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.
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.
|Dhopeshwarkar, Amey; Mackie, Ken (2016) Functional Selectivity of CB2 Cannabinoid Receptor Ligands at a Canonical and Noncanonical Pathway. J Pharmacol Exp Ther 358:342-51|
|Murataeva, Natalia; Dhopeshwarkar, Amey; Yin, Danielle et al. (2016) Where's my entourage? The curious case of 2-oleoylglycerol, 2-linolenoylglycerol, and 2-palmitoylglycerol. Pharmacol Res 110:173-180|
|Carey, Lawrence M; Slivicki, Richard A; Leishman, Emma et al. (2016) A pro-nociceptive phenotype unmasked in mice lacking fatty-acid amide hydrolase. Mol Pain 12:|
|Deng, Liting; Cornett, Benjamin L; Mackie, Ken et al. (2015) 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. Mol Pharmacol 88:64-74|
|Deng, Liting; Guindon, Josée; Cornett, Benjamin L et al. (2015) Chronic cannabinoid receptor 2 activation reverses paclitaxel neuropathy without tolerance or cannabinoid receptor 1-dependent withdrawal. Biol Psychiatry 77:475-87|
|Murataeva, Natalia; Li, Shimin; Oehler, Olivia et al. (2015) Cannabinoid-induced chemotaxis in bovine corneal epithelial cells. Invest Ophthalmol Vis Sci 56:3304-13|
|Dhopeshwarkar, Amey; Mackie, Ken (2014) CB2 Cannabinoid receptors as a therapeutic target-what does the future hold? Mol Pharmacol 86:430-7|
|Petrov, Ravil R; Knight, Lindsay; Chen, Shao-Rui et al. (2013) Mastering tricyclic ring systems for desirable functional cannabinoid activity. Eur J Med Chem 69:881-907|