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Selective Activation of Cannabinoid CB2 Receptors Suppresses Neuropathic Nociception Induced by Treatment with the Chemotherapeutic Agent Paclitaxel in Rats

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Rahn, Elizabeth J., Zvonok, Alexander M., Thakur, Ganesh A., Khanolkar, Atmaram D., Makriyannis, Alexandros, Hohmann, Andrea G.·2008·The Journal of Pharmacology and Experimental Therapeutics

DOI 10.1124/jpet.108.141994PMC PMC2682949

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Abstract

Activation of cannabinoid CB(2) receptors suppresses neuropathic pain induced by traumatic nerve injury. The present studies were conducted to evaluate the efficacy of cannabinoid CB(2) receptor activation in suppressing painful peripheral neuropathy evoked by chemotherapeutic treatment with the antitumor agent paclitaxel. Rats received paclitaxel (2 mg/kg i.p./day) on 4 alternate days to induce mechanical hypersensitivity (mechanical allodynia). Mechanical allodynia was defined as a lowering of the threshold for paw withdrawal to stimulation of the plantar hind paw surface with an electronic von Frey stimulator. Mechanical allodynia developed in paclitaxel-treated animals relative to groups receiving the Cremophor EL/ethanol/saline vehicle at the same times. Two structurally distinct cannabinoid CB(2) agonists, the aminoalkylindole (R,S)-AM1241 [(R,S)-(2-iodo-5-nitrophenyl)-[1-((1-methyl-piperidin-2-yl)methyl)-1H-indol-3-yl]-methanone] and the cannabilactone AM1714 (1,9-dihydroxy-3-(1',1'-dimethylheptyl)-6H-benzo[c]chromene-6-one), produced a dose-related suppression of established paclitaxel-evoked mechanical allodynia after systemic administration. Pretreatment with the CB(2) antagonist SR144528 [5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)-1H-pyrazole-3-carboxamide], but not the CB(1) antagonist SR141716 [5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide], blocked the antiallodynic effects of both (R,S)-AM1241 and AM1714. Moreover, (R)-AM1241, but not (S)-AM1241, suppressed paclitaxel-evoked mechanical allodynia relative to either vehicle treatment or preinjection thresholds, consistent with mediation by CB(2). Administration of either the CB(1) or CB(2) antagonist alone failed to alter paclitaxel-evoked mechanical allodynia. Moreover, (R,S)-AM1241 did not alter paw withdrawal thresholds in rats that received the Cremophor EL vehicle in lieu of paclitaxel, whereas AM1714 induced a modest antinociceptive effect. Our data suggest that cannabinoid CB(2) receptors may be important therapeutic targets for the treatment of chemotherapy-evoked neuropathy.

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Authors: Rahn, E. J., Zvonok, A. M., Thakur, G. A., Khanolkar, A. D., Makriyannis, A., & Hohmann, A. G.
Affiliations: University of Georgia (US)
Northeastern University (US)
ORCID: Thakur, Ganesh A.
Makriyannis, Alexandros
Hohmann, Andrea G.
Venue: The Journal of Pharmacology and Experimental Therapeutics
Publisher: Elsevier BV
Published: 2008-11
Volume: 327
Issue: 2
Pages: 584-591
ISSN: 0022-3565 (ISSN-L)
DOI: 10.1124/jpet.108.141994
PMC: PMC2682949
OpenAlex: W2093570206
Cited by: 116
References: 41
Citations by year: 2026: 1 · 2025: 7 · 2024: 5 · 2023: 4 · 2022: 5 · 2021: 9 · 2020: 7 · 2019: 10 · 2018: 10 · 2017: 8 · 2016: 4 · 2015: 2 · 2014: 6 · 2013: 6 · 2012: 11
FWCI: 4.90
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute on Drug Abuse (DA3801, DA022478, DA-022702, DA 9158, R01DA003801, R21DA022478, R01DA021644, R37DA003801, R21DA022702, P01DA009158, DA021644)
Topics: Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
Keywords: CB2 receptor, paclitaxel-induced neuropathic pain, chemotherapy-induced peripheral neuropathy, mechanical allodynia, CB2 receptor agonist, AM1241, SR144528, CB1 receptor, enantiomers, analgesia
MeSH terms: Animals, Antineoplastic Agents, Phytogenic, Cannabinoids, Chromones, Dimethyl Sulfoxide, Male, Morphine, Neuralgia, Stereoisomerism, Rats, Sprague-Dawley, Paclitaxel, Pain Threshold, Receptor, Cannabinoid, CB2, Rats

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Selective Activation of Cannabinoid CB2 Receptors Suppresses Neuropathic Nociception Induced by Treatment with the Chemotherapeutic Agent Paclitaxel in Rats

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