Opioid receptors, the proteins that bind morphine and heroin, mediate many important neuronal functions, including pain and mood. Alterations of these functions underlie the narcotic addiction process. Current investigations are directed at elucidating the molecular basis of opioid neuropharmacology. Studies are also directed at characterizing the biochemical and pharmacological changes that occur at the whole animal, at the opioid receptor, and in second-messenger systems during the development of tolerance and dependence to opiates. Also, studies are focused on medications development for treating drug abuse. Mu opioid antagonists, such as naltrexone, and kappa opioid agonists decrease dopamine release in the nucleus accumbens, a brain region directly involved in the reinforcing effects of drugs that are abused. In collaboration with chemists and behavioral pharmacologists, we are working on medications that will decrease the drug craving that is experienced by drug abusers.

This laboratory was the first to demonstrate the presence of opioid receptors on lymphocytes. Like brain opioid receptors, the receptors expressed on lymphocytes bind endogenous opioid peptides, and are negatively coupled to adenylyl cyclase. Using flow cytometry, this laboratory has developed an indirect fluorescent detection method that results in the identification of subpopulations of cells from the immune system that express an opioid receptor. Current studies are directed at determining which populations of immune cells express which types of opioid receptors. Additional studies are focused on determining the role of opioid receptors in modulating immune function, and if the number and distribution of opioid receptors are altered in drug abusers, HIV-infected individuals, and AIDS patients.

Bidlack, J.M. and Parkhill, A.L.  (2004)  Assay of G protein coupled-receptor activation in native cell membranes using [35S]GTPgS binding.   In: G Proteins and Their Receptors:  Methods and Protocols, ed. A. Smrcka, Humana Press, Totowa, NJ, Methods Mol. Biol., 237:135-144. 

Csutoras, C., Zhang, A., Bidlack, J.M., and Neumeyer, J.L.  (2004)  An investigation of the N-demethylation of 3-deoxymorphine and the affinity of the alkylation products to m, d and k receptors.  Bioorg. Med. Chem. Lett. 12:2687-2690.

Gekker, G., Hu, S., Bidlack, J.M., Wentland, M.P., Lokensgard, J.R., and Peterson, P.K.  (2004)  k-Opioid receptor ligands inhibit cocaine-induced HIV-1 expression in microglial cells.  J. Pharmacol. Exp. Ther. 309:600-606.

Rusovici, D.E., Negus, S.S., Mello, N.K., and Bidlack, J.M.  (2004)  Kappa opioid receptors are differentially labeled by arylacetamides and benzomorphans.  Eur. J. Pharmacol. 485:119-125.

Stevenson, G.W., Wentland, M.P., Bidlack, J.M., Mello, N.K., and Negus, S.S.  (2004)  Effects of the mixed action k/m opioid agonist 8-carboxamidocyclazocine on cocaine- and food- maintained responding in rhesus monkeys.  Eur. J. Pharmacol. 506:133-141.

Zhang, A., Xiong, W., Bidlack, J.M., Hilbert, J.E., Knapp, B.I., Wentland, M.P., and Neumeyer, J.L.  (2004)  10-Ketomorphinan and 3-substituted-3-desoxymorphinan analogues as mixed k and m opioid ligands: Synthesis and biological evaluation of their binding affinity at opioid receptors.  J. Med. Chem. 47:165-174.

Zhang, A., Xiong, W., Hilbert, J.E., DeVita, E.K., Bidlack, J.M., and Neumeyer, J.L.  (2004)  2-Aminothiazole-derived opioids. Biosteric replacement of phenols.  J. Med. Chem. 47:1886-1888.

Zhen, Z., Bradel-Tretheway, B.G., Dewhurst, S., and Bidlack, J.M.  (2004)  Transient overexpression of k and m opioid receptors using recombinant adenovirus vectors.  J. Neurosci. Meth. 136:133-139.

Bart, G., Schluger, J.H., Borg, L., Ho, A., Bidlack, J.M., and Kreek, M.J.  (2005)  Nalmefene induced elevation in serum prolactin in normal human volunteers:  Partial kappa opioid agonist activity?  Neuropsychopharmacology 30:2254-2262.

Mathews, J.L., Neumeyer, J.L., Negus, S.S., and Bidlack, J.M.  (2005)  Characterization of a novel bivalent morphinan possessing kappa agonist and mu agonist/antagonist properties.  J. Pharmacol. Exp. Ther.  315:821-827.

Peng, X., Knapp, B.I., Bidlack, J.M., and Neumeyer, J.L.  (2006)  Synthesis and preliminary in-vitro investigation of bivalent ligands containing homo- and hetero-pharmacophores at m, d and k opioid receptors.  J. Med. Chem. 49:256-262.

Wentland, M.P., Lu, Q., Lou, R., Bu, Y., Knapp, B.I., and Bidlack, J.M.  (2005)  Synthesis and opioid receptor binding properties of a highly potent 4-hydroxy analogue of naltrexone.  Bioorg. Med. Chem. Lett. 15:2107-2110.

Wentland, M.P., Sun, X., Bu, Y., Lou, R., Cohen, D.J,. and Bidlack, J.M.  (2005)  Redefining the structure-activity relationships of 2,6-methano-3-benzazocines.  Part 3.  8-Thiocarboxamido and 8-thioformamido derivatives of cyclazocine.  Bioorg. Med. Chem. Lett 15:2547-2551.

Zhen, Z., Bradel-Trethewey, B., Sumagin, S., Bidlack, J.M., and Dewhurst, S.  (2005)  The human herpes virus 6 protein-coupled receptor homolog U51 positively regulates virus replication and enhances cell-cell fusion in vitro.  J. Virol. 79:11914-11924.