title: CB1 Knockout Mice Unveil Sustained CB2-Mediated Antiallodynic Effects of the Mixed CB1/CB2 Agonist CP55,940 in a Mouse Model of Paclitaxel-Induced Neuropathic Pain.
abstract: Cannabinoids suppress neuropathic pain through activation of cannabinoid CB1 and/or CB2 receptors; however, unwanted CB1-mediated cannabimimetic effects limit clinical use. We asked whether CP55,940 [(-)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexanol], a potent cannabinoid that binds with similar affinity to CB1 and CB2 in vitro, produces functionally separable CB1- and CB2-mediated pharmacological effects in vivo. We evaluated antiallodynic effects, possible tolerance, and cannabimimetic effects (e.g., hypothermia, catalepsy, CB1-dependent withdrawal signs) after systemic CP55,940 treatment in a mouse model of toxic neuropathy produced by a chemotherapeutic agent, paclitaxel. The contribution of CB1 and CB2 receptors to in vivo actions of CP55,940 was evaluated using CB1 knockout (KO), CB2KO, and wild-type (WT) mice. Low-dose CP55,940 (0.3 mg/kg daily, i.p. ) suppressed paclitaxel-induced allodynia in WT and CB2KO mice, but not CB1KO mice. Low-dose CP55,940 also produced hypothermia and rimonabant-precipitated withdrawal in WT, but not CB1KO, mice. In WT mice, tolerance developed to CB1-mediated hypothermic effects of CP55,940 earlier than to antiallodynic effects. High-dose CP55,940 (10 mg/kg daily, i.p.) produced catalepsy in WT mice, which precluded determination of antiallodynic efficacy but produced sustained CB2-mediated suppression of paclitaxel-induced allodynia in CB1KO mice; these antiallodynic effects were blocked by the CB2 antagonist 6-iodopravadoline (AM630). High-dose CP55,940 did not produce hypothermia or rimonabant-precipitated withdrawal in CB1KO mice. Our results using the mixed CB1/CB2 agonist CP55,940 document that CB1 and CB2 receptor activations produce mechanistically distinct suppression of neuropathic pain. Our study highlights the therapeutic potential of targeting cannabinoid CB2 receptors to bypass unwanted central effects associated with CB1 receptor activation.
authors.affiliation: Department of Molecular and Cellular Biochemistry (L.D.), Department of Psychological and Brain Sciences (L.D., B.L.C., K.M., A.G.H.), The Linda and Jack Gill Center for Biomolecular Science (L.D., B.L.C., K.M., A.G.H.), Indiana University, Bloomington, Indiana.
authors.forename: Liting
authors.initials: L
authors.lastname: Deng
authors.affiliation: Department of Molecular and Cellular Biochemistry (L.D.), Department of Psychological and Brain Sciences (L.D., B.L.C., K.M., A.G.H.), The Linda and Jack Gill Center for Biomolecular Science (L.D., B.L.C., K.M., A.G.H.), Indiana University, Bloomington, Indiana.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Cornett
authors.affiliation: Department of Molecular and Cellular Biochemistry (L.D.), Department of Psychological and Brain Sciences (L.D., B.L.C., K.M., A.G.H.), The Linda and Jack Gill Center for Biomolecular Science (L.D., B.L.C., K.M., A.G.H.), Indiana University, Bloomington, Indiana.
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
authors.affiliation: Department of Molecular and Cellular Biochemistry (L.D.), Department of Psychological and Brain Sciences (L.D., B.L.C., K.M., A.G.H.), The Linda and Jack Gill Center for Biomolecular Science (L.D., B.L.C., K.M., A.G.H.), Indiana University, Bloomington, Indiana hohmanna@indiana.edu.
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Hohmann
mesh_terms: D000700:Analgesics / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D003511:Cyclohexanols / Q000008:administration & dosage* / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000700:Analgesics; C578453:CNR1 protein, mouse; D063387:Cannabinoid Receptor Antagonists; C571431:Cnr2 protein, mouse; D003511:Cyclohexanols; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D017239:Paclitaxel