An evaluation of the anti-hyperalgesic effects of cannabidiolic acid-methyl ester (CBDA-ME) in a preclinical model of peripheral neuropathic pain.

Posted on January 29, 2020 by David Worrell

Publication cover image “Chronic neuropathic pain (NEP) is associated with growing therapeutic cannabis use. To promote quality of life without psychotropic effects, cannabinoids other than Δ9-tetrahydrocannabidiol, including cannabidiol and its precursor cannabidiolic acid (CBDA), are being evaluated. Due to its instability, CBDA has been understudied, particularly as an anti-nociceptive agent. Adding a methyl ester group (CBDA-ME) significantly enhances its stability, facilitating analyses of its analgesic effects in vivo. This study examines early treatment efficacy of CBDA-ME in a rat model of peripherally induced NEP and evaluates sex as a biological variable.

KEY RESULTS:

In males, CBDA-ME elicited a significant concentration-dependent chronic anti-hyperalgesic effect, also influencing both nociceptive and non-nociceptive mechanoreceptors, which were not observed in females at any of the concentrations tested.

CONCLUSION AND IMPLICATIONS:

Initiating treatment of a peripheral nerve injury with CBDA-ME at an early stage post-surgery provides anti-nociception in males, warranting further investigation into potential sexual dimorphisms underlying this response.”

https://www.ncbi.nlm.nih.gov/pubmed/31981216

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14997

Antiepileptogenic Effect of Subchronic Palmitoylethanolamide Treatment in a Mouse Model of Acute Epilepsy.

Posted on March 30, 2018 by David Worrell

“Research on the antiepileptic effects of (endo-)cannabinoids has remarkably progressed in the years following the discovery of fundamental role of the endocannabinoid (eCB) system in controlling neural excitability. Moreover, an increasing number of well-documented cases of epilepsy patients exhibiting multi-drug resistance report beneficial effects of cannabis use. Pre-clinical and clinical research has increasingly focused on the antiepileptic effectiveness of exogenous administration of cannabinoids and/or pharmacologically induced increase of eCBs such as anandamide (also known as arachidonoylethanolamide [AEA]). Concomitant research has uncovered the contribution of neuroinflammatory processes and peripheral immunity to the onset and progression of epilepsy. Accordingly, modulation of inflammatory pathways such as cyclooxygenase-2 (COX-2) was pursued as alternative therapeutic strategy for epilepsy. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide related to the centrally and peripherally present eCB AEA, and is a naturally occurring nutrient that has long been recognized for its analgesic and anti-inflammatory properties. Neuroprotective and anti-hyperalgesic properties of PEA were evidenced in neurodegenerative diseases, and antiepileptic effects in pentylenetetrazol (PTZ), maximal electroshock (MES) and amygdaloid kindling models of epileptic seizures. Moreover, numerous clinical trials in chronic pain revealed that PEA treatment is devoid of addiction potential, dose limiting side effects and psychoactive effects, rendering PEA an appealing candidate as antiepileptic compound or adjuvant. In the present study, we aimed at assessing antiepileptic properties of PEA in a mouse model of acute epileptic seizures induced by systemic administration of kainic acid (KA). Here, we demonstrate that subchronic administration of PEA significantly alleviates seizure intensity, promotes neuroprotection and induces modulation of the plasma and hippocampal eCB and eiC levels in systemic KA-injected mice.” https://www.ncbi.nlm.nih.gov/pubmed/29593494 https://www.frontiersin.org/articles/10.3389/fnmol.2018.00067/full

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The Cannabinoids Δ8THC, CBD, and HU-308 Act via Distinct Receptors to Reduce Corneal Pain and Inflammation

