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

doi:10.1016/j.biopsych.2014.04.009

Biological Psychiatry

Volume 77, Issue 5, 1 March 2015, Pages 475-487

https://doi.org/10.1016/j.biopsych.2014.04.009 Get rights and content

Abstract

Background

Mixed cannabinoid receptor 1 and 2 (CB₁ and 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 antiallodynic 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 CB₁ knockout (CB₁KO), CB₂ knockout (CB₂KO), and wild-type (WT) mice. Comparisons were made with the prototypic classic cannabinoid Δ⁹-THC. We also explored the site and possible mechanism of action of AM1710.

Results

Paclitaxel-induced mechanical and cold allodynia developed to an equivalent degree in CB₁KO, CB₂KO, and WT mice. Both AM1710 and Δ⁹-THC suppressed established paclitaxel-induced allodynia in WT mice. In contrast to Δ⁹-THC, chronic administration of AM1710 did not engage CB₁ activity or produce antinociceptive tolerance, CB₁-mediated cannabinoid withdrawal, hypothermia, or motor dysfunction. Antiallodynic efficacy of systemic administration of AM1710 was absent in CB₂KO mice and WT mice receiving the CB₂ antagonist AM630, administered either systemically or intrathecally. Intrathecal administration of AM1710 also attenuated paclitaxel-induced allodynia in WT mice, but not CB₂KO mice, implicating a possible role for spinal CB₂ receptors in AM1710 antiallodynic efficacy. Finally, both acute and chronic administration of AM1710 decreased messenger RNA levels of tumor necrosis factor-α 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.

Section snippets

Subjects

Adult CB₂KO mice, strain B6.129P2-CNR2(tm1Dgen/J) (Jackson Laboratory, Bar Harbor, Maine) and WT littermates (Jackson Laboratory) on C57BL/6J background, and CB₁KO mice (generated as previously described (4)) and WT littermates (Charles River Laboratories, Wilmington, Massachusetts) on CD1 background, weighing 25–33 g and of both sexes, were used in these experiments. Mice were periodically backcrossed to maintain genetic integrity. Animals were single-housed in a temperature-controlled

Paclitaxel-Induced Allodynia Developed Similarly in WT, CB₂KO, and CB₁KO Mice

In both CB₂KO and WT mice, paclitaxel decreased mechanical thresholds [F_3,20 = 519.03, p < .0001] (Figure 1A) and increased response time to cold stimulation [F_3,20 = 553.78, p < .0001] (Figure 1B). Similarly, paclitaxel induced mechanical [F_3,20 = 426.66, p < .0001] (Figure 1C) and cold [F_3,20 = 707.28, p < .0001] (Figure 1D) allodynia in CB₁KO mice and WT littermates. Mechanical and cold allodynia were present in paclitaxel-treated CB₂KO, CB₁KO, and WT mice relative to cremophor-vehicle since

Discussion

Drug development for management of neuropathic pain has been a challenge partly because of limited efficacy and troubling side-effect profiles. These challenges also apply to potential therapeutic use of cannabinoids (44). In the present study, we showed that repeated systemic administration of the CB₂-preferring agonist AM1710 suppressed chemotherapy-induced allodynia without tolerance or significant CB₁ involvement (i.e., the absence of CB₁ antagonist–precipitated withdrawal symptoms, motor

Acknowledgments and Disclosures

This work was supported by National Institute on Drug Abuse (NIDA) Grant Nos. DA021644 (AGH), DA037673 (AGH), DA011322 (KM), DA021696 (KM), DA3801 (AM), DA07215 (AM), DA09158 (AM), and DA035068 (KM and AGH). AM serves as a consultant for MAKScientific.

We thank Vishnu Kodumuru for providing AM1710 and James Wager-Miller for designing and providing the reverse transcription polymerase chain reaction primers.

The authors report no biomedical financial interests or potential conflicts of interest.

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

Abstract

Background

Methods

Results

Conclusions

Section snippets

Subjects

Paclitaxel-Induced Allodynia Developed Similarly in WT, CB2KO, and CB1KO Mice

Discussion

Acknowledgments and Disclosures

Eur J Pharmacol

J Pain

Pain

Neuroscience

Exp Neurol

Pain

Pain

Adv Drug Deliv Rev

Pain

Pharmacol Res

Pain

Neuroscience

Neurobiol Dis

Eur J Pharmacol

Neuropharmacology

Lancet

Pharmacol Biochem Behav

Drug Alcohol Depend

Drug Alcohol Depend

Pharmacol Biochem Behav

Neuropharmacology

Life Sci

Eur J Pharmacol

Pain

J Pain

J Pain

Neurosci Lett

Pain

Neuropharmacology

Pain

Modulating the endocannabinoid system in human health and disease—successes and failures

FEBS J

Targeting the endocannabinoid system with cannabinoid receptor agonists: Pharmacological strategies and therapeutic possibilities

Philos Trans R Soc Lond B Biol Sci

Cannabinoids: Reward, dependence, and underlying neurochemical mechanisms—a review of recent preclinical data

Psychopharmacology

Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice

Science

CB2: A cannabinoid receptor with an identity crisis

Br J Pharmacol

The endocannabinoid system and pain

CNS Neurol Disord Drug Targets

The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration

Curr Neuropharmacol

Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: Relevance for Huntington’s disease

Glia

Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer’s disease brains

J Neurosci

Cannabinoid CB2 receptor-mediated anti-nociception in models of acute and chronic pain

Mol Neurobiol

CB2 cannabinoid receptor-mediated peripheral antinociception

Pain

Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors

Anesthesiology

Central and peripheral sites of action for CB(2) receptor mediated analgesic activity in chronic inflammatory and neuropathic pain models in rats

Br J Pharmacol

Spinal microglial and perivascular cell cannabinoid receptor type 2 activation reduces behavioral hypersensitivity without tolerance after peripheral nerve injury

Anesthesiology

Spinal and peripheral analgesic effects of the CB2 cannabinoid receptor agonist AM1241 in two models of bone cancer-induced pain

Br J Pharmacol

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

Paclitaxel-Induced Allodynia Developed Similarly in WT, CB₂KO, and CB₁KO Mice