Cannabidiol Prevents the Development of Cold and Mechanical Allodynia in Paclitaxel-Treated Female C57Bl6 Mice

Ward, Sara Jane; Ramirez, Michael David; Neelakantan, Harshini; Walker, Ellen A.

doi:10.1213/ane.0b013e3182283486

Cited by 119 publications

(112 citation statements)

References 11 publications

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“…was administered four times on alternate days (cumulative dose: 16 mg/kg i.p.) to induce neuropathy (39). Controls received an equal volume of cremophor-vehicle.…”

Section: Methodsmentioning

confidence: 99%

Chronic Cannabinoid Receptor 2 Activation Reverses Paclitaxel Neuropathy Without Tolerance or Cannabinoid Receptor 1–Dependent Withdrawal

Deng

Guindon

Cornett

et al. 2015

Biological Psychiatry

180

229

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Background Mixed cannabinoid CB1/CB2 agonists such as Δ9-tetrahydrocannabinol (Δ9-THC) can produce tolerance, physical withdrawal, and unwanted CB1-mediated central nervous system side effects. Whether repeated systemic administration of a CB2-preferring agonist engages CB1 receptors or produces CB1-mediated side effects is unknown. Methods We evaluated anti-allodynic efficacy, possible tolerance, and cannabimimetic side effects of repeated dosing with a CB2-preferring agonist AM1710 in a model of chemotherapy-induced neuropathy produced by paclitaxel using CB1KO, CB2KO, and WT mice. Comparisons were made with the prototypic classical cannabinoid Δ9-THC. We also explored the site and possible mechanism of action of AM1710. Results Paclitaxel-induced mechanical and cold allodynia developed equivalently in CB1KO, CB2KO, and WT mice. Both AM1710 and Δ9-THC suppressed established paclitaxel-induced allodynia in WT mice. Unlike Δ9-THC, chronic AM1710 did not engage CB1 activity or produce antinociceptive tolerance, CB1-mediated cannabinoid withdrawal, hypothermia, or motor dysfunction. Anti-allodynic efficacy of systemic AM1710 was absent in CB2KO mice or WT mice receiving the CB2 antagonist AM630, administered either systemically or intrathecally. Intrathecal AM1710 also attenuated paclitaxel-induced allodynia in WT but not CB2KO mice, implicating a possible role for spinal CB2 receptors in AM1710 anti-allodynic efficacy. Finally, both acute and chronic treatment with AM1710 decreased mRNA levels of tumor necrosis factor alpha and monocyte chemoattractant protein-1 in lumbar spinal cord of paclitaxel-treated WT mice. Conclusions Our results highlight the potential of prolonged use of CB2 agonists for managing chemotherapy-induced allodynia with a favorable therapeutic ratio marked by sustained efficacy and absence of tolerance, physical withdrawal, or CB1-mediated side effects.

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“…was administered four times on alternate days (cumulative dose: 16 mg/kg i.p.) to induce neuropathy (39). Controls received an equal volume of cremophor-vehicle.…”

Section: Methodsmentioning

confidence: 99%

Chronic Cannabinoid Receptor 2 Activation Reverses Paclitaxel Neuropathy Without Tolerance or Cannabinoid Receptor 1–Dependent Withdrawal

Deng

Guindon

Cornett

et al. 2015

Biological Psychiatry

180

229

View full text Add to dashboard Cite

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“…was administered four times on days 0, 2, 4, and 6 after initiation of paclitaxel dosing in a volume of 6.67 ml/kg (cumulative dose: 16 mg/kg, i.p.) to induce neuropathy, as previously described (Ward et al, 2011;Deng et al, 2015). The control group received an equivalent volume of CR-vehicle.…”

Section: Methodsmentioning

confidence: 99%

CB₁ Knockout Mice Unveil Sustained CB₂-Mediated Antiallodynic Effects of the Mixed CB₁/CB₂ Agonist CP55,940 in a Mouse Model of Paclitaxel-Induced Neuropathic Pain

