Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: Pain inhibition by receptors not present in the CNS

Mohab M. Ibrahim, Hongfeng Deng, Alexander Zvonok, Debra A. Cockayne, Joyce Kwan, Heriberto P. Mata, Todd W Vanderah, Josephine Lai, Frank Porreca, Alexandros Makriyannis, T. Philip Malan

Research output: Contribution to journalArticle

385 Citations (Scopus)

Abstract

We designed AM1241, a selective CB2, cannabinoid receptor agonist, and used it to test the hypothesis that CB2 receptor activation would reverse the sensory hypersensitivity observed in neuropathic pain states. AM1241 exhibits high affinity and selectivity for CB2 receptors. It also exhibits high potency in vivo. AM1241 dose-dependently reversed tactile and thermal hypersensitivity produced by ligation of the L5 and L6 spinal nerves in rats. These effects were selectively antagonized by a CB2 but not by a CB1 receptor antagonist, suggesting that they were produced by actions of AM1241 at CB2 receptors. AM1241 was also active in blocking spinal nerve ligation-induced tactile and thermal hypersensitivity in mice lacking CB1 receptors (CB1 -/- mice), confirming that AM1241 reverses sensory hypersensitivity independent of actions at CB1 receptors. These findings demonstrate a mechanism leading to the inhibition of pain, one that targets receptors localized exclusively outside the CNS. Further, they suggest the potential use of CB2 receptor-selective agonists for treatment of human neuropathic pain, a condition currently without consistently effective therapies. CB2 receptor-selective agonist medications are predicted to be without the CNS side effects that limit the effectiveness of currently available medications.

Original languageEnglish (US)
Pages (from-to)10529-10533
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number18
DOIs
StatePublished - Sep 2 2003

Fingerprint

Cannabinoid Receptor CB2
Nociceptors
Neuralgia
Cannabinoid Receptor CB1
Hypersensitivity
Spinal Nerves
Touch
Ligation
Hot Temperature
Cannabinoid Receptor Agonists
AM 1241
Inhibition (Psychology)
Pain
Therapeutics

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain : Pain inhibition by receptors not present in the CNS. / Ibrahim, Mohab M.; Deng, Hongfeng; Zvonok, Alexander; Cockayne, Debra A.; Kwan, Joyce; Mata, Heriberto P.; Vanderah, Todd W; Lai, Josephine; Porreca, Frank; Makriyannis, Alexandros; Malan, T. Philip.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 18, 02.09.2003, p. 10529-10533.

Research output: Contribution to journalArticle

Ibrahim, Mohab M. ; Deng, Hongfeng ; Zvonok, Alexander ; Cockayne, Debra A. ; Kwan, Joyce ; Mata, Heriberto P. ; Vanderah, Todd W ; Lai, Josephine ; Porreca, Frank ; Makriyannis, Alexandros ; Malan, T. Philip. / Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain : Pain inhibition by receptors not present in the CNS. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 18. pp. 10529-10533.
@article{c2c39108d12e424ca84b223551bed330,
title = "Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: Pain inhibition by receptors not present in the CNS",
abstract = "We designed AM1241, a selective CB2, cannabinoid receptor agonist, and used it to test the hypothesis that CB2 receptor activation would reverse the sensory hypersensitivity observed in neuropathic pain states. AM1241 exhibits high affinity and selectivity for CB2 receptors. It also exhibits high potency in vivo. AM1241 dose-dependently reversed tactile and thermal hypersensitivity produced by ligation of the L5 and L6 spinal nerves in rats. These effects were selectively antagonized by a CB2 but not by a CB1 receptor antagonist, suggesting that they were produced by actions of AM1241 at CB2 receptors. AM1241 was also active in blocking spinal nerve ligation-induced tactile and thermal hypersensitivity in mice lacking CB1 receptors (CB1 -/- mice), confirming that AM1241 reverses sensory hypersensitivity independent of actions at CB1 receptors. These findings demonstrate a mechanism leading to the inhibition of pain, one that targets receptors localized exclusively outside the CNS. Further, they suggest the potential use of CB2 receptor-selective agonists for treatment of human neuropathic pain, a condition currently without consistently effective therapies. CB2 receptor-selective agonist medications are predicted to be without the CNS side effects that limit the effectiveness of currently available medications.",
author = "Ibrahim, {Mohab M.} and Hongfeng Deng and Alexander Zvonok and Cockayne, {Debra A.} and Joyce Kwan and Mata, {Heriberto P.} and Vanderah, {Todd W} and Josephine Lai and Frank Porreca and Alexandros Makriyannis and Malan, {T. Philip}",
year = "2003",
month = "9",
day = "2",
doi = "10.1073/pnas.1834309100",
language = "English (US)",
volume = "100",
pages = "10529--10533",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "18",

