Marijuana is currently the most widely abused illegal drug. However, the functional significance of the cannabinoid receptor system in health and disease includes the use of cannabinoids as analgesics, antiemetics in cancer patients, anticonvulsants for epilepsy and as antiglaucoma agents as well as immunomodulatory agents. To date, two cannabinoid receptor subtypes, CBt and CB2, have been identified by cDNA cloning, yet the complex pharmacological properties of anandamide as well as exogenous cannabinoids are not fully defined by these two subtypes. Anandamide produces the full range of behavioral effects (antinociception, catalepsy and impaired locomotor activity) in CBi receptor knockout mice. In addition, anandamide-stimulated GTPyS activity can be elicited in brain membranes from these mice. Finally, radioligand binding studies indicate the existence of additional binding sites in brain and spinal cord. The goal of this project is to identify and characterize additional subtypes of the cannabinoid receptors in order to elucidate their role in vivo. The first specific aim is to characterize candidate orphan GPCRs for cannabinoid receptor activity. GPR55 has recently been identified as a candidate cannabinoid receptor, and we have evidence that GPR35 has cannabinoid receptor activity. GPR18 is a receptor for Narachinoylglycine, an endocannabinoid. GPR119 is a receptor for oleoylethanolamide and palmitoylethanolamide. We propose to characterize these candidate cannabinoid receptors by expression in heterologous cell lines, allowing the detailed characterization of ligand selectivity and signaling. The second specific aim will identify additional orphan GPCRs with cannabinoid receptor activity using an expression cloning strategy.
In specific aim 3, we will investigate the functional role of novel cannabinoid receptors. The experiments in this aim are designed to utilize our collaborations with other Center Grant Investigators in order to understand the functional roles of the candidate cannabinoid receptors. These studies will facilitate the design of new therapeutic strategies involving the cannabinoid system. Furthermore, insight into the molecular mechanisms of activation of cannabinoid receptors may lead to a better understanding of marijuana abuse in humans.
|Bagdas, Deniz; Alkhlaif, Yasmin; Jackson, Asti et al. (2018) New insights on the effects of varenicline on nicotine reward, withdrawal and hyperalgesia in mice. Neuropharmacology 138:72-79|
|Jackson, Kia J; Muldoon, Pretal P; Walters, Carrie et al. (2016) Neuronal calcium/calmodulin-dependent protein kinase II mediates nicotine reward in the conditioned place preference test in mice. Behav Pharmacol 27:50-6|
|Nass, Sara R; Long, Jonathan Z; Schlosburg, Joel E et al. (2015) Endocannabinoid Catabolic Enzymes Play Differential Roles in Thermal Homeostasis in Response to Environmental or Immune Challenge. J Neuroimmune Pharmacol 10:364-70|
|Muldoon, P P; Chen, J; Harenza, J L et al. (2015) Inhibition of monoacylglycerol lipase reduces nicotine withdrawal. Br J Pharmacol 172:869-82|
|Ignatowska-Jankowska, B M; Ghosh, S; Crowe, M S et al. (2014) In vivo characterization of the highly selective monoacylglycerol lipase inhibitor KML29: antinociceptive activity without cannabimimetic side effects. Br J Pharmacol 171:1392-407|
|Bagdas, Deniz; Muldoon, Pretal P; Zhu, Andy Z X et al. (2014) Effects of methoxsalen, a CYP2A5/6 inhibitor, on nicotine dependence behaviors in mice. Neuropharmacology 85:67-72|
|Wolf, Carl E; Goldstein, Ashley; Poklis, Justin L et al. (2014) Evaluation of an enzyme immunoassay for the detection of methadone metabolite EDDP [2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine] in urine. J Clin Lab Anal 28:136-40|
|Poklis, Justin L; Devers, Kelly G; Arbefeville, Elise F et al. (2014) Postmortem detection of 25I-NBOMe [2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine] in fluids and tissues determined by high performance liquid chromatography with tandem mass spectrometry from a traumatic death. Forensic Sci Int 234:e14-20|
|Poklis, Justin L; Nanco, Carol R; Troendle, Michelle M et al. (2014) Determination of 4-bromo-2,5-dimethoxy-N-[(2-methoxyphenyl)methyl]-benzeneethanamine (25B-NBOMe) in serum and urine by high performance liquid chromatography with tandem mass spectrometry in a case of severe intoxication. Drug Test Anal 6:764-9|
|Burston, James J; Sagar, Devi Rani; Shao, Pin et al. (2013) Cannabinoid CB2 receptors regulate central sensitization and pain responses associated with osteoarthritis of the knee joint. PLoS One 8:e80440|
Showing the most recent 10 out of 106 publications