Cannabidiol-induced panicolytic-like effects and fear-induced antinociception impairment: the role of the CB1 receptor in the ventromedial hypothalamus.

Image result for Springer Link“The behavioural effects elicited by chemical constituents of Cannabis sativa, such as cannabidiol (CBD), on the ventromedial hypothalamus (VMH) are not well understood. There is evidence that VMH neurons play a relevant role in the modulation of unconditioned fear-related defensive behavioural reactions displayed by laboratory animals.

OBJECTIVES:

This study was designed to explore the specific pattern of distribution of the CB1 receptors in the VMH and to investigate the role played by this cannabinoid receptor in the effect of CBD on the control of defensive behaviours and unconditioned fear-induced antinociception.

METHODS:

A panic attack-like state was triggered in Wistar rats by intra-VMH microinjections of N-methyl-D-aspartate (NMDA). One of three different doses of CBD was microinjected into the VMH prior to local administration of NMDA. In addition, the most effective dose of CBD was used after pre-treatment with the CB1 receptor selective antagonist AM251, followed by NMDA microinjections in the VMH.

RESULTS:

The morphological procedures demonstrated distribution of labelled CB1 receptors on neuronal perikarya situated in dorsomedial, central and ventrolateral divisions of the VMH. The neuropharmacological approaches showed that both panic attack-like behaviours and unconditioned fear-induced antinociception decreased after intra-hypothalamic microinjections of CBD at the highest dose (100 nmol). These effects, however, were blocked by the administration of the CB1 receptor antagonist AM251 (100 pmol) in the VMH.

CONCLUSION:

These findings suggest that CBD causes panicolytic-like effects and reduces unconditioned fear-induced antinociception when administered in the VMH, and these effects are mediated by the CB1 receptor-endocannabinoid signalling mechanism in VMH.”

https://www.ncbi.nlm.nih.gov/pubmed/31919563

https://link.springer.com/article/10.1007%2Fs00213-019-05435-5

“panicolytic: That reduces the flight reflex in animals when faced with danger. Any drug that has this effect.” https://en.wiktionary.org/wiki/panicolytic

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Investigation of the Involvement of the Endocannabinoid System in TENS-induced Antinociception.

“Transcutaneous electrical nerve stimulation (TENS) promotes antinociception by activating the descending pain modulation pathway and consequently releasing endogenous analgesic substances.

In addition, recent studies have shown that the endocannabinoid system controls pain. Thus, the present study investigated the involvement of the endocannabinoid system in TENS-induced antinociception of cancer pain using a cancer pain model induced by intraplantar (i.pl.) injections of Ehrlich tumor cells in male Swiss mice.

These results suggest that low- and high-frequency TENS is effective in controlling cancer pain, and the endocannabinoid system is involved in this effect at both the peripheral and central levels.

Perspective: TENS is a non-pharmacological strategy that may be used to control cancer pain. Identification of a new mechanism involved in its analgesic effect could lead to the development of clinical studies as well as an increase in its application, lessening the need for pharmacological treatments.”

https://www.ncbi.nlm.nih.gov/pubmed/31785404

https://www.jpain.org/article/S1526-5900(19)30868-5/fulltext

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Endogenous cannabinoid modulation of restraint stress-induced analgesia in thermal nociception.

Journal of Neurochemistry banner“It is thought that endogenous cannabinoids have a role in the analgesia induced by specific forms of stress.

We examined if the role of endogenous cannabinoids is also dependent upon the mode of nociception, and whether this could be altered by drugs which block their enzymatic degradation.

These findings indicate the role of endocannabinoids in stress-induced analgesia differs with the type of thermal pain behaviour. However, by inhibiting their breakdown, endocannabinoids can be recruited to substitute for endogenous opioid signalling when their activity is blocked, indicating a degree of redundancy between opioid and cannabinoid systems.

Together these data suggest targeting endocannabinoid breakdown could provide an alternative, or adjuvant to mainstream analgesics such as opioids.”

https://www.ncbi.nlm.nih.gov/pubmed/31571215

https://onlinelibrary.wiley.com/doi/abs/10.1111/jnc.14884

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Involvement of Spinal Cannabinoid CB2 Receptors in Exercise-Induced Antinociception.

