Tag Archives: anti-nociceptive

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

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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

Allosteric Cannabinoid Receptor 1 (CB1) Ligands Reduce Ocular Pain and Inflammation.

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molecules-logo“Cannabinoid receptor 1 (CB1) activation has been reported to reduce transient receptor potential cation channel subfamily V member 1 (TRPV1)-induced inflammatory responses and is anti-nociceptive and anti-inflammatory in corneal injury.

We examined whether allosteric ligands, can modulate CB1 signaling to reduce pain and inflammation in corneal hyperalgesia.

Corneal hyperalgesia was generated by chemical cauterization of cornea in wildtype and CB2 knockout (CB2-/-) mice. The novel racemic CB1 allosteric ligand GAT211 and its enantiomers GAT228 and GAT229 were examined alone or in combination with the orthosteric CB1 agonist Δ8-tetrahydrocannabinol (Δ8-THC). Pain responses were assessed following capsaicin (1 µM) stimulation of injured corneas at 6 h post-cauterization. Corneal neutrophil infiltration was also analyzed. GAT228, but not GAT229 or GAT211, reduced pain scores in response to capsaicin stimulation.

Combination treatments of 0.5% GAT229 or 1% GAT211 with subthreshold Δ8-THC (0.4%) significantly reduced pain scores following capsaicin stimulation. The anti-nociceptive effects of both GAT229 and GAT228 were blocked with CB1 antagonist AM251, but remained unaffected in CB2-/- mice. Two percent GAT228, or the combination of 0.2% Δ8-THC with 0.5% GAT229 also significantly reduced corneal inflammation.

CB1 allosteric ligands could offer a novel approach for treating corneal pain and inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/31968549

https://www.mdpi.com/1420-3049/25/2/417

Cannabichromene is a cannabinoid CB2 receptor agonist.

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British Journal of Pharmacology banner“Cannabichromene (CBC) is one of the most abundant phytocannabinoids in Cannabis spp. It has modest anti-nociceptive and anti-inflammatory effects and potentiates some effects of Δ9 – tetrahydrocannabinol (THC) in vivo. How CBC exerts these effects is poorly defined and there is little information about its efficacy at cannabinoid receptors. We sought to determine the functional activity of CBC at CB1 and CB2 receptors.

KEY RESULTS:

CBC activated CB2 but not CB1 receptors to produce a hyperpolarization of AtT20 cells. This activation was inhibited by a CB2 antagonist AM630, and sensitive to pertussis toxin. Application of CBC reduced activation of CB2 receptors (but not CB1 receptors) by subsequent co-application of CP55,940, an efficacious CB1 and CB2 agonist. Continuous CBC application induced loss of cell surface CB2 receptors and desensitisation of the CB2-induced hyperpolarization.

CONCLUSIONS AND IMPLICATIONS:

CBC is a selective CB2 receptor agonist displaying higher efficacy than THC in hyperpolarising AtT20 cells. CBC can also recruit CB2 receptor regulatory mechanisms. CBC may contribute to the potential therapeutic effectiveness of some cannabis preparations, potentially through CB2-mediated modulation of inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/31368508

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14815

Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis.

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“Osteoarthritis (OA) is a multifactorial joint disease, which includes joint degeneration, intermittent inflammation, and peripheral neuropathy. Cannabidiol (CBD) is a non-euphoria producing constituent of cannabis that has the potential to relieve pain.

The aim of this study was to determine if CBD is anti-nociceptive in OA, and whether inhibition of inflammation by CBD could prevent the development of OA pain and joint neuropathy.

The therapeutic and prophylactic effects of peripheral CBD (100-300μg) were assessed. In end stage OA, CBD dose-dependently decreased joint afferent firing rate, and increased withdrawal threshold and weight bearing (p<0.0001; n=8). Acute, transient joint inflammation was reduced by local CBD treatment (p<0.0001; n=6). Prophylactic administration of CBD prevented the development of MIA-induced joint pain at later time points (p<0.0001; n=8), and was also found to be neuroprotective (p<0.05; n=6-8).

The data presented here indicate that local administration of CBD blocked OA pain. Prophylactic CBD treatment prevented the later development of pain and nerve damage in these OA joints.

