Journal article

Authors list: Richter, Katrin; Herz, Sara M.; Stokes, Clare; Damaj, M. Imad; Grau, Veronika; Papke, Roger L.

Publication year: 2023

Journal: Neuropharmacology

Volume number: 240

ISSN: 0028-3908

eISSN: 1873-7064

Open access status: Green

DOI Link: https://doi.org/10.1016/j.neuropharm.2023.109717

Publisher: Elsevier

Abstract: 
Pain due to inflammation can be reduced by targeting the noncanonical nicotinic receptors (NCNR) in cells of the immune system that regulate the synthesis and release of pro-and anti-inflammatory cytokines. Although NCNR do not generate ion channel currents, the pharmacology of ion-channel forms of the receptors can predict drugs which may be effective regulators of the cholinergic anti-inflammatory system (CAS). Agonists of alpha 7 type receptors have been definitively associated with CAS. Receptors containing alpha 9 and alpha 10 subunits have also been implicated. We have recently characterized two small molecules, pCN-diEPP and mCN-diEPP, as selective alpha 9 alpha 10 agonists and antagonists, respectively. We used these drugs, along with nicotine, an alpha 7 agonist and alpha 9 alpha 10 antagonist, to probe the mixed populations of receptors that are formed when alpha 7, alpha 9, and alpha 10 are all expressed together in Xenopus oocytes. We also evaluated the effects of the CN-diEPP compounds on regulating the ATP-induced release of interleukin-1 beta from monocytic THP-1 cells, which express NCNR. The compounds success-fully identified separate populations of receptors when all three subunits were co-expressed, including a potential population of homomeric alpha 10 receptors. The alpha 9 alpha 10 agonist pCN-diEPP was the more effective regulator of interleukin-1 beta release in THP-1 cells. pCN-diEPP was also fully effective in a mouse model of inflammatory pain, while mCN-diEPP had only partial effects, requiring a higher dosage. The analgetic effects of pCN-diEPP and mCN-diEPP were retained in alpha 7 knockout mice. Taken together, our results suggest that drugs that selectively activate alpha 9 alpha 10 receptors may useful to reduce inflammatory pain through the CAS.

Harvard Citation style: Richter, K., Herz, S., Stokes, C., Damaj, M., Grau, V. and Papke, R. (2023) Pharmacological profiles and anti-inflammatory activity of pCN-diEPP and mCN-diEPP, new alpha9alpha10 nicotinic receptor ligands, Neuropharmacology, 240, Article 109717. https://doi.org/10.1016/j.neuropharm.2023.109717

APA Citation style: Richter, K., Herz, S., Stokes, C., Damaj, M., Grau, V., & Papke, R. (2023). Pharmacological profiles and anti-inflammatory activity of pCN-diEPP and mCN-diEPP, new alpha9alpha10 nicotinic receptor ligands. Neuropharmacology. 240, Article 109717. https://doi.org/10.1016/j.neuropharm.2023.109717