National Institute on Drug Abuse RESEARCH MONOGRAPH SERIES Discovery of Novel Opioid Medications 147 U.S. Department of Health and Human Services • Public Health Service • National Institutes of Health Discovery of Novel Opioid Medications Editors: Rao S. Rapaka, Ph.D. Heinz Sorer, Ph.D. NIDA Research Monograph 147 1995 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health National Institute on Drug Abuse 5600 Fishers Lane Rockville, MD 20857 ACKNOWLEDGEMENT This monograph is based on the papers from a technical review on “Discovery of Novel Opioid Medications” held on July 28-29, 1993. The review meeting was sponsored by the National Institute on Drug Abuse. COPYRIGHT STATUS The National Institute on Drug Abuse has obtained permission from the copyright holders to reproduce certain previously published material as noted in the text. Further reproduction of this copyrighted material is permitted only as part of a reprinting of the entire publication or chapter. For any other use, the copyright holder’s permission is required. All other material in this volume except quoted passages from copyrighted sources is in the public domain and may be used or reproduced without permission from the Institute or the authors. Citation of the source is appreciated. Opinions expressed in this volume are those of the authors and do not necessarily reflect the opinions or official policy of the National Institute on Drug Abuse or any other part of the U.S. Department of Health and Human Services. The U.S. Government does not endorse or favor any specific commercial product or company. Trade, proprietary, or company names appearing in this publication are used only because they are considered essential in the context of the studies reported herein. National Institute on Drug Abuse NIH Publication No. 95-3887 Printed 1995 NIDA Research Monographs are indexed in the Index Medicus. They are selectively included in the coverage of American Statistics Index, Biosciences information Service, Chemical Abstracts, Current Contents, Psychological Abstracts, and Psychopharmacology Abstracts. ii Contents Page Introduction . v Rao S. Rapaka and Heinz Sorer Targeting Drugs to the Brain by Sequential Metabolism . 1 Nicholas Bodor Action of Opioid Drugs on the Brain-Reward System . 33 Conan Kornetsky Drugs That Modify Opioid Tolerance, Physical Dependence, and Abstinence Symptoms: Preclinical and Clinical Studies . 53 Hemendra N. Bhargava Future Directions in the Pharmacological Management of Hyperalgesic and Allodynic Pain States: The NMDA Receptor . 84 Tony L. Yaksh, Sandra R. Chaplan, and Annika B. Malmberg Dual Inhibitors of Enkephalin-Degrading Enzymes (Neutral Endopeptidase 24.11 and Aminopeptidase N) as Potential New Medications in the Management of Pain and Opioid Addiction . 104 Bernard P. Rogues and Florence Noble Enhanced N-Methyl-D-Aspartate (NMDA)-Induced Activity Following Morphine: Sensitivity to Sigma and PCP Ligands . 146 Alice A. Larson, Rustam Yu. Yukhananov, and Julie S. Kreeger Dynorphin A: A Rectifying Peptide . 161 Nancy M. Lee Inhibitors of Nitric Oxide Synthase and the Opioid Withdrawal Syndrome ............................................. 170 Edythe D. London, Alane S. Kimes, and D. Bruce Vaupel iii Nitric Oxide and Opioid Tolerance 182 Gavril W. Pasternak Methoclocinnamox: A µ Partial Agonist With Pharmacotherapeutic Potential for Heroin Abuse . 195 James H. Woods, John W. Lewis, Gail Winger, Eduardo Butelman, Jillian Broadbear, and Gerald Zernig ACEA-1011, a Novel NMDA Receptor/Glycine Site Antagonist, Produces Antinociception but Not Tolerance in the Formalin Test in Mice . 220 Kabirullah Lutfy, John F. W. Keana, and Eckard Weber Etorphine Elicits Unique Inhibitory-Agonist and Excitatory-Antagonist Actions at Opioid Receptors on Sensory Neurons: New Rationale for Improved Clinical Analgesia and Treatment of Opiate Addiction . 234 Stanley M. Crain and Ke-Fei Shen The Association of Neuropathic Pain, Morphine Tolerance and Dependence, and the Translocation of Protein Kinase C . 269 David J. Mayer, Jianren Mao, and Donald D. Price iv Introduction Rao S. Rapaka and Heinz Sorer Heroin is an illegal and highly addictive narcotic. Addictive or dependence-producing properties are exhibited by (1) persistent regular use of a drug; (2) attempts to stop such use that lead to significant and painful withdrawal symptoms; (3) continued use despite damaging physical or psychological problems, or both; (4) compulsive drug-seeking behavior; and (5) need for increasing doses of the drug. Many health problems related to heroin use are caused by uncertain dosage levels (due to fluctuations in purity), use of unsterile equipment, contamination of heroin by cutting agents, or use of heroin in combination with other