A possible role for the endocannabinoid system in the neurobiology of depression

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“The present review synthetically describes the currently advanced hypotheses for a neurobiological basis of depression, ranging from the classical monoaminergic to the more recent neurotrophic hypothesis. Moreover, the Authors review the available preclinical and clinical evidence suggesting a possible role for the endocannabinoid system in the physiopathology of depression. Indeed, in spite of the reporting of conflicting results, the pharmacological enhancement of endocannabinoid activity at the CB1 cannabinoid receptor level appears to exert an antidepressant-like effect in some animal models of depression. On the contrary, a reduced activity of the endogenous cannabinoid system seems to be associated with the animal model of depression, namely the chronic mild stress model. Moreover, a few studies have reported an interaction of antidepressants with the endocannabinoid system. “

“The endocannabinoid system”

“A detailed description of the endocannabinoid system is beyond the scope of this paper. Thus, in this section we briefly describe those components of the endocannabinoid system that act as targets for the pharmacological interventions aimed at determining the activity of the endocannabinoid system.”

“The term “endocannabinoid system” refers to the recently discovered neuromodulator system comprising cannabinoid receptors (which represent the receptors of Tetrahydrocannabinol (THC), the major active component of cannabis) and their endogenous ligands.”

“To date, two types of cannabinoid receptors have been identified: CB1 and CB2 receptors. These receptors belong to the superfamily of G protein coupled receptors, the CB1 receptor is widely distributed in the terminals of neurons, while the CB2 receptor is extensively expressed throughout the immune system. However, it has recently been reported that these receptors are present also in the brain.”

“No clinical trials carried out using cannabinoids in the treatment of affective disorders have been published to date, although anecdotal reports have described both antidepressant and antimanic properties of cannabis.”

“Indeed, pharmacological manipulations of the endocannabinoid system have elicited antidepressant-like effects in animal models of depression. Moreover, some animal models of depression seem to be associated to alterations in the endocannabinod system.”

“Although no clinical trials performed using cannabinoids in the treatment of affective disorders have been published to date, anecdotal reports have described both antidepressant and antimanic properties of cannabis”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2169225/

Is there a role for the endocannabinoid system in the etiology and treatment of melancholic depression?

Abstract

“With advances in basic and clinical neuroscience, many gaps have appeared in the traditional monoamine theory of depression that have led to reformulation of the hypotheses concerning the neurobiology of depression. The more recent hypotheses suggest that melancholic depression is characterized by central glucocorticoid resistance that results in hypercortisolemia, which in turn leads to down-regulation of neurotrophins and subsequent neurodegeneration. Examining the neurobiology of depression from this perspective suggests that the endocannabinoid system may play a role in the etiology of melancholic depression. Specifically, pharmacological and genetic blockade of the cannabinoid CB1 receptor induces a phenotypic state that is analogous to melancholic depression, including symptoms such as reduced food intake, heightened anxiety, increased arousal and wakefulness, deficits in extinction of aversive memories and supersensitivity to stress. These similarities between melancholic depression and an endocannabinoid deficiency become more interesting in light of recent findings that endocannabinoid activity is down-regulated by chronic stress and possibly increased by some antidepressant regimens. We propose that an endocannabinoid deficiency may underlie some of the symptoms of melancholic depression, and that enhancement of this system may ultimately be a novel form of pharmacotherapy for treatment-resistant depression.”

http://www.ncbi.nlm.nih.gov/pubmed/16148438

Role of the endocannabinoid system in depression and suicide.

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“Depression is one of the most prevalent forms of neuropsychiatric disorder and is a major cause of suicide worldwide. The prefrontal cortex is a crucial brain region that is thought to be involved in the regulation of mood, aggression and/or impulsivity and decision making, which are altered in suicidality.

Evidence of the role of the endocannabinoid (EC) system in the neurobiology of neuropsychiatric disorders is beginning to emerge. The behavioral effects of ECs are believed to be mediated through the central cannabinoid CB1 receptor. Alterations in the levels of ECs, and in the density and coupling efficacy of CB1 receptors, have been reported in the prefrontal cortex of depressed and alcoholic suicide victims.

These findings support our hypothesis that altered EC function contributes to the pathophysiological aspects of suicidal behavior. Here, we provide a brief overview of the role of the EC system in alcoholism, depression and suicide, and discuss possible therapeutic interventions and directions for future research.”

https://www.ncbi.nlm.nih.gov/pubmed/16919786

http://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(06)00186-6

 

The endocannabinoid system as a target for novel anxiolytic and antidepressant drugs.

