title: Intrathecal cannabilactone CB(2)R agonist, AM1710, controls pathological pain and restores basal cytokine levels.
abstract: Spinal glial and proinflammatory cytokine actions are strongly implicated in pathological pain. Spinal administration of the anti-inflammatory cytokine interleukin (IL)-10 abolishes pathological pain and suppresses proinflammatory IL-1β and tumor necrosis factor alpha (TNF-α). Drugs that bind the cannabinoid type-2 receptor (CB(2)R) expressed on spinal glia reduce mechanical hypersensitivity. To better understand the CB(2)R-related anti-inflammatory profile of key anatomical nociceptive regions, we assessed mechanical hypersensitivity and protein profiles following intrathecal application of the cannabilactone CB(2)R agonist, AM1710, in 2 animal models; unilateral sciatic nerve chronic constriction injury (CCI), and spinal application of human immunodeficiency virus-1 glycoprotein 120 (gp120), a model of peri-spinal immune activation. In CCI animals, lumbar dorsal spinal cord and corresponding dorsal root ganglia (DRG) were evaluated by immunohistochemistry for expression of IL-10, IL-1β, phosphorylated p38-mitogen-activated-kinase (p-p38MAPK), a pathway associated with proinflammatory cytokine production, glial cell markers, and degradative endocannabinoid enzymes, including monoacylglycerol lipase (MAGL). AM1710 reversed bilateral mechanical hypersensitivity. CCI revealed decreased IL-10 expression in dorsal spinal cord and DRG, while AM1710 resulted in increased IL-10, comparable to controls. Adjacent DRG and spinal sections revealed increased IL-1β, p-p38MAPK, glial markers, and/or MAGL expression, while AM1710 suppressed all but spinal p-p38MAPK and microglial activation. In spinal gp120 animals, AM1710 prevented bilateral mechanical hypersensitivity. For comparison to immunohistochemistry, IL-1β and TNF-α protein quantification from lumbar spinal and DRG homogenates was determined, and revealed increased DRG IL-1β protein levels from gp120, that was robustly prevented by AM1710 pretreatment. Cannabilactone CB(2)R agonists are emerging as anti-inflammatory agents with pain therapeutic implications.
authors.affiliation: Department of Neurosciences, Health Sciences Center, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA Department of Anesthesiology and Critical Care Medicine, Health Sciences Center, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA Health Sciences Center, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA Center for Drug Discovery, Northeastern University, Boston, MA 02115, USA.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Wilkerson
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Gentry
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Dengler
authors.forename: James A
authors.initials: JA
authors.lastname: Wallace
authors.forename: Audra A
authors.initials: AA
authors.lastname: Kerwin
authors.forename: Leisha M
authors.initials: LM
authors.lastname: Armijo
authors.forename: Megan N
authors.initials: MN
authors.lastname: Kuhn
authors.forename: Ganesh A
authors.initials: GA
authors.lastname: Thakur
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
authors.forename: Erin D
authors.initials: ED
authors.lastname: Milligan
mesh_terms: D000818:Animals; D002867:Chromones / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
chemical_list: C500321:3-(1,1-dimethyl-heptyl)-1-hydroxy-9-methoxy-benzo(c)chromen-6-one; D002867:Chromones; D016207:Cytokines; D043885:Receptor, Cannabinoid, CB2