Posted on February 17, 2018 by David Worrell

“Corneal injury can result in dysfunction of corneal nociceptive signaling and corneal sensitization. Activation of the endocannabinoid system has been reported to be analgesic and anti-inflammatory. The purpose of this research was to investigate the antinociceptive and anti-inflammatory effects of cannabinoids with reported actions at cannabinoid 1 (CB₁R) and cannabinoid 2 (CB₂R) receptors and/or noncannabinoid receptors in an experimental model of corneal hyperalgesia. Topical cannabinoids reduce corneal hyperalgesia and inflammation. The antinociceptive and anti-inflammatory effects of Δ⁸THC are mediated primarily via CB₁R, whereas that of the cannabinoids CBD and HU-308, involve activation of 5-HT_1A receptors and CB₂Rs, respectively. Cannabinoids could be a novel clinical therapy for corneal pain and inflammation resulting from ocular surface injury.” https://www.ncbi.nlm.nih.gov/pubmed/29450258 http://online.liebertpub.com/doi/abs/10.1089/can.2017.0041]]>

The Direct Actions of Cannabidiol and 2-Arachidonoyl Glycerol at GABAA Receptors.

Posted on March 3, 2017 by David Worrell

“Cannabidiol (CBD) is a major non-intoxicating component of cannabis and possesses anti-epileptic, anxiolytic and anti-hyperalgesic properties. Despite evidence that some endogenous and synthetic cannabinoids interact with GABA_A receptors, no-one has yet investigated the effects of CBD. Here we used two-electrode voltage clamp electrophysiology to compare the actions of CBD with those of the major central endocannabinoid, 2-arachidonoyl glycerol (2-AG) on human recombinant GABA_A receptors (synaptic α1-6βg2 and extrasynaptic α4β2δ) expressed on Xenopus oocytes. Taken together these results reveal a mode of action of CBD on specifically configured GABA_A receptors that may be relevant to the anticonvulsant and anxiolytic effects of the compound.” https://www.ncbi.nlm.nih.gov/pubmed/28249817]]>

β-caryophyllene, a dietary cannabinoid, complexed with β-cyclodextrin produced anti-hyperalgesic effect involving the inhibition of Fos expression in superficial dorsal horn.

Posted on February 19, 2016 by David Worrell

“Evaluate the anti-hyperalgesic effect of the complex containing β-caryophyllene (βCP) and β-cyclodextrin (βCD) in a non-inflammatory chronic muscle pain mice model and investigated its action on superficial dorsal horn of the lumbar spinal cord.

The characterization tests indicated that βCP were efficiently incorporated into βCD. The oral treatment with βCP-βCD, at all doses tested, produced a significant reduction on mechanical hyperalgesia and a significant increase in muscle withdrawal thresholds, without produce any alteration in force. In addition, βCP-βCD was able to significantly decrease Fos expression in the superficial dorsal horn.

SIGNIFICANCE:

Thus, βCP-βCD attenuates the non-inflammatory chronic muscle pain in mice and inhibits the Fos expression in the lumbar spinal cord.”

http://www.ncbi.nlm.nih.gov/pubmed/26883973

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.” http://www.ncbi.nlm.nih.gov/pubmed/23138934

“β (beta)-cyclodextrin: 7-membered sugar ring molecule” https://en.wikipedia.org/wiki/Cyclodextrin

Tonic Modulation of Nociceptive Behavior and Allodynia by Cannabinoid Receptors in Formalin Test in Rats.

Posted on February 18, 2015 by David Worrell

“Cannabinoids produce anti-nociceptive and anti-hyperalgesic effects in acute, inflammatory and neuropathic pain models.

The current study investigated the role of cannabinoid (CB1 and CB2) receptors in modulating formalin-induced nociceptive behavior and mechanical allodynia in the rat…

The results indicate that CB1 and CB2 receptors mediate a tonically inhibitory action on formalin-induced inflammatory pain, especially long-term allodynia, in bilateral hind paws.”

http://www.ncbi.nlm.nih.gov/pubmed/25687494

http://www.thctotalhealthcare.com/category/pain-2/

Protective effects of cannabidiol on lesion-induced intervertebral disc degeneration.

