Role of endocannabinoid system in pain, anxiety, and depression

Here are several  rigorous scientific studies (Full Text PubMub articles) investigating the critical role of endocannabinoids in pain, depression, and anxiety: 3 studies from within the last 2 months (March and April 2014), a recent post from the NIH Director’s Blog, and 4 more studies from within the last 5 years. Especially interesting is: “An emerging literature documents the “eCB deficiency syndrome” as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions.

Highlights of these articles:

  • cannabinoid receptor agonists have analgesic efficacy in neuropathic pain models – There is growing clinical evidence indicating that the cannabis constituent, Δ9-tetrahydrocannabinol (THC), and synthetic cannabinoid agonists have efficacy in chronic pain states – A wide range of animal models of neuropathic pain have demonstrated that cannabinoid agonists reverse the common symptoms of neuropathic pain
  • when endocannabinoids interacted with CB1 receptors of neurons located in the central amygdala, the natural chemicals reduced the excitability of these brain cells. This suggests that THC and/or other external cannabinoids found in marijuana may also serve to reduce anxiety
  • An emerging literature documents the “eCB deficiency syndrome” as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions.
  • Behaviorally, substrate-selective inhibition of COX-2 reduced anxiety-like behaviors in mice via increased eCB signaling
  • Endocannabinoids are key modulators of synaptic function. By activating cannabinoid receptors expressed in the central nervous system, these lipid messengers can regulate several neural functions and behaviors.
  • Cannabidiol (CBD), the main non-psychotropic component of the Cannabis sativa plant, has shown therapeutic potential in several neuropsychiatric disorders
  • alterations in endocannabinoid (eCB) signaling in the NAc contribute to depression-like behaviors induced by chronic unpredictable stress (CUS) in mice.

Inhibition of Fatty Acid binding proteins elevates brain anandamide levels and produces analgesia.  PLoS One. Apr 2014

The endocannabinoid anandamide (AEA) is an antinociceptive lipid that is inactivated through cellular uptake and subsequent catabolism by fatty acid amide hydrolase (FAAH). Fatty acid binding proteins (FABPs) are intracellular carriers that deliver AEA and related N-acylethanolamines (NAEs) to FAAH for hydrolysis.

Recent work from our group has revealed that pharmacological inhibition of FABPs reduces inflammatory pain in mice  The goal of the current work was to explore the effects of FABP inhibition upon nociception in diverse models of pain.  Inhibition of FABPs reduced nociception associated with inflammatory, visceral, and neuropathic pain.

Targeting the endogenous cannabinoid system to treat neuropathies  Front Pharmacol. Mar 2014

Chronic neuropathic pain is a debilitating condition that remains poorly treated by current medications. Preclinical studies have indicated that cannabinoid receptor agonists have analgesic efficacy in neuropathic pain models, but this is accompanied by undesirable side effects. In recent years, novel strategies targeting the endogenous cannabinoid system have emerged, which are being mooted as safer alternatives. A recent clinical trial, however, has demonstrated that a new endocannabinoid modulator is ineffective against osteoarthritic pain, despite exhibiting efficacy during the preclinical stage.

There is growing clinical evidence indicating that the cannabis constituent, Δ9-tetrahydrocannabinol (THC), and synthetic cannabinoid agonists have efficacy in chronic pain states (Lynch and Campbell, 2011). These human studies are based upon substantial preclinical evidence. A wide range of animal models of neuropathic pain have demonstrated that cannabinoid agonists reverse the common symptoms of neuropathic pain, including allodynia (to cool and innocuous mechanical stimuli) and hyperalgesia (to noxious thermal and mechanical stimuli) (Fox et al., 2001; Scott et al., 2004). Unfortunately, this therapeutic intervention is also associated with a number of adverse effects, including sedation and motor/cognitive impairment. Having said this, the therapeutic window between the desired and adverse effects of cannabinoids has not been systematically examined. Thus, it remains to be determined whether cannabinoids can produce pain relief at doses below the side effect threshold.

Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System  PLoS One. Mar 2014

The “classic” endocannabinoid (eCB) system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. An emerging literature documents the “eCB deficiency syndrome” as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system-ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation.

Evidence indicates that several classes of pharmaceuticals upregulate the eCB system, including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids), antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as “complementary and alternative medicine” also upregulate the eCB system: massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification (diet, weight control, exercise, and the use of psychoactive substances-alcohol, tobacco, coffee, cannabis) also modulate the eCB system.

