GRANT NUMBER:  R01 DA023281-07S1

ABSTRACT:  The high expression level of NOP receptors in brain regions involved in nociceptive responses and reward strongly suggest this as a target for therapeutics for both pain and drug abuse. In fact, NOP agonists have been demonstrated to block CPP of a large number of abused drugs. The parent grant of this supplement has a Specific Aim that tests hypotheses related to the plasticity of the NOP system subsequent to chronic pain and chronic morphine treatment, and another Specific Aim intended to identify and synthesize novel NOP receptor-active compounds that will have an improved profile with respect to analgesia with low abuse potential as well as improved drug abuse medications. Both chronic pain and morphine/cocaine abuse are co-morbid with alcohol abuse. It is not known how alcohol affects the NOP receptor system or the involvement of the NOP system in chronic pain and substance abuse. In Specific Aim 1 of the supplement we will test the hypothesis that co-treatment with ethanol will modulate the changes in NOP receptor mRNA and protein induced by both chronic pain and chronic morphine treatment. mRNA levels will be measured by standard quantitative PCR procedures. NOP receptor protein will be measured using novel eGFP-NOP receptor mice recently obtained from Dr. Brigitte Kieffer. Although alcohol is known to potentiate the rewarding nature of morphine, its affect on low efficacy mu opiates, such as buprenorphine, or on NOP/mu active compounds is unknown. Because of the parent grant and other collaborations, we have novel compounds with high affinity to both NOP and mu receptors with varying in vivo profiles. In Specific Aim 2 of the supplement we will determine whether co-treatment with alcohol affects the CPP of buprenorphine and other mixed NOP/mu compounds that have shown antinociception without reward and potential as a drug abuse medications. These studies will fulfill the mission of the Collaborative Research on Addiction at NIH (CRAN) and examine comorbidity of alcohol, morphine, and chronic pain and determine the effect of polydrug use on the plasticity and function of the important NOP receptor system.


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