strictly dependent on cell type [ 97 ]. The endocannabinoid system response in inflammation is indeed dependent on type and state of the disease. While CB2 receptor activation in general mediates immunosuppressive effects limiting inflammation and being associated with tissue damage in several pathological conditions, in some disease states activation of the CB2 receptor may enhance or even trigger tissue damage [ 84 ].
In physiological conditions, the endocannabinoid production by neurons is high and in microglia low [ 98 ]. In diseased CNS tissue with an activated immune system the cell-specific expression profile of cannabinoid receptors changes, resulting in higher expression of CB2 receptors in activated microglia [ 16 , 98 ], which can secondarily activate astrocytes leading to further induction of expression of inflammatory factors [ 5 ]. Such an upregulation on activated microglia cells was also seen in the evaluated canine inflammatory CNS diseases and could be the reason for the excessive immune response in SRMA.
As the disorder progresses, the blood brain barrier BBB becomes partially disrupted and blood macrophages, B cells, T cells, natural killer cells and other infiltrating leukocytes start upregulating CB2 [ 5 , 42 , 93 ].
Although the initial enhancement of the endocannabinoid system has been proven to have an endogenous protective response and attempts to control inflammation, as the disease progresses, a later dysregulation of the endocannabinoid system during neuroinflammation leads to increased CB2 receptor expression, excessive endocannabinoid production leading to an exacerbated inflammatory response.
Thus, both CB2 agonists and antagonists might be beneficial in counteracting the inflammatory consequences depending on the disease phase [ 42 ]. The present study revealed an upregulated endocannabinoid system in canines with inflammatory CNS diseases, highlighting the endocannabinoid system as a potential target for treatment of inflammatory CNS diseases.
Furthermore, dogs with eosinophilic pleocytosis showed higher level of ECs than those with neutrophilic pleocytosis. Such an upregulation of AEA and 2-AG together with an overexpression of CB2 receptors may indicate a dysregulation of the endocannabinoid system and may be involved in the inflammatory response. Therefore, the development of new anti-inflammatory treatment strategies in canine CNS inflammation should involve the EC system.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Center for Biotechnology Information , U. Published online Feb 6. Author information Article notes Copyright and License information Disclaimer. The authors have declared that no competing interests exist. Received Nov 25; Accepted Oct This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract Endocannabinoids ECs are involved in immunomodulation, neuroprotection and control of inflammation in the central nervous system CNS. Introduction In the last decades an increasing interest emerged in the use of derivatives of the plant Cannabis sativa and Cannabis indica commonly known as Marijuana to treat a variety of disorders both in humans and animals.
Materials and methods Serum and cerebrospinal fluid samples A total of 41 cerebrospinal fluid CSF samples and 36 serum samples were retrospectively analyzed. Animals and tissue samples A total of 8 dogs with SRMA, 2 dogs with confirmed IS, and 5 healthy controls were included in the immunohistochemical evaluation. Open in a separate window. Immunohistochemistry Immunohistochemistry IHC was performed using the avidin-biotin-peroxidase complex ABC method as previously described [ 36 , 40 ].
Spatiotemporal localization of CB2 receptors in healthy dogs Cannabinoid receptor type 2 immunoreaction was detected in spleen and liver samples of healthy dogs serving as positive controls. CB2 immunoreaction in spleen and liver of a healthy control dog. Spatiotemporal localization of CB2 receptors in IS lesions On thoracic spinal cord sections of dogs with IS, strong CB2 expressing leucocytes, predominantly lymphocytes, plasma cells and macrophages but also eosinophils and neutrophils were found adjacent to the parasite or the parasite tracts, accompanied by severe, multifocal to coalescing necrosis and hemorrhage but also within the subarachnoidal space Fig 5B, 5C and 5D.
Immunohistochemistry of anti-CB2 antibody in spinal cord lesions of dogs with intraspinal spirocercosis. Discussion In the present study, it could be proven that the endocannabinoid system is involved in two different canine inflammatory CNS diseases. Conclusions The present study revealed an upregulated endocannabinoid system in canines with inflammatory CNS diseases, highlighting the endocannabinoid system as a potential target for treatment of inflammatory CNS diseases.