These findings suggest that CBD may be a safe, useful therapeutic for treating OA joint neuropathic pain.”

https://www.ncbi.nlm.nih.gov/pubmed/28885454             https://insights.ovid.com/crossref?an=00006396-900000000-99152

Anti-nociceptive interactions between opioids and a cannabinoid receptor 2 agonist in inflammatory pain.

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SAGE Journals

“The cannabinoid 1 receptor and cannabinoid 2 receptor can both be targeted in the treatment of pain; yet, they have some important differences. Cannabinoid 1 receptor is expressed at high levels in the central nervous system, whereas cannabinoid 2 receptor is found predominantly, although not exclusively, outside the central nervous system. The objective of this study was to investigate potential interactions between cannabinoid 2 receptor and the mu-opioid receptor in pathological pain. The low level of adverse side effects and lack of tolerance for cannabinoid 2 receptor agonists are attractive pharmacotherapeutic traits. This study assessed the anti-nociceptive effects of a selective cannabinoid 2 receptor agonist (JWH-133) in pathological pain using mice subjected to inflammatory pain using the formalin test. Furthermore, we examined several ways in which JWH-133 may interact with morphine. JWH-133 produces dose-dependent anti-nociception during both the acute and inflammatory phases of the formalin test. This was observed in both male and female mice. However, a maximally efficacious dose of JWH-133 (1 mg/kg) was not associated with somatic withdrawal symptoms, motor impairment, or hypothermia. After eleven once-daily injections of 1 mg/JWH-133, no tolerance was observed in the formalin test. Cross-tolerance for the anti-nociceptive effects of JWH-133 and morphine were assessed to gain insight into physiologically relevant cannabinoid 2 receptor and mu-opioid receptor interaction. Mice made tolerant to the effects of morphine exhibited a lower JWH-133 response in both phases of the formalin test compared to vehicle-treated morphine-naïve animals. However, repeated daily JWH-133 administration did not cause cross-tolerance for morphine, suggesting opioid and cannabinoid 2 receptor cross-tolerance is unidirectional. However, preliminary data suggest co-administration of JWH-133 with morphine modestly attenuates morphine tolerance. Isobolographic analysis revealed that co-administration of JWH-133 and morphine has an additive effect on anti-nociception in the formalin test. Overall these findings show that cannabinoid 2 receptor may functionally interact with mu-opioid receptor to modulate anti-nociception in the formalin test.”

https://www.ncbi.nlm.nih.gov/pubmed/28879802

http://journals.sagepub.com/doi/10.1177/1744806917728227

 

Endocannabinoids Have Opposing Effects On Behavioral Responses To Nociceptive And Non-nociceptive Stimuli.

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“The endocannabinoid system is thought to modulate nociceptive signaling making it a potential therapeutic target for treating pain.

However, there is evidence that endocannabinoids have both pro- and anti-nociceptive effects. In previous studies using Hirudo verbana (the medicinal leech), endocannabinoids were found to depress nociceptive synapses, but enhance non-nociceptive synapses. Here we examined whether endocannabinoids have similar bidirectional effects on behavioral responses to nociceptive vs. non-nociceptive stimuli in vivo.

These results provide evidence that endocannabinoids can have opposing effects on nociceptive vs. non-nociceptive pathways and suggest that cannabinoid-based therapies may be more appropriate for treating pain disorders in which hyperalgesia and not allodynia is the primary symptom.”

 https://www.ncbi.nlm.nih.gov/pubmed/28724917
https://www.nature.com/articles/s41598-017-06114-1

Antagonism of cannabinoid receptor 1 attenuates the anti-inflammatory effects of electroacupuncture in a rodent model of migraine.

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“The anti-nociceptive effects of electroacupuncture (EA) in migraine have been documented in multiple randomised controlled trials.

Neurogenic inflammation plays a key role in migraine attacks, and the anti-inflammatory effects of acupuncture have been associated with the type 1 cannabinoid (CB1) receptor.

CB1 receptors appear to mediate anti-inflammatory effects of EA in a rat model of migraine.”

https://www.ncbi.nlm.nih.gov/pubmed/27834685

Therapeutic potential of fatty acid amide hydrolase, monoacylglycerol lipase, and N-acylethanolamine acid amidase inhibitors.

