Behavioural and pharmacological effects of cannabidiol (CBD) and the cannabidiol analogue KLS‐13019 in mouse models of pain and reinforcement

Foss, Jeffery D.; Farkas, Daniel; Huynh, L. M.; Kinney, William A.; Brenneman, Douglas E.; Ward, Sara Jane

doi:10.1111/bph.15486

Cited by 18 publications

(21 citation statements)

References 35 publications

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“…Here, we found that pure CBD alone had little impact on acute pain associated with CIPN. This is in contrast to several other studies that have found that CBD can reduce neuropathic pain in animal models [ 10 , 12 , 19 ]. An important difference between our study and the previous work is that we are looking at the acute effects of CBD administration as compared to those studies that looked at more prolonged effects of CBD treatment.…”

Section: Discussioncontrasting

confidence: 95%

Combinations of Cannabidiol and Δ9-Tetrahydrocannabinol in Reducing Chemotherapeutic Induced Neuropathic Pain

et al. 2022

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Neuropathic pain is a condition that impacts a substantial portion of the population and is expected to affect a larger percentage in the future. This type of pain is poorly managed by current therapies, including opioids and NSAIDS, and novel approaches are needed. We used a cisplatin-induced model of neuropathic pain in mice to assess the effects of the cannabinoids THC and CBD alone or in varying ratios as anti-nociceptive agents. In addition to testing pure compounds, we also tested extracts containing high THC or CBD at the same ratios. We found that pure CBD had little impact on mechanical hypersensitivity, whereas THC reduced mechanical hypersensitivity in both male and female mice (as has been reported in the literature). Interestingly, we found that high CBD cannabis extract, at the same CBD dose as pure CBD, was able to reduce mechanical hypersensitivity, although not to the same level as high THC extract. These data suggest that, at least for CBD-dominant cannabis extracts, there is an increase in the anti-nociceptive activity that may be attributed to other constitutes of the plant. We also found that high THC extract or pure THC is the most efficacious treatment for reducing neuropathic pain in this model.

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Section: Discussioncontrasting

confidence: 95%

Combinations of Cannabidiol and Δ9-Tetrahydrocannabinol in Reducing Chemotherapeutic Induced Neuropathic Pain

et al. 2022

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“…A second major goal of these studies was to test if changes in GPR55 IR area were reversible after treatment with KLS-13019, a novel compound that has been shown to reverse mechanical allodynia in paclitaxel-treated mice (Foss et al 2021). To test for reversibility of paclitaxel-induced increases in cell body GPR55 IR area, DRG cultures were pre-treated for 8 hours with 3 mM paclitaxel and then the cultures were co-treated for an additional 16 hours with various concentration of KLS-13019 in the continuing presence of paclitaxel.…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, we and others have demonstrated that CBD and other non-psychoactive cannabinoids are effective in animal models of spinal cord injury-associated neuropathic pain (Li et al 2018). However, CBD has limitations in terms of potency, e cacy, safety, and oral bioavailability (Brenneman et al 2018;Foss et al 2021). With the recognition that optimization of CBD was warranted, the development of analogues of CBD was undertaken with the eventual emergence of KLS-13019 (Kinney et al 2016), a novel compound that has been shown to be effective in both the prevention and reversal of allodynia in a mouse model of CIPN (Foss et al 2021).…”

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory Properties of KLS-13019: a Novel GPR55 Antagonist for Dorsal Root Ganglion and Hippocampal Cultures

