Cannabidiol Inhibits Paclitaxel-Induced Neuropathic Pain Through 5-HT(1A) Receptors Without Diminishing Nervous System Function or Chemotherapy Efficacy

Br J Pharmacol. 2014 Feb;171(3):636-45. doi: 10.1111/bph.12439.

Abstract

Background and purpose: Paclitaxel (PAC) is associated with chemotherapy-induced neuropathic pain (CIPN) that can lead to the cessation of treatment in cancer patients even in the absence of alternate therapies. We previously reported that chronic administration of the non-psychoactive cannabinoid cannabidiol (CBD) prevents PAC-induced mechanical and thermal sensitivity in mice. Hence, we sought to determine receptor mechanisms by which CBD inhibits CIPN and whether CBD negatively effects nervous system function or chemotherapy efficacy.

Experimental approach: The ability of acute CBD pretreatment to prevent PAC-induced mechanical sensitivity was assessed, as was the effect of CBD on place conditioning and on an operant-conditioned learning and memory task. The potential interaction of CBD and PAC on breast cancer cell viability was determined using the MTT assay.

Key results: PAC-induced mechanical sensitivity was prevented by administration of CBD (2.5 - 10 mg·kg⁻¹) in female C57Bl/6 mice. This effect was reversed by co-administration of the 5-HT(1A) antagonist WAY 100635, but not the CB₁ antagonist SR141716 or the CB₂ antagonist SR144528. CBD produced no conditioned rewarding effects and did not affect conditioned learning and memory. Also, CBD + PAC combinations produce additive to synergistic inhibition of breast cancer cell viability.

Conclusions and implications: Our data suggest that CBD is protective against PAC-induced neurotoxicity mediated in part by the 5-HT(1A) receptor system. Furthermore, CBD treatment was devoid of conditioned rewarding effects or cognitive impairment and did not attenuate PAC-induced inhibition of breast cancer cell viability. Hence, adjunct treatment with CBD during PAC chemotherapy may be safe and effective in the prevention or attenuation of CIPN.

Keywords: 5-HT1A; CIPN; breast cancer; cannabidiol; cannabinoid; chemotherapy-induced neuropathic pain; mechanical sensitivity; paclitaxel.

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / adverse effects
  • Antineoplastic Agents, Phytogenic / agonists
  • Antineoplastic Agents, Phytogenic / antagonists & inhibitors
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Behavior, Animal / drug effects
  • Brain / drug effects
  • Brain / metabolism
  • Breast Neoplasms / drug therapy
  • Cannabidiol / adverse effects
  • Cannabidiol / antagonists & inhibitors
  • Cannabidiol / therapeutic use*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Conditioning, Operant / drug effects
  • Drug Synergism
  • Female
  • Humans
  • Memory / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Neuralgia / chemically induced
  • Neuralgia / metabolism
  • Neuralgia / physiopathology
  • Neuralgia / prevention & control*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neuroprotective Agents / adverse effects
  • Neuroprotective Agents / antagonists & inhibitors
  • Neuroprotective Agents / therapeutic use*
  • Paclitaxel / adverse effects
  • Paclitaxel / agonists
  • Paclitaxel / antagonists & inhibitors*
  • Paclitaxel / pharmacology
  • Receptor, Serotonin, 5-HT1A / chemistry
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Serotonin 5-HT1 Receptor Agonists / adverse effects
  • Serotonin 5-HT1 Receptor Agonists / chemistry
  • Serotonin 5-HT1 Receptor Agonists / therapeutic use*
  • Serotonin 5-HT1 Receptor Antagonists / pharmacology

Substances

  • Antineoplastic Agents, Phytogenic
  • Neuroprotective Agents
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin 5-HT1 Receptor Antagonists
  • Receptor, Serotonin, 5-HT1A
  • Cannabidiol
  • Paclitaxel