Neuroscience“Muscle pain affects approximately 11-24% of the global population.

Several studies have shown that exercise is a non-pharmacological therapy to pain control. It has been suggested that the endocannabinoid system is involved in this antinociceptive effect.

The present study aimed to investigate whether spinal cannabinoid CB2 receptors participate in the exercise-induced antinociception.

The present study suggests that activation of spinal cannabinoid CB2 receptors and reduction of activated microglia are involved in exercise-induced antinociception.”

https://www.ncbi.nlm.nih.gov/pubmed/31473278

https://www.sciencedirect.com/science/article/abs/pii/S0306452219306165?via%3Dihub

“Exercise activates the endocannabinoid system.”  https://www.ncbi.nlm.nih.gov/pubmed/14625449

“The endocannabinoid system and pain.”  https://www.ncbi.nlm.nih.gov/pubmed/19839937

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Age-related differences in Δ⁹-tetrahydrocannabinol-induced antinociception in female and male rats.

Cover image for Experimental and Clinical Psychopharmacology

“Given the use of cannabis as an analgesic by a broadening age range of patients, the aim of this study was to determine whether the antinociceptive effects of Δ9-tetrahydrocannabinol (THC) differ by age.

On the tail withdrawal test, THC was significantly more effective in middle-aged adult than in young adult rats and significantly less effective in adolescent than in young adult rats.

Sex differences in THC’s antinociceptive effects were consistent across the 3 ages examined, with greater THC effects observed in females than males of each age. Age-related differences in THC’s locomotor-suppressing effect were also observed, with the greatest effect in young adult female rats. Serum THC levels were slightly higher in adolescent than in young adult rats, and levels of the active metabolites 11-OH-THC and cannabinol, as well as the inactive metabolite 11-nor-9-carboxy-THC, did not differ between adolescent and young adult rats.

These results suggest that the pain-relieving effects of THC may be more limited in adolescents than in adults and that these age-related differences in THC effect are not attributable to differential absorption or metabolism of THC.”

https://www.ncbi.nlm.nih.gov/pubmed/31120286

https://psycnet.apa.org/doiLanding?doi=10.1037%2Fpha0000257

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Characterization of Cancer-Induced Nociception in a Murine Model of Breast Carcinoma.

“Severe and poorly treated pain often accompanies breast cancer. Thus, novel mechanisms involved in breast cancer-induced pain should be investigated. Then, it is necessary to characterize animal models that are reliable with the symptoms and progression of the disease as observed in humans. Explaining cancer-induced nociception in a murine model of breast carcinoma was the aim of this study. 4T1 (104) lineage cells were inoculated in the right fourth mammary fat pad of female BALB/c mice; after this, mechanical and cold allodynia, or mouse grimace scale (MGS) were observed for 30 days. To determine the presence of bone metastasis, we performed the metastatic clonogenic test and measure calcium serum levels. At 20 days after tumor induction, the antinociceptive effect of analgesics used to relieve pain in cancer patients (acetaminophen, naproxen, codeine or morphine) or a cannabinoid agonist (WIN 55,212-2) was tested. Mice inoculated with 4T1 cells developed mechanical and cold allodynia and increased MGS. Bone metastasis was confirmed using the clonogenic assay, and hypercalcemia was observed 20 days after cells inoculation. All analgesic drugs reduced the mechanical and cold allodynia, while the MGS was decreased only by the administration of naproxen, codeine, or morphine. Also, WIN 55,212-2 improved all nociceptive measures. This pain model could be a reliable form to observe the mechanisms of breast cancer-induced pain or to observe the efficacy of novel analgesic compounds.”

https://www.ncbi.nlm.nih.gov/pubmed/30850915

https://link.springer.com/article/10.1007%2Fs10571-019-00666-8

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Ketamine induces central antinociception mediated by endogenous cannabinoids and activation of CB1 receptors.

Neuroscience Letters

“The participation of endocannabinoids in central and peripheral antinociception induced by several compounds has been shown by our group.

In this study, we investigated the effect of endocannabinoids on the central antinociception induced by ketamine.

It was concluded that central antinociception induced by ketamine involves the activation of CB1 cannabinoidreceptors.