Data Availability All relevant data are within the paper. Miller AM, Stella N. CB2 receptor-mediated migration of immune cells: British journal of pharmacology. Cannabinoids as novel anti-inflammatory drugs. The pharmacology of cannabinoid receptors and their ligands: International journal of obesity The endocannabinoid system and its therapeutic exploitation. Nature reviews Drug discovery.
Emerging role of the cannabinoid receptor CB2 in immune regulation: The external stimulation from CBD is causing some big excitement in the medical world today. You may have read about how people are already using medicinal cannabis and other cannabinoids such as CBD to treat various illnesses. Some well educated pet owners are also using CBD to treat their pets as well.
The Endocannabinoid system was first discovered by scientists who were carrying out research into why cannabis has the effect on people that it does, hence the name Endocannabinoid System. Cannabinoid is the term used to describe the compounds that are responsible for activating the endocannabinoid system.
The Endocannabinoid system is the biological system that is responsible for the effects that cannabis has, both the psychosocial and physical.
The Endocannabinoid system in dogs has recently become the subject of much scientific research, because of the many effects that it has on the body and the potential for using the stimulation of the system to treat disease. Scientists understand the basic functioning of the endocannabinoid system, but researchers are uncovering more new exciting therapeutic uses of the system everyday.
Cannabinoid receptors are located on the surface of cells and they monitor the conditions outside of the cell. They transmit what they detect to the inside of the cell and that triggers the appropriate cellular response. There are several types of cannabinoid receptors in the endocannabinoid system in dogs and other animals, but the two major ones are known as CB1 and CB2. CB1 receptors are found throughout the body, but are more concentrated in the spinal cord and the brain than anywhere else.
CB1 receptors in the brain are found in the regions of the brain that control certain behaviors. For example, CB1 receptors have been found in the hypothalamus, which is the part of the brain that is responsible for regulating appetite. There are also CB1 receptors in the region of the brain that is related to emotions and memory, which is called the amygdala. CB1 receptors that are believed to able to control pain have also been identified in the nerve endings. CB2 receptors are found mainly in the nervous system and in the immune system.
The activation of CB2 receptors has been shown to regulate inflammation, a property that is believed to be responsible for many of the known therapeutic effects of CBD.
Cannabinoids are compounds that occur naturally in the cannabis plant. There have been cannabinoids identified in the cannabis plant to date. They may be of value in treatment of cancer, nausea and vomiting, pain, epilepsy, inappetence, and inflammatory bowel disease 1 , 2. Cannabinoids are used in several countries in the palliative therapy of patients with cancer because it inhibits some side-effects due to chemotherapy and radiotherapy.
In particular they are used to inhibit vomiting and nausea, combat pain, and stimulate the appetite. They are also used for treatment of epilepsy that is refractory to conventional treatments. There are studies in vitro and in animal models that indicate that cannabinoids also possess antitumor activity 2 ; however, concerns have been expressed that cannabinoids may exert an adverse effect on cancers because of their ability to suppress anti-tumor immunity.
A number of synthetic analogs of cannabinoids found in marijuana have been developed in an effort to obtain potent anti-inflammatory activity while avoiding the psychotropic activity of marijuana.
These products offer biochemical uniformity, a reliable delivery system, and relief of symptoms. However, some argue that herbal synergy among components of the plant may be important. In animals, there is much less information on the effects of cannabinoids. Researchers have concentrated on the toxic effects on dogs, in particular.
There are less than 60 papers in PubMed on marijuana in dogs and they are almost all on toxic effects — due to accidental ingestion, experimental administration to study toxicity, or ingestion of synthetic cannabinoids. The information on toxicity is likely to gain increasing importance as legal access to marijuana comes into effect in Canada and spreads across the United States. In Colorado, a State with legalized marijuana for medical use, the frequency of marijuana toxicosis in dogs at 2 veterinary hospitals increased 4-fold over a 5-year period to 3.
The authors found a positive correlation between the increased number of cases of marijuana toxicosis in dogs and the increased number of medical marijuana licenses issued.
Endocannabinoid System in Dogs & Cats Explained
Anxiety, joint pain, skin conditions, cancer if your dog has any of these health concerns, Dogs have the same endocannabinoid system (ECS) as humans. Additionally, 3 serum and 7 CSF samples from seven dogs affected with IS presented to the Koret School of Veterinary. Endogenous cannabinoids use these receptors as part of a signaling system that Dogs are reported to have a higher number of cannabinoid receptors in the.