Anxiety Reduction: Exploring the Role of Cannabinoid Receptors  NH Directors Blog April 2014

In humans, mice, and other mammals, the body makes natural chemicals, called endocannabinoids, that interact with certain proteins, called type 1 cannabinoid receptors (CB1), that are located on the surface of nerve cells. We know that the endocannabinoid system is critical for normal brain development and activity, immunity, and the physiological regulation of stress responses. We also know that CB1 receptors interact with the primary cannabinoid in marijuana, a mind-altering chemical known as delta-9-tetrahydrocannabinol (THC)

In addition, the researchers found that when endocannabinoids interacted with CB1 receptors of neurons located in the central amygdala, the natural chemicals reduced the excitability of these brain cells. This suggests that THC and/or other external cannabinoids found in marijuana may also serve to reduce anxiety by binding to CB1 receptors in the amygdala, rendering neurons less active [3]. However, this hypothesis must be confirmed by further studies.

Last year, also in a mouse study, these same researchers showed that if they inhibited an enzyme called cyclooxygenase-2 (COX-2), which deactivates natural endocannabinoids, the levels of these chemicals remain higher in the brain and reduce anxious behaviors in the animals.

Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation  Nat Neurosci. Sep 2013

Augmentation of endogenous cannabinoid (eCB) signaling represents an emerging approach to the treatment of affective disorders. Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid to form prostaglandins, but also inactivates eCBs in vitro. However, the viability of COX-2 as a therapeutic target for in vivo eCB augmentation has not been explored. Using medicinal chemistry and in vivo analytical and behavioral pharmacological approaches, we found that COX-2 is important for the regulation of eCB levels in vivo. We used a pharmacological strategy involving substrate-selective inhibition of COX-2 to augment eCB signaling without affecting related non-eCB lipids or prostaglandin synthesis. Behaviorally, substrate-selective inhibition of COX-2 reduced anxiety-like behaviors in mice via increased eCB signaling. Our data suggest a key role for COX-2 in the regulation of eCB signaling and indicate that substrate-selective pharmacology represents a viable approach for eCB augmentation with broad therapeutic potential.

Endocannabinoid signaling and synaptic function.  Neuron. Oct 2012

Endocannabinoids are key modulators of synaptic function. By activating cannabinoid receptors expressed in the central nervous system, these lipid messengers can regulate several neural functions and behaviors. As experimental tools advance, the repertoire of known endocannabinoid-mediated effects at the synapse, and their underlying mechanism, continues to expand. Retrograde signaling is the principal mode by which endocannabinoids mediate short- and long-term forms of plasticity at both excitatory and inhibitory synapses. However, growing evidence suggests that endocannabinoids can also signal in a nonretrograde manner. In addition to mediating synaptic plasticity, the endocannabinoid system is itself subject to plastic changes. Multiple points of interaction with other neuromodulatory and signaling systems have now been identified. In this Review, we focus on new advances in synaptic endocannabinoid signaling in the mammalian brain. The emerging picture not only reinforces endocannabinoids as potent regulators of synaptic function but also reveals that endocannabinoid signaling is mechanistically more complex and diverse than originally thought.

Endocannabinoid System and Psychiatry: In Search of a Neurobiological Basis for Detrimental and Potential Therapeutic Effects  Front Behav Neurosci. Oct 2011;

Cognition and emotionality are the most affected functions in neuropsychiatric disorders, i.e., anxiety disorders, depression, and schizophrenia. In this review, most relevant literature on the role of the endocannabinoid (eCB) system in neuropsychiatric disorders will be presented.

Cannabidiol (CBD), the main non-psychotropic component of the Cannabis sativa plant, has shown therapeutic potential in several neuropsychiatric disorders. Although further studies are needed, recent studies indicate that CBD therapeutic effects may partially depend on facilitation of eCB-mediated neurotransmission

Deficiency in endocannabinoid signaling in the nucleus accumbens induced by chronic unpredictable stress.  Neuropsychopharmacology. Oct 2010

The nucleus accumbens (NAc) is a critical component of the reward circuitry, and dysfunction of the NAc may account for anhedonia and other symptoms of depression. Here, we investigated whether alterations in endocannabinoid (eCB) signaling in the NAc contribute to depression-like behaviors induced by chronic unpredictable stress (CUS) in mice.

CUS (5–6-week exposure to stressors), but not sub-CUS (1 week exposure to stressors), induces depression-like behaviors and impairs these forms of eCB/CB1 receptor-mediated plasticity examined in the NAc core.

Both CUS-induced deficiency in eCB signaling and depression-like behaviors were reversed by in vivo administration of antidepressant fluoxetine. These results suggest that downregulation of eCB signaling in the NAc occurs after CUS and contributes to the pathophysiology of depression.

1 thought on “Role of endocannabinoid system in pain, anxiety, and depression

  1. Pingback: Endocannabinoids mediate runner’s high | EDS Info (Ehlers-Danlos Syndrome)

Other thoughts?

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.