Mobilization of cannabinoids might be required for the activation of those receptors, since inhibitors of the endogenous cannabinoids potentiate the effect of Ketamine.”

https://www.ncbi.nlm.nih.gov/pubmed/30716423

https://www.sciencedirect.com/science/article/abs/pii/S0304394019300771?via%3Dihub

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Cannabidiol enhances morphine antinociception, diminishes NMDA-mediated seizures and reduces stroke damage via the sigma 1 receptor.

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“Cannabidiol (CBD), the major non-psychotomimetic compound present in the Cannabis sativa plant, exhibits therapeutic potential for various human diseases, including chronic neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, ischemic stroke, epilepsy and other convulsive syndromes, neuropsychiatric disorders, neuropathic allodynia and certain types of cancer.

CBD does not bind directly to endocannabinoid receptors 1 and 2, and despite research efforts, its specific targets remain to be fully identified. Notably, sigma 1 receptor (σ1R) antagonists inhibit glutamate N-methyl-D-aspartate acid receptor (NMDAR) activity and display positive effects on most of the aforesaid diseases. Thus, we investigated the effects of CBD on three animal models in which NMDAR overactivity plays a critical role: opioid analgesia attenuation, NMDA-induced convulsive syndrome and ischemic stroke.

In an in vitro assay, CBD disrupted the regulatory association of σ1R with the NR1 subunit of NMDAR, an effect shared by σ1R antagonists, such as BD1063 and progesterone, and prevented by σ1R agonists, such as 4-IBP, PPCC and PRE084. The in vivo administration of CBD or BD1063 enhanced morphine-evoked supraspinal antinociception, alleviated NMDA-induced convulsive syndrome, and reduced the infarct size caused by permanent unilateral middle cerebral artery occlusion.

These positive effects of CBD were reduced by the σ1R agonists PRE084 and PPCC, and absent in σ1R-/- mice. Thus, CBD displays antagonist-like activity toward σ1R to reduce the negative effects of NMDAR overactivity in the abovementioned experimental situations.”

https://www.ncbi.nlm.nih.gov/pubmed/30223868

https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-018-0395-2

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Role of the cannabinoid signaling in the brain orexin- and ghrelin-induced visceral antinociception in conscious rats.

Journal of Pharmacological Sciences

“We hypothesized that the cannabinoid (CB) system may mediate the brain orexin- or ghrelin-induced visceral antinociception. Intraperitoneal injection of either CB1/2 agonist, WIN 55212 or O-Arachidonoyl ethanolamine increased the threshold volume of colonic distension-induced abdominal withdrawal reflex in rats, suggesting CB could induce visceral antinociception. Pretreatment with either the CB1 or CB2 antagonist potently blocked the centrally injected orexin-A-induced antinociceptive action against colonic distension while CB2 but not CB1 antagonist blocked the brain ghrelin-induced visceral antinociception. These results suggest that the cannabinoid signaling may be involved in the central orexin- or ghrelin-induced antinociceptive action in a different mechanistic manner.”

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Brain endocannabinoid signaling exhibits remarkable complexity.

Image result for Brain Res Bull.

“The endocannabinoid (eCB) signaling system is one of the most extensive of the mammalian brain. Despite the involvement of only few specific ligands and receptors, the system encompasses a vast diversity of triggered mechanisms and driven effects. It mediates a wide range of phenomena, including the regulation of transmitter release, neural excitability, synaptic plasticity, impulse spread, long-term neuronal potentiation, neurogenesis, cell death, lineage segregation, cell migration, inflammation, oxidative stress, nociception and the sleep cycle. It is also known to be involved in the processes of learning and memory formation. This extensive scope of action is attained by combining numerous variables. In a properly functioning brain, the correlations of these variables are kept in a strictly controlled balance; however, this balance is disrupted in many pathological conditions. However, while this balance is known to be disrupted by drugs in the case of addicts, the stimuli and mechanisms influencing the neurodegenerating brain remain elusive. This review examines the multiple factors and phenomena affecting the eCB signaling system in the brain. It evaluates techniques of controlling the eCB system to identify the obstacles in their applications and highlights the crucial interdependent variables that may influence biomedical research outcomes.”

https://www.ncbi.nlm.nih.gov/pubmed/29953913

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