This is a proposal to investigate if CB2 cannabinoid receptor agonist functional selectivity can be exploited to identify more specific and effective CB2 receptor agonists for the treatment of chronic pain. Functional selectivity (also known as biased agonism and ligand-directed trafficking) is an increasingly appreciated property of receptor signaling. When a functionally selective agonist binds to a receptor capable of activating multiple signaling pathways, only a subset of those pathways are activated, or the rank order potency of activating specific pathways varies among agonists. Most G protein-coupled receptors (GPCRs) engage multiple signaling pathways, offering many opportunities for functional selectivity. Functional selectivity has substantial therapeutic implications. Properly applied, it may allow activation of specific pathways that are beneficial for treating a specific condition, while avoiding activation of pathways that may contribute to unwanted side effects. Thus, functional selectivity adds another dimension beyond potency, subtype selectivity and intrinsic efficacy to GPCR agonists-a dimension that may be exploited for therapeutic benefit. In preliminary studies examining CB2 receptor signaling we identified striking functional selectivity in several classes of CB2 agonists. For example, members of the aminoalkylindole family of CB2 agonists activated several CB2 signaling pathways, but failed to inhibit voltage dependent calcium channels or internalize CB2 receptors. This degree of functional selectivity is important for both mechanistic and therapeutic reasons. Mechanistically, it offers us the possibility of identifying the signaling pathways underlying CB2-mediated analgesia in specific pain states. Therapeutically, it offers us the possibility of designing drugs that may be efficacious for pain based upon their functional selectivities, while lessening the possibility of undesired effects. Ths proposal will evaluate the therapeutic potential of functional selectivity of CB2 agonists through two specific aims. The first specific aim will complete the characterization of the signaling of currently available CB2 agonists, including CB2 agonists that have failed clinically, using a battery of biochemical and cell-based functional assays. The second specific aim will take the three compounds with the most striking functional selectivity in the in vitro assays and examine their efficacy in preclinical models of neuropathic (paclitaxel and spinal nerve ligation) and inflammatory (complete Freund's adjuvant) pain using CB1 receptor knockout mice. Efficacy of these functional selective CB2 agonists will be compared to a """"""""balanced""""""""-CB2 agonist (CP55,940) that activates all tested signaling pathways to a similar extent (see Table 1 in Research Strategy). Completion of these specific aims will give us a comprehensive understanding on how functional selectivity contributes to the therapeutic efficacy of CB2 ligands and also provide a rich pharmacological characterization of CB2 signaling that will be crucial for the future evaluation of CB2 agonists for other therapeutic indications.

Public Health Relevance

The adequate treatment of chronic pain in the US is a substantial public health problem. The work proposed here will take advantage of recently appreciated signaling properties of CB2 cannabinoid receptor agonists (functional selectivity) to identify those properties that are most beneficial in treating chronic pain, as assessed in well-accepted preclinical pain models. Elucidating the signaling properties associated with distinct CB2 agonists offers the potential to maximize and predict therapeutic potential while minimizing unwanted side- effects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA035068-02
Application #
8634759
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (03))
Program Officer
Rapaka, Rao
Project Start
2013-03-15
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
2
Fiscal Year
2014
Total Cost
$234,000
Indirect Cost
$84,000
Name
Indiana University Bloomington
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
006046700
City
Bloomington
State
IN
Country
United States
Zip Code
47401
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