NIDA - Director's Report - May 2004 Home > Publications > Director's Reports Director's Report to the National Advisory Council on Drug Abuse - May, 2004 Index Report Index Research Findings Report for February, 2004 Basic Research Report for Behavioral Research September, 2003 Treatment Research and Development Report for May, Research on AIDS and Other Medical Consequences of Drug 2003 Abuse - AIDS Research Report for February, Research on AIDS and Other Medical Consequences of Drug 2003 Abuse - Non-AIDS Medical Consequences of Drug Abuse Report for Epidemiology and Etiology Research September, 2002 Prevention Research Report for May, 2002 Services Research Report for February, Intramural Research 2002 Program Activities Report for September, 2001 Extramural Policy and Review Activities Report for May, 2001 Congressional Affairs Report for February, 2001 International Activities Report for September, 2000 Meetings and Conferences Report for May, 2000 Media and Education Activities Report for February, 2000 Planned Meetings Report for September, 1999 Publications Report for May, 1999 Staff Highlights Report for February, 1999 Grantee Honors Report for September, 1998 Report for May, 1998 Report for February, 1998 Report for September, 1997 Report for May, 1997 Report for February, 1997 https://archives.drugabuse.gov/DirReports/DirRep504/Default.html[11/17/16, 10:22:07 PM] NIDA - Director's Report - May 2004 Report from September, 1996 Report from May, 1996 Report from February, 1996 Report from September, 1995 Report from May, 1995 Report from February, 1995 NACDA Legislation Archive Home | Accessibility | Privacy | FOIA (NIH) | Current NIDA Home Page The National Institute on Drug Abuse (NIDA) is part of the National Institutes of Health (NIH) , a component of the U.S. Department of Health and Human Services. Questions? _ See our Contact Information. https://archives.drugabuse.gov/DirReports/DirRep504/Default.html[11/17/16, 10:22:07 PM] NIDA - Director's Report - May, 2004 Home > Publications > Director's Reports Director's Report to the National Advisory Council on Drug Abuse - May, 2004 Research Findings - Basic Research Index Design of Novel Peptide Ligands that have Opioid Agonist Activity and CCK Research Findings Antagonist Activity for the Treatment of Pain Basic Research There is a need for a new paradigm in drug discovery for pathological conditions Behavioral Research including disease states such as neuropathic pain and conditions of opioid analgesic Treatment Research tolerance. It is now known from multiple experimental approaches that many disease and Development states lead to changes in expressed proteins (adaptation/neuroplasticity). Drug design based on normal states is inadequate or even possibly counter-indicated. Therefore Research on AIDS the system changes that have occurred must be considered in any treatment for the and Other Medical disease. Such "systems changes" are clearly evident in neuropathic pain and in Consequences of conditions of opioid tolerance where opioids can actually heighten pain. In these pain Drug Abuse - AIDS states there are increased levels and/or activity of pronociceptive neurotransmitters Research such as cholecystokinin (CCK) and their receptors. CCK and enkephalins and their Research on AIDS receptors are co-localized in the CNS and, as a pronociceptive peptide, CCK acts as an and Other Medical "antiopioid" and alternate analgesic to diminish opioid antinociception. In view of Consequences of these and other findings, NIDA grantee, Dr. Victor Hruby and colleagues have Drug Abuse - Non- investigated a new paradigm for drug discovery aimed at treatment of pathological AIDS Medical pain (such as neuropathic pain) and in conditions of opioid tolerance. In this approach Consequences of a single peptide or peptidomimetic molecule that can interact with opioid receptors as Drug Abuse agonists and at CCK receptors as antagonists is designed. Specifically, compounds Epidemiology and that are agonists at opioid mu or delta receptors and antagonists at CCK-1 or CCK-2 Etiology Research receptors (preferably both representing a "balanced" CCK receptor antagonist) are developed. It is postulated that such a molecule would show superior efficacy to Prevention Research opioid agonists for the treatment of pathological pain states since it would block the Services Research antiopioid effects of CCK and be resistant to the development of paradoxical opioid- induced pain and antinociceptive tolerance. In this paper, Dr. Hruby and his Intramural Research colleagues report progress toward these objectives using various approaches to Program Activities rational peptide ligand based drug design. De novo design based on the concept of overlapping pharmacophores was a central hypothesis