Intrathecal cannabilactone CB2R 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-10 (IL-10) abolishes pathological pain and suppresses proinflammatory interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α). Drugs that bind the cannabinoid type 2 receptor (CB2R) expressed on spinal glia reduce mechanical hypersensitivity. To better understand the CB2R-related anti-inflammatory profile of key anatomical nociceptive regions, we assessed mechanical hypersensitivity and protein profiles following intrathecal application of the cannabilactone CB2R agonist, AM1710, in two animal models; unilateral sciatic nerve chronic constriction injury(CCI), and spinal application of HIV-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 monoacyl glycerol 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 CB2R agonists are emerging as anti-inflammatory agents with pain therapeutic implications.

Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities

“…One possibility for pain relief would be to administer a CB 2 -selective agonist intrathecally instead of orally. Thus, there have been reports that JWH-015 can reduce signs of post-operative pain in rats [127], and that signs of neuropathic pain can be reduced by JWH-133 in mice [128], and by AM1710 in rats [129] when these three CB 2 -selective agonists are injected intrathecally. There is evidence too that signs of analgesia induced in models of acute pain by transdermal administration of an opioid can be enhanced by transdermal or intrathecal co-administration of a low dose of a CB 1 /CB 2 receptor agonist [24,84].…”

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

“…Activation of spinal and/or peripheral CB 2 receptors by CB 2 agonists, after acute or chronic administration, suppresses neuropathic pain (Yamamoto et al, 2008;Hsieh et al, 2011;Landry et al, 2012;Deng et al, 2015). CB 2 agonists are likely to suppress neuropathic nociception by downregulation of proinflammatory cytokines and chemokines (Klegeris et al, 2003;Eljaschewitsch et al, 2006;Wilkerson et al, 2012;Deng et al, 2015) as well as inhibition of central sensitization (Elmes et al, 2004;Nackley et al, 2004). CP55,940 binds with similar affinity to mouse CB 1 (K d 5 0.77 nM) (Abood et al, 1997) and CB 2 receptors (K d 5 0.73 nM) (Griffin et al, 2000) in in vitro assays.…”

Inflammatory mediators of neuropathic pain

“…Spinal and interneuron IL-10 may significantly attenuate hypersensitivity of nerve injury-induced pain, associated to decreased infiltration by immune cells and decreased IL-1b and adenosine expression 8 . Adenosine receptor reverse agonists 2A and CBR2 stabilize hypersensitivity pathway of pain induced by IL-10 release 66,67 . IL-10 has analgesic effects due to its ability to inhibit pro-inflammatory cytokines.…”