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“Fatty acid ethanolamides (FAEs) and endocannabinoids (ECs) have been shown to alleviate pain and inflammation, regulate motility and appetite, and produce anti-cancer, anxiolytic, and neuroprotective efficacies via cannabinoid receptor type 1 (CB1) or type 2 (CB2), or via peroxisome proliferator-activated receptor α (PPAR-α) stimulation.

FAEs and ECs are synthesized by a series of endogenous enzymes, including N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD), diacylglycerol lipase (DAGL), or phospholipase C (PLC), and their metabolism is mediated by several metabolic enzymes, including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), N-acylethanolamine acid amidase (NAAA), or cyclooxygenase-2 (COX-2).

Over the last decades, increasing the concentration of FAEs and ECs through the inhibition of degrading enzymes has been considered to be a viable therapeutic approach to enhance their anti-nociceptive and anti-inflammatory effects, as well as protecting the nervous system.”

 https://www.ncbi.nlm.nih.gov/pubmed/27766867

Evaluation of Two Commercially Available Cannabidiol Formulations for Use in Electronic Cigarettes.

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“Since 24 states and the District of Columbia have legalized marijuana in some form, suppliers of legal marijuana have developed Cannabis sativa products for use in electronic cigarettes (e-cigarettes).

Personal battery powered vaporizers, or e-cigarettes, were developed to deliver a nicotine vapor such that smokers could simulate smoking tobacco without the inherent pathology of inhaled tobacco smoke. The liquid formulations used in these devices are comprised of an active ingredient such as nicotine mixed with vegetable glycerin (VG) and/or propylene glycol (PG) and flavorings.

A significant active ingredient of C. sativa, cannabidiol (CBD), has been purported to have anti-convulsant, anti-nociceptive, and anti-psychotic properties. These properties have potential medical therapies such as intervention of addictive behaviors, treatments for epilepsy, management of pain for cancer patients, and treatments for schizophrenia.

However, CBD extracted from C. sativa remains a DEA Schedule I drug since it has not been approved by the FDA for medical purposes.

Two commercially available e-cigarette liquid formulations reported to contain 3.3 mg/mL of CBD as the active ingredient were evaluated. These products are not regulated by the FDA in manufacturing or in labeling of the products and were found to contain 6.5 and 7.6 mg/mL of CBD in VG and PG with a variety of flavoring agents. Presently, while labeled as to content, the quality control of manufacturers and the relative safety of these products is uncertain.”

http://www.ncbi.nlm.nih.gov/pubmed/27621706

The multiplicity of spinal AA-5-HT anti-nociceptive action in a rat model of neuropathic pain.

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“There is considerable evidence to support the role of anandamide (AEA), an endogenous ligand of cannabinoid receptors, in neuropathic pain modulation. AEA also produces effects mediated by other biological targets, of which the transient receptor potential vanilloid type 1 (TRPV1) has been the most investigated. Both, inhibition of AEA breakdown by fatty acid amide hydrolase (FAAH) and blockage of TRPV1 have been shown to produce anti-nociceptive effects.

Recent research suggests the usefulness of dual-action compounds, which may afford greater anti-allodynic efficacy. Therefore, in the present study, we examined the effect of N-arachidonoyl-serotonin (AA-5-HT), a blocker of FAAH and TRPV1, in a rat model of neuropathic pain after intrathecal administration.

We found that treatment with AA-5-HT increased the pain threshold to mechanical and thermal stimuli, with highest effect at the dose of 500nM, which was most strongly attenuated by AM-630, CB2 antagonist, administration. The single action blockers PF-3845 (1000nM, for FAAH) and I-RTX (1nM, for TRPV1) showed lower efficacy than AA-5-HT. Moreover AA-5-HT (500nM) elevated AEA and palmitoylethanolamide (PEA) levels.

Among the possible targets of these mediators, only the mRNA levels of CB2, GPR18 and GPR55, which are believed to be novel cannabinoid receptors, were upregulated in the spinal cord and/or DRG of CCI rats. It was previously reported that AA-5-HT acts in CB1 and TRPV1-dependent manner after systemic administration, but here for the first time we show that AA-5-HT action at the spinal level involves CB2, with potential contributions from GRP18 and/or GPR55 receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27326920