Tags

Type your tag names separated by a space and hit enter

The CB2 cannabinoid receptor-selective agonist O-3223 reduces pain and inflammation without apparent cannabinoid behavioral effects.

Abstract

Although Δ(9)-tetrahydrocannabinol (THC) and other mixed CB(1)/CB(2) receptor agonists are well established to elicit antinociceptive effects, their psychomimetic actions and potential for abuse have dampened enthusiasm for their therapeutic development. Conversely, CB(2) receptor-selective agonists have been shown to reduce pain and inflammation, without eliciting apparent cannabinoid behavioral effects. In the present study, we developed a novel ethyl sulfonamide THC analog, O-3223, and compared its pharmacological effects to those of the potent, mixed CB(1)/CB(2) receptor agonist, CP55,940, in a battery of preclinical pain models. Competitive cannabinoid receptor binding experiments revealed that O-3223 was approximately 80-fold more selective for CB(2) than CB(1) receptors. Additionally, O-3223 behaved as a full CB(2) receptor agonist in [(35)S]GTPγS binding. O-3223 reduced nociceptive behavior in both phases of the formalin test, reduced thermal hyperalgesia in the chronic constriction injury of the sciatic nerve (CCI) model, and reduced edema and thermal hyperalgesia elicited by intraplantar injection of LPS. These effects were blocked by pretreatment with the CB(2) receptor-selective antagonist SR144528, but not by the CB(1) receptor antagonist, rimonabant. Unlike CP55,940, O-3223 did not elicit acute antinociceptive effects in the hot-plate test, hypothermia, or motor disturbances, as assessed in the rotarod test. These data indicate that the CB(2) receptor-selective agonist, O-3223, reduces inflammatory and neuropathic nociception, without affecting basal nociception or eliciting overt behavioral effects. Moreover, this compound can serve as a template to develop new CB(2) receptor agonists with increased receptor selectivity and increased potency in treating inflammatory and neuropathic pain.

Links

  • PMC Free PDF
  • PMC Free Full Text
  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, PO Box 980613, VA 23298, USA.

    , , , , , , ,

    Source

    Neuropharmacology 60:2-3 pg 244-51

    MeSH

    Animals
    Cannabinoids
    Cyclohexanols
    Dose-Response Relationship, Drug
    Dronabinol
    Inflammation
    Male
    Mice
    Pain
    Pain Measurement
    Piperidines
    Pyrazoles
    Receptor, Cannabinoid, CB2
    Rimonabant

    Pub Type(s)

    Comparative Study
    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    20849866

    Citation

    Kinsey, Steven G., et al. "The CB2 Cannabinoid Receptor-selective Agonist O-3223 Reduces Pain and Inflammation Without Apparent Cannabinoid Behavioral Effects." Neuropharmacology, vol. 60, no. 2-3, 2011, pp. 244-51.
    Kinsey SG, Mahadevan A, Zhao B, et al. The CB2 cannabinoid receptor-selective agonist O-3223 reduces pain and inflammation without apparent cannabinoid behavioral effects. Neuropharmacology. 2011;60(2-3):244-51.
    Kinsey, S. G., Mahadevan, A., Zhao, B., Sun, H., Naidu, P. S., Razdan, R. K., ... Lichtman, A. H. (2011). The CB2 cannabinoid receptor-selective agonist O-3223 reduces pain and inflammation without apparent cannabinoid behavioral effects. Neuropharmacology, 60(2-3), pp. 244-51. doi:10.1016/j.neuropharm.2010.09.004.
    Kinsey SG, et al. The CB2 Cannabinoid Receptor-selective Agonist O-3223 Reduces Pain and Inflammation Without Apparent Cannabinoid Behavioral Effects. Neuropharmacology. 2011;60(2-3):244-51. PubMed PMID: 20849866.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - The CB2 cannabinoid receptor-selective agonist O-3223 reduces pain and inflammation without apparent cannabinoid behavioral effects. AU - Kinsey,Steven G, AU - Mahadevan,Anu, AU - Zhao,Bingjun, AU - Sun,Hang, AU - Naidu,Pattipati S, AU - Razdan,Raj K, AU - Selley,Dana E, AU - Imad Damaj,M, AU - Lichtman,Aron H, Y1 - 2010/09/16/ PY - 2010/01/06/received PY - 2010/08/01/revised PY - 2010/09/06/accepted PY - 2010/9/21/entrez PY - 2010/9/21/pubmed PY - 2011/12/13/medline SP - 244 EP - 51 JF - Neuropharmacology JO - Neuropharmacology VL - 60 IS - 2-3 N2 - Although Δ(9)-tetrahydrocannabinol (THC) and other mixed CB(1)/CB(2) receptor agonists are well established to elicit antinociceptive effects, their psychomimetic actions and potential for abuse have dampened enthusiasm for their therapeutic development. Conversely, CB(2) receptor-selective agonists have been shown to reduce pain and inflammation, without eliciting apparent cannabinoid behavioral effects. In the present study, we developed a novel ethyl sulfonamide THC analog, O-3223, and compared its pharmacological effects to those of the potent, mixed CB(1)/CB(2) receptor agonist, CP55,940, in a battery of preclinical pain models. Competitive cannabinoid receptor binding experiments revealed that O-3223 was approximately 80-fold more selective for CB(2) than CB(1) receptors. Additionally, O-3223 behaved as a full CB(2) receptor agonist in [(35)S]GTPγS binding. O-3223 reduced nociceptive behavior in both phases of the formalin test, reduced thermal hyperalgesia in the chronic constriction injury of the sciatic nerve (CCI) model, and reduced edema and thermal hyperalgesia elicited by intraplantar injection of LPS. These effects were blocked by pretreatment with the CB(2) receptor-selective antagonist SR144528, but not by the CB(1) receptor antagonist, rimonabant. Unlike CP55,940, O-3223 did not elicit acute antinociceptive effects in the hot-plate test, hypothermia, or motor disturbances, as assessed in the rotarod test. These data indicate that the CB(2) receptor-selective agonist, O-3223, reduces inflammatory and neuropathic nociception, without affecting basal nociception or eliciting overt behavioral effects. Moreover, this compound can serve as a template to develop new CB(2) receptor agonists with increased receptor selectivity and increased potency in treating inflammatory and neuropathic pain. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/20849866/The_CB2_cannabinoid_receptor_selective_agonist_O_3223_reduces_pain_and_inflammation_without_apparent_cannabinoid_behavioral_effects_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(10)00225-X DB - PRIME DP - Unbound Medicine ER -