of this design, and led to Extramural Policy and Review compounds such as H-Tyr-DPhe-Gly-DTrp-NMeNle-Asp-Phe-NH2 (i.e., RSA 601), Activities which have the designed properties. Hruby, V.J., Agnes, R.S., Davis, P., Ma, S-W., Lee, Y.S., Vanderah, T.W., Lai, J. and Porreca, F. Design of Novel Peptide Ligands Congressional Affairs which have Opioid Agonist Activity and CCK Antagonist Activity for the Treatment of Pain. Life Sciences 73, pp. 699-704, 2003. International Activities The Effect of Hair Color on the Incorporation of Codeine into Human Hair Meetings and Conferences The purpose of this study was to determine if codeine, as a model compound for abused drugs, would be incorporated into black, brown, blond, or red hair as a Media and Education Activities function of melanin concentration. Male and female Caucasians with black (n=6), brown (n=12), blond (n=8) or red hair (n=6) and non Caucasians with black hair Planned Meetings (n=12), aged 21-40 years of age were administered oral codeine phosphate syrup in a dose of 30 mg three times a day for five days. Twenty-four hours after the end of Publications the treatment period, a 30 mg codeine dose was administered and the subject's plasma area under the concentration time curve (AUC) for codeine was determined. Staff Highlights Codeine and melanin were measured in the first 3 cm of hair closest to scalp prior to and 1,4,5, 6,and 7 weeks after dosing. The quantitative and qualitative melanin Grantee Honors profiles were determined for each subject's hair to provide an objective measure of hair color. The plasma concentrations of codeine were measured to eliminate differences in the bioavailability and clearance of codeine as factors that might account for the differences in codeine hair concentrations. The mean hair codeine concentrations 5 weeks after dosing were 1,429 pg/mg in black hair; 208 pg/mg in brown hair; 99 pg/mg in blond hair; and 69 pg/mg in red hair. In black hair, codeine https://archives.drugabuse.gov/DirReports/DirRep504/DirectorReport1.html[11/17/16, 10:22:12 PM] NIDA - Director's Report - May, 2004 concentrations were 2,564 pg/mg for Asians and 865 pg/mg for Caucasians. Similar concentration relationships were observed at weeks 4, 6, and 7. A strong relationship between the hair concentrations of codeine and melanin was observed. These data demonstrate that the interpretation and reporting of hair test results for codeine are influenced by hair color. After this dosing protocol, the proposed federal guideline cut- off of 200 pg/mg of codeine would result in 100% of subjects with black hair and 50% of subjects with brown hair being reported as positive, and subjects with blond or red hair would be reported as negative. The incorporation of these drugs into hair should be studied carefully in humans to ensure the appropriate interpretation of drug concentrations. Rollins, D.E., Wilkins, D.G., Kruger, G.G., Augsburger, M.P., Mizuno, A., O'Neal, C., Borges, C.R. and Slawson, M.S. Journal of Analytical Toxicology, 27, pp. 545-551, 2003. Morphine Tolerance and Development In a recent paper, Dr. Gordon Barr and Dr. Hongbo Zhu report their findings on ontogeny of N-methyl-D-aspartate (NMDA) receptor mediated morphine tolerance in the postnatal rat. This study is the first to provide conclusive evidence that NMDA receptor antagonists are not effective in attenuating tolerance in the newborn rat and that there is a transition age, around the second postnatal week in the rat, for NMDA receptor antagonists to be effective in suppressing opiate tolerance and withdrawal. This study was undertaken because of the known effectiveness of NMDA receptor antagonists to inhibit the development of morphine tolerance in adults and the dramatic changes that occur in NMDA receptors during the first few weeks of postnatal life. Zhu, H. and Barr, G.A. Ontogeny of NMDA Receptor-Mediated morphine Tolerance in the Postnatal Rat. Pain. 104, pp. 437-447, 2003. Mixed Mu Agonists/Delta Antagonists There is a continuing effort and interest in developing ligands exhibiting agonist action at the mu receptor for purposes of chronic pain treatment, but which also possess antagonist properties at the delta receptor, in order to lessen or minimize the known side effects of mu ligands, such as respiratory depression and development of tolerance/dependence. Evidence has been provided by immunoprecipitation and immunoblotting results of an interaction or complex formation between mu and delta receptors, when they are co- expressed in COS cells. These co-expressed receptors showed altered binding profiles (reduced affinity of morphine, DAMGO, and DPDPE) as compared to the values reported in separate cell expressions of mu or delta receptors. Additionally, the development of acute tolerance