Antiallodynic effect of β-caryophyllene on paclitaxel-induced peripheral neuropathy in mice

Neuropharmacology. 2017 Oct;125:207-219. doi: 10.1016/j.neuropharm.2017.07.015. Epub 2017 Jul 18.


Painful peripheral neuropathy is a common side effect of paclitaxel (PTX). The use of analgesics is an important component for management of PTX-induced peripheral neuropathy (PINP). However, currently employed analgesics have several side effects and are poorly effective. β-caryophyllene (BCP), a dietary selective CB2 agonist, has shown analgesic effect in neuropathic pain models, but its role in chemotherapy-induced neuropathic pain has not yet been investigated. Herein, we used the mouse model of PINP to show the therapeutic effects of BCP in this neuropathy. Male Swiss mice receiving PTX (2 mg kg-1, ip, four alternate days) were treated with BCP (25 mg kg-1, po, twice a day) either during or after PTX administration. Some groups were also pretreated with AM630 (CB2 antagonist, 3 mg kg-1, ip) or AM251 (CB1 antagonist, 1 mg kg-1, ip). Spinal cord samples were collected in different time points to perform immunohistochemical analysis. BCP attenuated the established mechanical allodynia induced by PTX (p < 0.0001) in a CB2-dependent manner. Of note, when given concomitantly with PTX, BCP was able to attenuate the development of PINP (p < 0.0001). Spinal cord immunohistochemistry revealed that preventive treatment with BCP reduced p38 MAPK and NF-κB activation, as well as the increased Iba-1 and IL-1β immunoreactivity promoted by PTX. Our findings show that BCP effectively attenuated PINP, possibly through CB2-activation in the CNS and posterior inhibition of p38 MAPK/NF-κB activation and cytokine release. Taken together, our results suggest that BCP could be used to attenuate the establishment and/or treat PINP.

Keywords: Cannabinoid; Neuropathic pain; Paclitaxel; β-caryophyllene.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Antineoplastic Agents, Phytogenic / toxicity
  • Cannabinoid Receptor Modulators / pharmacology
  • Cytokines / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Hyperalgesia / chemically induced
  • Hyperalgesia / drug therapy*
  • Hyperalgesia / immunology
  • Hyperalgesia / pathology
  • Indoles / pharmacology
  • Male
  • Neuralgia / chemically induced
  • Neuralgia / drug therapy*
  • Neuralgia / immunology
  • Neuralgia / pathology
  • Paclitaxel / toxicity*
  • Pain Threshold / drug effects
  • Pain Threshold / physiology
  • Peripheral Nervous System Diseases / chemically induced*
  • Peripheral Nervous System Diseases / drug therapy
  • Peripheral Nervous System Diseases / immunology
  • Peripheral Nervous System Diseases / pathology
  • Piperidines / pharmacology
  • Polycyclic Sesquiterpenes
  • Pyrazoles / pharmacology
  • Random Allocation
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptor, Cannabinoid, CB2 / agonists
  • Receptor, Cannabinoid, CB2 / metabolism
  • Sesquiterpenes / pharmacology*
  • Spinal Cord / drug effects
  • Spinal Cord / immunology
  • Spinal Cord / pathology


  • Anti-Inflammatory Agents, Non-Steroidal
  • Antineoplastic Agents, Phytogenic
  • CNR1 protein, mouse
  • Cannabinoid Receptor Modulators
  • Cnr2 protein, mouse
  • Cytokines
  • Indoles
  • Piperidines
  • Polycyclic Sesquiterpenes
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Sesquiterpenes
  • AM 251
  • caryophyllene
  • Paclitaxel
  • iodopravadoline