Brenneman¹,

Kinney²,

McDonnell³

et al. 2022

J Mol Neurosci

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KLS-13019, a novel devised cannabinoid-like compound, was explored for anti-in ammatory actions in dorsal root ganglion cultures relevant to chemotherapy-induced peripheral neuropathy (CIPN). Time course studies with 3 mM paclitaxel indicated >1.9-fold increases in immunoreactive (IR) area for cell body GPR55 after 30 minutes as determined by high content imaging. To test for reversibility of paclitaxel-induced increases in GPR55, cultures were treated for 8 hours with paclitaxel alone and then a dose response to KLS-13019 added for another 16 hours. This: "reversal" paradigm indicated established increases in cell body GPR55 IR areas were decreased back to control levels (IC50: 0.117 nM). Because GPR55 had previously reported in ammatory actions, IL-1b and NLRP3 (in ammasome-3 marker) were also measured in the "reversal" paradigm. Signi cant increases in all in ammatory markers were produced after 8 hours of paclitaxel treatment alone that were reversed to control levels with KLS-13019 treatment. Accompanying studies using alamar blue indicated that decreased cellular viability produced by paclitaxel treatment was reverted back to control levels by KLS-13019. Similar studies conducted with lysophosphatidylinositol (GPR55 agonist) in DRG or hippocampal cultures demonstrated signi cant increases in neuritic GPR55, NLRP3 and IL-1b areas that were reversed to control levels with KLS-13019 treatment. Studies with a human GPR55-b-arrestin assay in DiscoverX cells indicated that KLS-13019 was an antagonist without agonist activity. These studies indicated that KLS-13019 has antiin ammatory properties mediated through GPR55 antagonist actions. Together with previous studies, KLS-13019 is a potent neuroprotective, anti-in ammatory cannabinoid with therapeutic potential for high e cacy treatment of neuropathic pain.

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“…Administration of cannabidiol or its analogue (KLS‐13019) prior to administration of paclitaxel reduced mechanical allodynia on the 14th day. Furthermore, treatment with the analogue (20 mg/kg, i.p), but not with cannabidiol (20 mg/kg, i.p) administered on the 12th, 13th, and 14th day in animals sensitized with paclitaxel, showed antinociceptive activity [30] . Our results reinforce the antiallodynic activity of CBD analogue and cannabidiol in the prevention of paclitaxel‐induced neuropathy and could serve as a basis for the development of new substances with better analgesic efficacy in models of chronic pain.…”

Section: Resultsmentioning

confidence: 94%

Synthesis and Antiallodynic Activity of Cannabidiol Analogue on Peripheral Neuropathy in Mice

Marques,

Braga,

Silva

et al. 2024

Chemistry & Biodiversity

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Cannabidiol (CBD) is a substance that exerts several therapeutic actions, including analgesia. CBD is generally administered orally, but its poor water solubility and metabolism impairs its bioavailability. Thus, the development of molecules with better pharmacokinetic profile from cannabidiol becomes an interesting strategy for the design of novel analgesic drugs for the relief of painful conditions that are difficult to manage clinically, such as neuropathic pain. In the present study, an unprecedented analogue of CBD (1) was synthesized and some of its physicochemical properties were evaluated in silico as well as its stability in an acid medium. Additionally, its effect was investigated in a model of neuropathic pain induced by the chemotherapy drug paclitaxel in mice, in comparison with cannabidiol itself. Cannabidiol (20 mg/kg), pregabalin (30 mg/kg) or analogue 1 (5, 10 and 20 mg/kg), administered on the fourteenth day after the first administration of paclitaxel, attenuated the mechanical allodynia of the sensitized animals. The antinociceptive activity of the 1 was attenuated by previous administration of a cannabinoid CB1 receptor antagonist, AM 251, which indicates that its mechanism of action is related to the activation of CB1 receptors.

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Behavioural and pharmacological effects of cannabidiol (CBD) and the cannabidiol analogue KLS‐13019 in mouse models of pain and reinforcement

Cited by 18 publications

References 35 publications

Combinations of Cannabidiol and Δ9-Tetrahydrocannabinol in Reducing Chemotherapeutic Induced Neuropathic Pain

Combinations of Cannabidiol and Δ9-Tetrahydrocannabinol in Reducing Chemotherapeutic Induced Neuropathic Pain

Anti-Inflammatory Properties of KLS-13019: a Novel GPR55 Antagonist for Dorsal Root Ganglion and Hippocampal Cultures

Synthesis and Antiallodynic Activity of Cannabidiol Analogue on Peripheral Neuropathy in Mice

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