The long-term goal of my research has been to investigate the fundamental mechanisms modulating cell-cell communication and neurotransmission with a focus on identifying novel therapeutic targets and therapeutics for the prevention and/or treatment of drug abuse. Our initial studies, which were focused on the opioid and cannabinoid systems, led to the identification of receptor interacting complexes as novel therapeutic targets as well as identification of small molecules targeting heteromers. The MERIT award has enabled me to broaden the scope of research to other receptor systems in the reward pathway and this led to the discovery of two completely new neuropeptide receptor systems. During the extension period I intend to pursue studies described in the base grant as well as the newly characterized receptor systems – these are described below. Identification of heterodimer-selective ligands as new therapeutics for the treatment of pain: μOR-δOR heteromer ligands: During the base grant period, we used high throughput screening (HTS) to identify small molecule agonists of the μOR-δOR heteromer. One of the compounds was found to have analgesic properties comparable to morphine but with reduced tolerance and dependence (Gomes et al., 2013a). Analogs of this compound are being synthesized by chemists at MLPCN (LaJolla, CA). During the MERIT extension period we will test these compounds using in vitro and in vivo assays (analgesia, hyperalgesia, addiction, reward etc). The HTS analysis has also yielded antagonists of the μOR-δOR heteromer. The screening center has provided us with top 90 hits. We will characterize them using in vitro assays and test the top 5 candidates in mice (analgesia, hyperalgesia, allodynia, addiction, reward etc). A μOR-δOR heteromer selective antagonist will be a valuable tool for the demonstration of the physiological significance of these heteromers in vivo. CB1R-δOR ligands: We have demonstrated CB1R-δOR heteromers to be a target for the treatment of neuropathic pain (Bushlin et al., 2012; Rozenfeld et al., 2012) and chemotherapy-induced pain (Sierra and Devi, in preparation). We have recently developed an assay that is suitable for HTS. During the MERIT extension period, I plan to carry out HTS analysis for the identification of CB1R-δOR-selective ligands and characterize the top hits for their ability to relieve neuropathic pain. Identification of new therapeutic targets for disorders of reward behaviors: Neuropeptides play important roles in a number of diverse physiological processes. Some of the most abundant neuropeptides found in the hypothalamus are generated from the protein named proSAAS; some of these peptides are involved in modulating feeding, drug addiction other rewarding behaviors. However, the receptor systems activated by these peptides were not known. During the base grant period, we deorphanized receptors for two of the proSAAS-derived peptides (Gomes et al., 2013b; Gomes et al., under review) and ide...