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.