Posted on January 23, 2015 by David Worrell

“Disc degeneration is a multifactorial process that involves hypoxia, inflammation, neoinnervation, accelerated catabolism, and reduction in water and glycosaminoglycan content…

Cannabidiol (CBD) is the major nonpsychotropic phytocannabinoid of Cannabis sativa (up to 40% of Cannabis extracts). Contrary to most cannabinoids, CBD does not produce psychotomimetic or cognitive effects. Interesting, in the last years it has been suggest that CBD produces a plethora of others pharmacological effects, including antioxidant, neuroprotective, anti-proliferative, anti-anxiety, hypnotic and antiepileptic, anti-nausea, anti-ischemic, anti-hyperalgesic, and anti-inflammatory…

The present study investigated the effects of cannabidiol intradiscal injection in the coccygeal intervertebral disc degeneration induced by the needle puncture model using magnetic resonance imaging (MRI) and histological analyses…

Cannabidiol significantly attenuated the effects of disc injury induced by the needle puncture. Considering that cannabidiol presents an extremely safe profile and is currently being used clinically, these results suggest that this compound could be useful in the treatment of intervertebral disc degeneration.

In summary our study revealed anti-degenerative effects of intradiscal microinjection of CBD 120 nmol. CBD represents one of the most promising candidates present in the Cannabis sativa plant for clinical use due to its remarkable lack of cognitive or psychotomimetic actions.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4269422/

http://www.thctotalhealthcare.com/category/spinal-cord-injury/

The anti-hyperalgesic actions of the cannabinoid anandamide and the putative CB2 receptor agonist palmitoylethanolamide in visceral and somatic inflammatory pain.

Posted on February 25, 2014 by David Worrell

“The therapeutic effects of the cannabinoid anandamide and the putative CB2 agonist palmitoylethanolamide were tested in a model of persistent visceral pain (turpentine inflammation of the urinary bladder)…

The results confirm the analgesic potential of endogenous ligands at cannabinoid receptor sites.

The anti-nociceptive effect of the putative CB2 receptor agonist, palmitoylethanolamide, is particularly interesting since it is believed to be a peripherally mediated effect.

This observation might be exploited to separate central psychotropic effects from peripheral analgesic actions of the cannabinoids, under inflammatory conditions.”

http://www.ncbi.nlm.nih.gov/pubmed/9696473

The role of androgen receptor in transcriptional modulation of cannabinoid receptor type 1 gene in rat trigeminal ganglia.

Posted on September 24, 2013 by David Worrell

“We have previously shown that anti-hyperalgesic effects of cannabinoid agonists under inflammatory condition are much greater in male than female, and that inflammatory cytokines upregulate cannabinoid receptor type 1 (CB1) expression in male, but not female, trigeminal ganglia (TG) in a testosterone-dependent manner. In this study, we investigated the mechanisms underlying the testosterone-mediated regulation of peripheral CB1 expression…

These experiments provided compelling evidence that testosterone regulates CB1 gene transcription in TG through AR following cytokine stimulation.

These results should provide mechanistic bases for understanding cytokine-hormone-neuron interactions in peripheral cannabinoid systems, and have important clinical implications for pain patients in whom testosterone level is naturally low, gradually declining or pharmacologically compromised.”

http://www.ncbi.nlm.nih.gov/pubmed/24055403

Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy.

Posted on January 17, 2013 by David Worrell

“To date, two cannabinoid receptors have been identified, CB1 and CB2. Activation of these receptors with non-selective cannabinoid receptor agonists reduces pain sensitivity in animals and humans. However, activation of CB1 receptors is also associated with central side effects… More recently, a role for selective CB2 agonists in pain modification has been demonstrated…a selective CB2 agonist, was recently reported to partially reverse the inflammation and hyperalgesia in a rat model of acute inflammation. In the current report, we extend the characterization and therapeutic potential of this compound…

These data support the tenet that selective CB2 receptor agonists have the potential to treat pain without eliciting the centrally-mediated side effects associated with non-selective cannabinoid agonists…”

http://www.ncbi.nlm.nih.gov/pubmed/15814101

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