Tags

Type your tag names separated by a space and hit enter

Chronic cannabinoid receptor 2 activation reverses paclitaxel neuropathy without tolerance or cannabinoid receptor 1-dependent withdrawal.

Abstract

BACKGROUND

Mixed cannabinoid receptor 1 and 2 (CB1 and CB2) agonists such as Δ(9)-tetrahydrocannabinol (Δ(9)-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 Δ(9)-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 Δ(9)-THC suppressed established paclitaxel-induced allodynia in WT mice. In contrast to Δ(9)-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.

Links

  • PMC Free PDF
  • PMC Free Full Text
  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Program in Neuroscience, Indiana University, Bloomington, Indiana; Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana; Interdisciplinary Biochemistry Graduate Program, Indiana University, Bloomington, Indiana.

    ,

    Program in Neuroscience, Indiana University, Bloomington, Indiana; Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana.

    ,

    Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana.

    ,

    Center for Drug Discovery, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts.

    ,

    Program in Neuroscience, Indiana University, Bloomington, Indiana; Interdisciplinary Biochemistry Graduate Program, Indiana University, Bloomington, Indiana; Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana.

    Program in Neuroscience, Indiana University, Bloomington, Indiana; Interdisciplinary Biochemistry Graduate Program, Indiana University, Bloomington, Indiana; Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana. Electronic address: hohmanna@indiana.edu.

    Source

    Biological psychiatry 77:5 2015 Mar 01 pg 475-87

    MeSH

    Animals
    Antineoplastic Agents, Phytogenic
    Cannabinoid Receptor Agonists
    Cannabinoid Receptor Antagonists
    Chemokine CCL2
    Chromones
    Disease Models, Animal
    Dronabinol
    Female
    Hyperalgesia
    Indoles
    Male
    Mice, Inbred C57BL
    Mice, Knockout
    Paclitaxel
    RNA, Messenger
    Random Allocation
    Receptor, Cannabinoid, CB1
    Receptor, Cannabinoid, CB2
    Spinal Cord
    Tumor Necrosis Factor-alpha

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    24853387

    Citation

    Deng, Liting, et al. "Chronic Cannabinoid Receptor 2 Activation Reverses Paclitaxel Neuropathy Without Tolerance or Cannabinoid Receptor 1-dependent Withdrawal." Biological Psychiatry, vol. 77, no. 5, 2015, pp. 475-87.
    Deng L, Guindon J, Cornett BL, et al. Chronic cannabinoid receptor 2 activation reverses paclitaxel neuropathy without tolerance or cannabinoid receptor 1-dependent withdrawal. Biol Psychiatry. 2015;77(5):475-87.
    Deng, L., Guindon, J., Cornett, B. L., Makriyannis, A., Mackie, K., & Hohmann, A. G. (2015). Chronic cannabinoid receptor 2 activation reverses paclitaxel neuropathy without tolerance or cannabinoid receptor 1-dependent withdrawal. Biological Psychiatry, 77(5), pp. 475-87. doi:10.1016/j.biopsych.2014.04.009.
    Deng L, et al. Chronic Cannabinoid Receptor 2 Activation Reverses Paclitaxel Neuropathy Without Tolerance or Cannabinoid Receptor 1-dependent Withdrawal. Biol Psychiatry. 2015 Mar 1;77(5):475-87. PubMed PMID: 24853387.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Chronic cannabinoid receptor 2 activation reverses paclitaxel neuropathy without tolerance or cannabinoid receptor 1-dependent withdrawal. AU - Deng,Liting, AU - Guindon,Josée, AU - Cornett,Benjamin L, AU - Makriyannis,Alexandros, AU - Mackie,Ken, AU - Hohmann,Andrea G, Y1 - 2014/04/25/ PY - 2013/12/13/received PY - 2014/03/21/revised PY - 2014/04/10/accepted PY - 2014/5/24/entrez PY - 2014/5/24/pubmed PY - 2015/11/3/medline KW - CB(2) KW - Chemotherapy-induced neuropathic pain KW - Knockout mouse KW - Precipitated withdrawal KW - Side effect KW - Tolerance SP - 475 EP - 87 JF - Biological psychiatry JO - Biol. Psychiatry VL - 77 IS - 5 N2 - BACKGROUND: Mixed cannabinoid receptor 1 and 2 (CB1 and CB2) agonists such as Δ(9)-tetrahydrocannabinol (Δ(9)-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 Δ(9)-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 Δ(9)-THC suppressed established paclitaxel-induced allodynia in WT mice. In contrast to Δ(9)-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. SN - 1873-2402 UR - https://www.unboundmedicine.com/medline/citation/24853387/Chronic_cannabinoid_receptor_2_activation_reverses_paclitaxel_neuropathy_without_tolerance_or_cannabinoid_receptor_1_dependent_withdrawal_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-3223(14)00274-1 DB - PRIME DP - Unbound Medicine ER -