et al. 2015

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Cannabinoids suppress neuropathic pain through activation of cannabinoid CB 1 and/or CB 2 receptors; however, unwanted CB 1 -mediated cannabimimetic effects limit clinical use. We asked whether CP55,940 [(2)-3-[2-hydroxy-4-(1,1-dimethylheptyl) phenyl]-4-(3-hydroxypropyl)cyclohexanol], a potent cannabinoid that binds with similar affinity to CB 1 and CB 2 in vitro, produces functionally separable CB 1 -and CB 2 -mediated pharmacological effects in vivo. We evaluated antiallodynic effects, possible tolerance, and cannabimimetic effects (e.g., hypothermia, catalepsy, CB 1 -dependent withdrawal signs) after systemic CP55,940 treatment in a mouse model of toxic neuropathy produced by a chemotherapeutic agent, paclitaxel. The contribution of CB 1 and CB 2 receptors to in vivo actions of CP55,940 was evaluated using CB 1 knockout (KO), CB 2 KO, and wild-type (WT) mice. Low-dose CP55,940 (0.3 mg/kg daily, i.p. ) suppressed paclitaxel-induced allodynia in WT and CB 2 KO mice, but not CB 1 KO mice. Low-dose CP55,940 also produced hypothermia and rimonabantprecipitated withdrawal in WT, but not CB 1 KO, mice. In WT mice, tolerance developed to CB 1 -mediated hypothermic effects of CP55,940 earlier than to antiallodynic effects. High-dose CP55,940 (10 mg/kg daily, i.p.) produced catalepsy in WT mice, which precluded determination of antiallodynic efficacy but produced sustained CB 2 -mediated suppression of paclitaxelinduced allodynia in CB 1 KO mice; these antiallodynic effects were blocked by the CB 2 antagonist 6-iodopravadoline (AM630). Highdose CP55,940 did not produce hypothermia or rimonabantprecipitated withdrawal in CB 1 KO mice. Our results using the mixed CB 1 /CB 2 agonist CP55,940 document that CB 1 and CB 2 receptor activations produce mechanistically distinct suppression of neuropathic pain. Our study highlights the therapeutic potential of targeting cannabinoid CB 2 receptors to bypass unwanted central effects associated with CB 1 receptor activation.

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“…Microinjections of 3 nM CBD in the ventrolateral periaqueductal gray appears to reduce the frequency of spikes generated by both ON cells and OFF cells (localized in the rostral ventromedial medulla (RVM), controlling the descending pathway of antinociception [250]. Furthermore, CBD appears to control allodynia and neuropathic pain caused by paclitaxel in mice [251,252].…”

Section: Painmentioning

confidence: 99%

“…A recent study suggests that each of them (e.g., TRPA1 and TRPV1) play distinct roles depending on the type of pain in rodent models [253]. So far, only TRPA1 and TRPV1 have been involved in the therapeutic action of CBD regarding the management of pain [249,251]. Capsazepine (intraperitoneally), a TRPV1 antagonist, abolished the therapeutic action of CBD in different rat models of pain such as carrageenaninduced thermal hyperalgesia, chronic constriction injury of the sciatic nerve, and the Freund's adjuvant model [248,249].…”

Section: Cbd Ion Channel Targets In Painmentioning

confidence: 99%

“…It is still not clear whether CBD is able to manage paclitaxel-induced neuropathic pain through the activation of 5-HT 1A receptor or through the inhibition of D 4 dopamine receptor [251,252], as studies that often investigate the involvement of 5-HT 1A receptor in therapeutic action of CBD employ WAY-100635, which not only acts as an antagonist of 5-HT 1A receptor [260], but is also a potent agonist at the D 4 dopamine receptor [48].…”

Section: Cbd Receptor Targets In Painmentioning

confidence: 99%

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Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

462

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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Cannabidiol Prevents the Development of Cold and Mechanical Allodynia in Paclitaxel-Treated Female C57Bl6 Mice

Cited by 119 publications

References 11 publications

Chronic Cannabinoid Receptor 2 Activation Reverses Paclitaxel Neuropathy Without Tolerance or Cannabinoid Receptor 1–Dependent Withdrawal

Chronic Cannabinoid Receptor 2 Activation Reverses Paclitaxel Neuropathy Without Tolerance or Cannabinoid Receptor 1–Dependent Withdrawal

CB₁ Knockout Mice Unveil Sustained CB₂-Mediated Antiallodynic Effects of the Mixed CB₁/CB₂ Agonist CP55,940 in a Mouse Model of Paclitaxel-Induced Neuropathic Pain

Molecular Targets of Cannabidiol in Neurological Disorders

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Cannabidiol Prevents the Development of Cold and Mechanical Allodynia in Paclitaxel-Treated Female C57Bl6 Mice

Cited by 119 publications

References 11 publications

Chronic Cannabinoid Receptor 2 Activation Reverses Paclitaxel Neuropathy Without Tolerance or Cannabinoid Receptor 1–Dependent Withdrawal

Chronic Cannabinoid Receptor 2 Activation Reverses Paclitaxel Neuropathy Without Tolerance or Cannabinoid Receptor 1–Dependent Withdrawal

CB1 Knockout Mice Unveil Sustained CB2-Mediated Antiallodynic Effects of the Mixed CB1/CB2 Agonist CP55,940 in a Mouse Model of Paclitaxel-Induced Neuropathic Pain

Molecular Targets of Cannabidiol in Neurological Disorders

Contact Info

Product

Resources

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CB₁ Knockout Mice Unveil Sustained CB₂-Mediated Antiallodynic Effects of the Mixed CB₁/CB₂ Agonist CP55,940 in a Mouse Model of Paclitaxel-Induced Neuropathic Pain