Abstract
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.
Highlights
Cannabidiol (CBD), a phytocannabinoid devoid of psychoactive properties, is currently being investigated in a series of clinical trials to determine its potential for treating diseases such as epilepsy, neuropsychiatric disorders, neurodegeneration and neuropathic allodynia [1,2,3,4]
We have described an in vitro assay that analyzes the capacity of drugs to alter the interaction of recombinant sigma 1 receptor (σ1R) with the regulatory cytosolic C0-C1-C2 region of the N-methyl-D-aspartate acid receptor (NMDAR) NMDAR subunit 1 (NR1) subunit [42]
The present study shows that CBD acting as an antagonist of σ1R diminishes the influence of glutamate NMDA receptors in three experimental paradigms in which this activity plays a key role, i.e., the level of morphine-evoked antinociception, the incidence of NMDA-induced convulsive activity and the extent of the neural damage caused
Summary
Cannabidiol (CBD), a phytocannabinoid devoid of psychoactive properties, is currently being investigated in a series of clinical trials to determine its potential for treating diseases such as epilepsy, neuropsychiatric disorders, neurodegeneration and neuropathic allodynia [1,2,3,4]. Unlike Δ9-tetrahydrocannabinol, the main psychoactive constituent of the marijuana plant, the effects of CBD do not involve direct binding to the endocannabinoid receptors CB1 and CB2 [5, 6]; instead, CBD behaves. Within this complex framework, CBD exhibits positive effects in situations in which glutamatergic signaling, that mediated by N-methyl-D-aspartate acid receptor (NMDAR), plays a critical role. CBD modulates morphine antinociception in mice [21] and exhibits anti-allodynia effects in rodent models of neuropathy [22, 23]. Clinical evidence suggests that CBD can be used to manage epilepsy in adults and children affected by refractory seizures and exhibits a favorable side effect profile [25]
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