Selective Activation of Cannabinoid CB2 Receptors Suppresses Neuropathic Nociception Induced by Treatment with the Chemotherapeutic Agent Paclitaxel in Rats
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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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Mixed CB1/CB2 receptor agonists and CB2 receptor-selective agonists are effective against paclitaxel-induced peripheral neuropathy.
“It has been reported that mixed CB 1 /CB 2 receptor agonists and CB 2 receptor-selective agonists are effective against paclitaxel-induced peripheral neuropathy (Deng et al, 2015a(Deng et al, , 2015b;;Pascual et al, 2005;Rahn et al, 2008).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Rahn et al, 2008
Pre-treatment with the CB1 antagonist SR141716 enhanced the effects of A-836339 when applied to the L5 dorsal root ganglion, indicating that blockade of CB1 receptors enhanced the antinociceptive effects of a CB2 agonist.
“Interestingly, pre-treatment with the CB1 antagonist, SR141716, enhanced the effects of A-836339 when applied to the L5 DRG,88 indicating that blockade of CB1 receptors enhanced the antinociceptive effects of a CB2 agonist, as reported previously.89”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [89]
In this model, rats showed signs of mechanical allodynia up to 72 days post-paclitaxel.
“In this model, rats showed signs of mechanical allodynia up to 72 days post-paclitaxel.89”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [89]
(S)-AM1241 failed to produce an anti-allodynic effect.
“(S)-AM1241, the enantiomer exhibiting lower affinity for the CB2 receptor, failed to produce an anti-allodynic effect.89”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [89]
The novel cannabilactone AM1714 reversed mechanical allodynia associated with paclitaxel treatment in a CB2-dependent manner.
“The novel cannabilactone, AM1714, also reversed mechanical allodynia associated with paclitaxel treatment in a CB2-dependent manner.89”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [89]
Systemic administration of either (R,S)-AM1241 or its receptor-active enantiomer (R)-AM1241 produced CB2-mediated suppressions of paclitaxel-induced mechanical allodynia.
“Systemic administration of either the CB2 agonist (R,S)-AM1241 or its receptor-active enantiomer (R)-AM1241 produced CB2-mediated suppressions of paclitaxel-induced mechanical allodynia.”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [89]
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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)
- 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)
- 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
- 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 › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology › 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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