}

TY - JOUR

T1 - Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain

T2 - Pain inhibition by receptors not present in the CNS

AU - Ibrahim, Mohab M.

AU - Deng, Hongfeng

AU - Zvonok, Alexander

AU - Cockayne, Debra A.

AU - Kwan, Joyce

AU - Mata, Heriberto P.

AU - Vanderah, Todd W

AU - Lai, Josephine

AU - Porreca, Frank

AU - Makriyannis, Alexandros

AU - Malan, T. Philip

PY - 2003/9/2

Y1 - 2003/9/2

N2 - We designed AM1241, a selective CB2, cannabinoid receptor agonist, and used it to test the hypothesis that CB2 receptor activation would reverse the sensory hypersensitivity observed in neuropathic pain states. AM1241 exhibits high affinity and selectivity for CB2 receptors. It also exhibits high potency in vivo. AM1241 dose-dependently reversed tactile and thermal hypersensitivity produced by ligation of the L5 and L6 spinal nerves in rats. These effects were selectively antagonized by a CB2 but not by a CB1 receptor antagonist, suggesting that they were produced by actions of AM1241 at CB2 receptors. AM1241 was also active in blocking spinal nerve ligation-induced tactile and thermal hypersensitivity in mice lacking CB1 receptors (CB1 -/- mice), confirming that AM1241 reverses sensory hypersensitivity independent of actions at CB1 receptors. These findings demonstrate a mechanism leading to the inhibition of pain, one that targets receptors localized exclusively outside the CNS. Further, they suggest the potential use of CB2 receptor-selective agonists for treatment of human neuropathic pain, a condition currently without consistently effective therapies. CB2 receptor-selective agonist medications are predicted to be without the CNS side effects that limit the effectiveness of currently available medications.

AB - We designed AM1241, a selective CB2, cannabinoid receptor agonist, and used it to test the hypothesis that CB2 receptor activation would reverse the sensory hypersensitivity observed in neuropathic pain states. AM1241 exhibits high affinity and selectivity for CB2 receptors. It also exhibits high potency in vivo. AM1241 dose-dependently reversed tactile and thermal hypersensitivity produced by ligation of the L5 and L6 spinal nerves in rats. These effects were selectively antagonized by a CB2 but not by a CB1 receptor antagonist, suggesting that they were produced by actions of AM1241 at CB2 receptors. AM1241 was also active in blocking spinal nerve ligation-induced tactile and thermal hypersensitivity in mice lacking CB1 receptors (CB1 -/- mice), confirming that AM1241 reverses sensory hypersensitivity independent of actions at CB1 receptors. These findings demonstrate a mechanism leading to the inhibition of pain, one that targets receptors localized exclusively outside the CNS. Further, they suggest the potential use of CB2 receptor-selective agonists for treatment of human neuropathic pain, a condition currently without consistently effective therapies. CB2 receptor-selective agonist medications are predicted to be without the CNS side effects that limit the effectiveness of currently available medications.

UR - http://www.scopus.com/inward/record.url?scp=0041836218&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0041836218&partnerID=8YFLogxK

U2 - 10.1073/pnas.1834309100

DO - 10.1073/pnas.1834309100

M3 - Article

C2 - 12917492

AN - SCOPUS:0041836218

VL - 100

SP - 10529

EP - 10533

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 18

ER -