Heroin abuse has increased significantly in recent years especially among the young. The statistics emphasize the need for new approaches to the treatment of maternal heroin abuse. Currently, the only drug approved for treating opiate dependence in pregnant U.S. women is methodone. Successful clinical trials suggest that buprenorphine will soon become a useful addition to the armamentarium of heroine addiction pharmacotherapy. Buprenorphine is an opiate alkaloid that acts as a mu opiate partial agonist, a nociceptin/orphanin receptor full agonist and a kappa antagonist. In comparison to methadone, buprenorphine has a lower abuse liability, a longer lasting action, a less intense withdrawal state and less physical dependence. Our previous findings demonstrate that in utero buprenorphine administration induces mu and kappa opioid receptor adaptation in developing rat brain. By acting at mu, kappa and nociceptin/orphanin receptors, buprenorphine may exert a blockade of mesolimbic reward mechanisms, thereby accounting for its ability to antagonize the reinforcing effects of heroine. Our focus will be to test the hypothesis that gestational opiates induce changes in opioid receptor binding density, phosphorylation and G protein coupling, an estimate of signaling capacity, thereby altering opioid receptor function in mesolimbic regions of offspring. We will determine whether correlative changes occur to these 3 signaling parameters. Discrete mesolimbic structures of developing rats exposed to gestational buprenorphine plu and minus naloxone will be compared to those treated with methadone and heroine. There are 3 specific aims:
AIM 1. Measure gestational buprenorphine-induced opioid receptor adaptation in mesolimbic brain regions of developing offspring and dams by receptor autoradiography and semi-quantitative immunofluorescence confocal microscopy.
AIM 2. Measure buprenorphine-induced mu opioid receptor phosphorylation in selected mesolimbic brain regions of developing offspring and dams by immunoblotting.
AIM 3. Measure changes in mesolimbic opioid receptor activation of G proteins induced by gestational buprenorphine. This is an exploratory/developmental grant proposal (R21) to develop semi-quantitative immunological and autoradiographic techniques with anatomical and cellular resolution in neonatal mesolimbic brain regions. They will be used to determine whether gestational opiate exposure alters opioid receptor adaptation, receptor phosphorylation and/or coupling to G proteins in the mesolimbic regions of offspring brain.
| Hou, Yanning; Belcheva, Mariana M; Clark, Amy L et al. (2006) Increased opioid receptor binding and G protein coupling in the accumbens and ventral tegmental area of postnatal day 2 rats. Neurosci Lett 395:244-8 |
| Hou, Yanning; Tan, Yun; Belcheva, Mariana M et al. (2004) Differential effects of gestational buprenorphine, naloxone, and methadone on mesolimbic mu opioid and ORL1 receptor G protein coupling. Brain Res Dev Brain Res 151:149-57 |
| Belcheva, Mariana M; Coscia, Carmine J (2002) Diversity of G protein-coupled receptor signaling pathways to ERK/MAP kinase. Neurosignals 11:34-44 |
| Belcheva, M M; Barg, J; McHale, R J et al. (1993) Differential down- and up-regulation of rat brain opioid receptor types and subtypes by buprenorphine. Mol Pharmacol 44:173-9 |
