The focus of the Slosky Lab is on understanding how G protein-coupled receptors (GPCRs) regulate pain and addiction-associated behaviors and how these receptors can be targeted for therapeutic benefit. Our long-term goal is to develop mechanism-based pharmacotherapies for stimulant and opioid use disorders and pain management regimens with reduced addiction potential. In pursuit of these goals, we are working at the interface of receptor biology, behavioral pharmacology, and systems neuroscience.
Substance use disorders are complex neurobehavioral pathologies for which there are a lack of effective medications. GPCRs are the largest class of cell surface receptors in the genome and the most successful family of targets of FDA-approved drugs. New frontiers in drug discovery remain, however, as GPCR-targeting therapeutics are often plagued by unwanted side effects and many GPCRs, including several promising anti-addiction candidates, have yet to be successfully targeted with xenobiotics. We recently characterized a class of receptor ligands, known as biased allosteric modulators. Biased allosteric modulators bind outside the binding pocket of the endogenous ligand and exert pathway-specific effects on receptor signaling. By increasing receptor subtype and pathway selectivity, these ligands present the opportunity to develop safer, more efficacious therapeutics and target previously ‘undruggable’ GPCRs.
Our ongoing work explores the mechanism and therapeutic potential of biased allosteric modulation of the neurotensin receptor 1 using state-of-the-art receptor signaling assays, behavioral assays, and non-invasive neuroimaging in genetically modified mice.
- Gross JD, Kim DW, Zhou Y, Jansen D, Slosky LM, Clark NB, Ray CR, Hu X, Southall N, Wang A, Xu X, Barnaeva E, Wetsel WC, Ferrer M, Marugan JJ, Caron MG, Barak LS, Toth K (2022) Discovery of a functionally selective ghrelin receptor (GHSR1a) ligand for modulating brain dopamine. Proc Natl Acad Sci U S A. Mar 8;119(10):e2112397119.
- Slosky LM, Caron MG & Barak LS (2021) β-arrestin-Biased Allosteric Modulators: New Frontiers in GPCR Drug Discovery. Trends in Pharmacological Sciences 42(4): 283-299.
- Slosky LM, Bai Y, Toth K, Rochelle L, Ray C, Badea A, Chandrasekhar R, Pogorelov V, Abraham DM, Atluri N, Peddibhotla S, Hedrick MP, Hershberger P, Maloney P, Yuan H, Li Z, Wetsel W, Pinkerton AP, Barak LS, Caron MG (2020) β-arrestin-Biased Allosteric Modulator of NTSR1 Selectively Attenuates Addictive Behaviors. Cell 181(6):1364-1379.
- Pinkerton AB, Peddibhotla S, Yamamoto F, Slosky LM, Bai Y, Maloney P, Hershberger P, Hedrick MP, Falter B, Ardecky RJ, Smith LH, Chung TDY, Jackson MR, Caron MG, Barak LS (2019) Discovery of β-Arrestin Biased, Orally Bioavailable, and CNS Penetrant Neurotensin Receptor 1 (NTR1) Allosteric Modulators. Journal of Medicinal Chemistry 62(17):8357-8363.
- Toth K, Nagi K, Slosky LM, Rochelle L, Ray C, Kaur S, Shenoy SK, Caron MG, Barak LS (2019) Encoding the β-arrestin Trafficking Fate of the Ghrelin Receptor GHSR1a: C-tail Independent Molecular Determinants in GPCRs. ACS Pharmacology & Translational Science 2: 230-246.
- Toth K, Slosky LM, Pack TF, Urs NM, Boone P, Mao L, Abraham D, Caron MG, Barak LS (2018) Ghrelin receptor antagonism of hyperlocomotion in cocaine‐sensitized mice requires βarrestin‐2. Synapse 72(1): 10.1002/syn.22012.
- Grenald SA, Doyle TM, Zhang H, Slosky LM, Chen Z, Largent-Milnes TM, Spiegel S, Vanderah TW, Salvemini D (2017) Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation. Pain 158:1733–1742.
- Forte BL, Slosky LM, Largent-Milnes TM, Vanderah TW (2016) Angiotensin-(1-7) as an Antinociceptive Agent in Cancer-Induced Bone Pain. Pain 157(12):2709-2721.
- Slosky LM, BassiriRad NM, Symons AM, Thompson M, Forte BL, Bui L, Salvemini D, Mantyh PW, Largent-Milnes TM, Vandearh TW (2016) The Cystine/Glutamate Antiporter System xc- Drives Breast Tumor Cell Glutamate Release and Cancer-Induced Bone Pain. Pain 157(11):2605-2616.
- Slosky LM, Largent-Milnes TM, Vanderah TW (2015) Use of Animal Models in Understanding Cancer-Induced Bone Pain. Cancer Growth and Metastasis 8(Suppl 1): 47–62.
- Slosky LM and Vanderah TW (2015) Therapeutic potential of peroxynitrite decomposition catalysts: a patent review. Expert Opin Ther Pat 25(4):443-66.
- Thompson BJ, Sanchez-Covarrubias L, Slosky LM, Zhang Y, Laracuente ML, Ronaldson, PT (2014) Hypoxia/reoxygenation stress signals an increase in organic anion transporting polypeptide 1a4 (Oatp1a4) at the blood-brain barrier: Relevance to CNS drug delivery. J Cereb Blood Flow Metab 34(4):699-707.
- Sanchez-Covarrubias L, Slosky LM, Thompson BJ, Zhang Y, Laracuente ML, DeMarco KM, Ronaldson PT, Davis TP (2014) P-glycoprotein modulates morphine uptake into the CNS: A role for the non-steroidal anti-inflammatory drug diclofenac. PLOS ONE 9(2): e88516.
- Slosky LM, Thompson BJ, Sanchez-Covarrubias L, Zhang Y, Laracuente ML, Vanderah TW, Ronaldson PT, Davis TP (2013) Acetaminophen modulates P-glycoprotein functional expression at the BBB by a constitutive androstane receptor-dependent mechanism. Mol Pharmacol 84(5): 774-86.
- Sanchez-Covarrubias L, Slosky LM, Thompson BJ, Ronaldson RT, Davis TP (2013) Transporters in the CNS: Obstacles or Opportunities for Drug Delivery. Curr Pharm Des 20(10):1422-4