“Observational studies in humans suggest that exposure to marijuana and other cannabis-derived drugs produces a wide range of subjective effects on mood tone and emotionality. These observations have their counterpart in animal studies, showing that cannabinoid agonists strongly affect emotional reactivity in directions that vary depending on dose and context. Based on these evidence, the activation of central CB(1) receptor has emerged as potential target for the development of antianxiety and antidepressant therapies…”

http://www.ncbi.nlm.nih.gov/pubmed/19607961

 

[Endogenous cannabinoid system and depression].

Abstract

“Endogenous cannabinoid system (ECS) is highly conserved during evolution of the body’s endocrine network. It is a regulator of mood, cognitive, autonomic nervous system and movement control system. ECS dysfunction can promote the progress and maintain of depression, phobia, and extreme anxiety. The antidepressant drugs to enhance the activity of ECS may represent a new direction, but rarely reported research in this regard.”

http://www.ncbi.nlm.nih.gov/pubmed/23189618

Intrathecal Administration of the Cannabinoid 2 Receptor Agonist JWH015 Can Attenuate Cancer Pain and Decrease mRNA Expression of the 2B Subunit of N-Methyl-d-Aspartic Acid

“Pain has a negative impact on the quality of life in cancer patients…

…we hypothesized that a cannabinoid receptor agonist might be a novel therapy for cancer pain. Taking into consideration the side effects of a CB1 receptor agonist (which limits their clinical application), we chose a CB2 receptor agonist to investigate its effect in cancer pain…

 Recent clinical trials have demonstrated that cannabinoids may have significant positive effects in refractory chronic and cancer pain. The cannabinoids are thought to exert most of their effects by binding to G protein–coupled cannabinoid receptors, which include 2 cloned metabotropic receptors: cannabinoid (CB)1 and CB2…

CONCLUSION: These data indicated that intrathecal administration of cannabinoid receptor agonists might relieve cancer pain… These results also suggested that cannabinoids might be a useful alternative or adjunct therapy for relieving cancer pain.

The use of a CB2 receptor agonist could be a novel option for treatment of cancer pain.”

 

 http://www.anesthesia-analgesia.org/content/113/2/405.long

[Role of cannabinoid 2 receptor in the development of bone cancer pain].

“OBJECTIVE:

To explore the effects of cannabinoid 2 receptor (CB2) in the development of bone cancer pain in mice.”

“CONCLUSION:

The cannabinoid 2 receptor plays an important role in the formation of bone cancer pain.”

http://www.ncbi.nlm.nih.gov/pubmed/22490961

Role of cannabinoids in the regulation of bone remodeling

Abstract

“The endocannabinoid system plays a key role in regulating a variety of physiological processes such as appetite control and energy balance, pain perception, and immune responses. Recent studies have implicated the endocannabinoid system in the regulation of bone cell activity and bone remodeling. These studies showed that endogenous cannabinoid ligands, cannabinoid receptors, and the enzymes responsible for ligand synthesis and breakdown all play important roles in bone mass and in the regulation of bone disease. These findings suggest that the endocannabinoid pathway could be of value as a therapeutic target for the prevention and treatment of bone diseases. Here, we review the role of the skeletal endocannabinoid system in the regulation of bone remodeling in health and disease.”

http://www.ncbi.nlm.nih.gov/pubmed/23181053

Increasing 2-arachidonoyl glycerol signaling in the periphery attenuates mechanical hyperalgesia in a model of bone cancer pain

“Metastatic and primary bone cancers are usually accompanied by severe pain that is difficult to manage. In light of the adverse side effects of opioids, manipulation of the endocannabinoid system may provide an effective alternative for the treatment of cancer pain…

These data extend our previous findings with anandamide in the same model and suggest that the peripheral endocannabinoid system is a promising target for the management of cancer pain.

Taken together, the data demonstrate that peripheral 2-AG signaling may be a significant target to exploit for the management of cancer pain. In contrast to AEA, which inhibits nociception through CB1 receptors… Dual pharmacological modulation of peripheral AEA and 2-AG signaling that directly and indirectly affects DRG neurons may be a novel approach to reducing cancer pain without the side effects…”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3104059/

 

Spinal and peripheral analgesic effects of the CB2 cannabinoid receptor agonist AM1241 in two models of bone cancer-induced pain

“…a great body of evidence demonstrates the analgesic efficacy of systemically administered CB2 agonists in acute and chronic experimental pain….

The activation of CB2 receptors induces analgesia in experimental models of chronic pain. The present experiments were designed to study whether the activation of peripheral or spinal CB2 receptors relieves thermal hyperalgesia and mechanical allodynia in two models of bone cancer pain.

Conclusions and implications:

Spinal CB2 receptors are involved in the antiallodynic effect… in two neoplastic models while peripheral and spinal receptors participate in the antihyperalgesic effects… The use of drugs that activate CB2 receptors could be a useful strategy to counteract bone cancer-induced pain symptoms.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931557/