The misuse of prescription opiates is on the rise with combination therapies (e.g. acetaminophen or NSAIDs) resulting in severe liver and kidney damage. In recent years, cannabinoid receptors have been identified as potential modulators of pain and rewarding behaviors associated with cocaine, nicotine and ethanol in preclinical models. Furthermore, activation of cannabinoid 2 (CB2) receptors on immune cells through the inhibition of monoacylglycerol lipase (MAGL), results in increased 2-arachidonylglycerol (2AG) production and analgesia in animal models. Yet, few studies have identified whether mu opioid and CB2 receptor agonists act synergistically to inhibit chronic pain while reducing unwanted side effects including reward liability, or if it could ameliorate the excruciating pain that is poorly managed with by opiates in bone cancer patients. We determined if analgesic synergy exists between the mu-opioid agonist morphine and the selective CB2 agonist, JWH015, or the inhibitor of MAGL, MJN110, in rodent models of acute and chronic inflammatory, post-operative, neuropathic, and cancer-induced bone pain (CIBP) using isobolographic analysis. We also investigated if the MOR-CB2 agonist combination decreased morphine-induced conditioned place preference (CPP) and slowing of gastrointestinal transit. Next, we examined whether JWH015 or the inhibition of MAGL decreased the release of pro-inflammatory mediators by activating nuclear factor kappa enhancer of activated B cells (NFkB), as dysregulation of NFkB is observed in various cancers. Here we show that MOR + CB2 agonism results in a significant synergistic inhibition of preclinical pain while significantly reducing opioid-induced unwanted side effects. The opioid sparing effect of CB2 receptor agonism strongly supports the advancement of a MOR-CB2 agonist combinatorial pain therapy for clinical trials.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/623184 |
| Date | January 2016 |
| Creators | Grenald, Shaness A., Grenald, Shaness A. |
| Contributors | Nelson, Mark, Nelson, Mark, Vanderah, Todd, Ossipov, Michael H., French, Edward D., Hruby, Victor J |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | en_US |
| Detected Language | English |
| Type | text, Electronic Dissertation |
| Rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
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