drugs such as alcohol or cocaine. Typical problems include skin abscesses, inflammation of the veins, serum hepatitis, and addiction with withdrawal symptoms. Utilization of unsterile needles by multiple individuals (needle sharing) increases the risk of exposure to the human immunodeficiency virus, the causative agent for Acquired Immune Deficiency Syndrome (AIDS). Heroin itself, as well as a drug-abusing lifestyle, may depress the body’s ability to withstand infection. While intravenous drug users account for approximately 25 percent of all reported AIDS cases, their proportion of the AIDS population appears to be increasing. In the first half of 1985, intravenous drug users accounted for 33 percent of all new AIDS cases. Moreover, 54 percent of newborns contracting AIDS have a parent who is an intravenous drug user, and intravenous drug users account for a similarly disproportionate share of the percentage of heterosexually transmitted AIDS cases. Estimates of heroin use from the National Institute on Drug Abuse (NIDA) Household Survey are considered very conservative due to the probable undercoverage of the population of heroin users. Estimates of lifetime heroin prevalence have fluctuated from 2 million users in 1985 to 2.7 million users in 1991, 1.8 million users in 1992, and 2.3 million users in 1993. No significant changes in past-year prevalence have been detected. v An estimated 1.3 percent of the U.S. civilian, noninstitutionalized population aged 12 and older had “ever used” heroin. Among the age groups, lifetime use was most common for adults aged 26 to 34 (1.8 percent) and among older adults aged 35 or older who were unemployed (7.5 percent). There were some statistically significant differences among demographic groups, but they should be interpreted cautiously because of the small number of users. Among the total population, males were significantly more likely than females (p < .001), college graduates were significantly less likely than those with less education (p > .01), and those unemployed were significantly more likely than those in the other employment categories (p < .05) to have ever used heroin. Heroin use differed little by race/ethnicity, population density, or region, and there were few statistically significant differences within the age groups. Because the rate of heroin use in the past year was 0.2 percent for the total population, no table is presented here for past-year use. Rates of use in the past month were so low among members of the target population that it was not possible to estimate them reliably using data from the 1991 NIDA Household Survey. A household survey such as the NIDA Household Survey may yield conservative estimates of the extent of drug use among members of the general population, particularly for rarely used drugs such as heroin. Although, in 1991, the NIDA Household Survey included individuals living in some types of group quarters (i.e., homeless shelters, college dormitories, and rooming houses), those living in many other types of nonhousehold arrangements (e.g., homeless people living on the streets or sentenced criminals in correctional institutions) were not included in the survey. To the extent that heroin users are disproportionately represented in the populations not included in the NIDA Household Survey, the 1991 survey (even with the inclusion of individuals in some group quarters) likely underestimates the prevalence of heroin use in the general population. In the 1992 NIDA Household Survey Populations Estimates Report, 0.9 percent of the civilian, noninstitutionalized U.S. population 12 years of age and older reported having used heroin in their lifetime, and 0.2 percent reported using it in the past year. In terms of population estimates, this amounts to 1.84 million persons for lifetime use and 323,000 persons for past-year use. vi One of the provisions of the Anti-Drug Abuse Act of 1988 consists of establishment of a new division within NIDA, the Medications Development Division, which became official in 1990. Its goals include: Conducting necessary studies to identify, develop, and obtain Food and Drug Administration marketing approval for new medications for the treatment of drug addiction and other brain and behavioral disorders; Developing and administering a national program of basic and clinical pharmaceutical research designed to develop innovative biological and pharmacological treatment approaches for addictive disorders; and Establishing a close working relationship with pharmaceutical and chemical companies in the United States and abroad and with medications development programs in other agencies in the United States and abroad. In late 1992, the Medications Development Division developed a preclinical program