Secrets of the opium poppy revealed
Introduction
Substance abuse, like many psychiatric illnesses, requires an environmental trigger—in this case, a drug. The assumption is that if drug supplies could be halted, addiction disorders would be less prevalent in society. However, it is difficult to predict the behavioral outcome of those susceptible to addictive disorders that do not indulge. It could be argued that drug abuse may actually be protective for society, focusing the reward system on an exogenous substance rather than more primal behaviors such as mating and survival, which the circuitry probably evolved to promote. Despite rigorous efforts to eradicate illicit opium-derived drugs, they remain readily obtainable. As soon as one source is quenched, another seems to emerge. According to the National Survey on Drug Use and Health (NSDUH), the prevalence of lifetime heroin use among youths aged 12–17 increased from 0.1% in 1995 to 0.4% in 2002. Over the same seven-year time period, the lifetime use rate doubled among youths aged 18–25, reaching 1.6% in 2002. The Drug Abuse Warning Network (DAWN) which monitors drug-related emergency room visits, reported 93,518 visits related to heroin in 2002, which was up from 63,158 in 1994. Prescription opiates such as morphine, oxycontin and vicodin are also significantly abused and addictive use is increasing, as society demands its library of pharmaceuticals to include effective drugs for pain suppression. In 2002, according to DAWN there were 119,185 emergency room visits as a result of opiate therapeutics, up from 44,518 visits in 1994. Nearly 50,000 of the emergency room visits in 2002 were associated with oxycodone or hydrocodone (e.g. oxycontin, percocet and vicodin), and this is probably an underestimate since in the approximately 42,000, visits to the emergency room, the opiate pharmaceutical was not recorded. These statistics underline the caution needed when prescribing opiate analgesics for pain. Results from the 2002 NSDUH survey also suggested that non-medical pain reliever use is increasing. For young adults, 6.8% reported misuse of an opiate pain medication in 1992 and 22.1% in 2002. Clinicians working with abusing populations paint an extremely bleak picture for opiate addicts, including the destructive drug-focused behaviors, the high rates of incarceration resulting in disruption of relationships and social structure and the associated diseases such as AIDS and hepatitis C virus as a consequence of needle sharing and risky sexual behaviors. Clearly opiate abuse is on the rise, and with the low cure rate of opiate addicts (for heroin addicts relapse is close to 100%) it can be assumed that opiate addiction will continue as a medical problem, undaunted by the current punitive repercussions, financial burden and poor prognosis.
One goal, or rather dream, of opioid research has been the development of opiate drugs that are analgesic yet lack abuse potential, tolerance and withdrawal. Given the statistics for opiate pharmaceutical abuse, a non-addictive opiate would clearly fulfill an important medical niche. Over the years, I have vacillated between considering a non-addictive opiate analgesic as pie in the sky or an intriguing possibility. The reason for my vacillating opinions has been the continuing emergence of knowledge of how opioid drugs trigger cellular signaling cascades that eventually lead to analgesia and addiction. I will frame this article with discoveries, including those from our NIDA Center, The Center for Study of Opioid Receptors and Drugs of Abuse (CSORDA), that have defined the molecules of the endogenous opioid system and rekindled hope for more sophisticated opiate drug development. I will also speculate that recent and future substance abuse research will provide critical insight to our understanding of plasticity mechanisms in the brain by studying cellular and molecular reorganization that accompanies altered behaviors as a result of drug taking.
Section snippets
Revealing the endogenous opioid system
Parallel with the demonstration that opiate drugs interact with receptor binding sites was the concept of multiple opioid receptors. This notion first emerged following pharmacological analyses of different opiate drugs in dogs. In early studies, a series of behavioral effects and cross-tolerance among drugs were the tools used to differentiate receptor types (Martin et al., 1976). The discovery of the endogenous opioid peptides, methionine and leucine–enkephalin, provided an entirely new
Receptor trafficking
Ligand-regulated receptor trafficking is an area of research that has blossomed since the molecular characterization of G-protein coupled receptors. The analysis of the opioid receptors has been particularly insightful given the variety of alkaloid and peptide ligands, including agonists, partial agonists, antagonists and inverse agonists. The finding that many opioid agonists, including the endogenous opioids, can induce mu receptor internalization whilst morphine does not, resulted in much
Receptor cross-talk
The concept of opioid receptor cross-talk, in particularly between mu and delta opioid receptors, has been with the field for many years and stems from a number of pharmacological observations, mostly in vivo (reviewed by Zaki et al., 1996). Two recent studies in which CSORDA was involved illustrate the potential importance of receptor signaling cross-talk on the outcome of receptor activation. The first is the modulation of insulin receptor kinase signaling cascades by mu receptors, a study
Opioid receptors as multiple complexes
Many convergent areas of receptor research including signaling, oligomerization and trafficking now visualize membrane receptors not as isolated units in the membrane but as dynamic complexes with many interacting proteins. Analysis of the NMDA receptor has been illustrative of the complexity with to date more than 180 anticipated protein partners (Grant, 2003). Clearly not all are partners with the NMDA receptor at the same time and many are competitive and their interaction dependent on
Mechanisms of plasticity
Opiate administration leads to major changes in behaviors such as tolerance, sensitization, craving and withdrawal. Presumably, changes in neuronal circuitry underlying these drug behaviors share mechanisms utilized in adapting to other environmental inputs, such as stress. As has been articulated elsewhere, the questions now being addressed in many areas of substance abuse research parallel closely those in other areas of plasticity research such as learning and memory. In recent years,
Summary
Over the last four decades, since the inception of NIDA, secrets of how opiate drugs target and regulate cells have been revealed. The molecular components of the endogenous system, including the endogenous opioid peptides and their receptors, have been mapped and signaling pathways elucidated. Mouse knockout studies have clearly identified the mu receptor as the principle target for opiate analgesia and reward. With our current understanding, we now must consider opioid receptors as
Acknowledgements
I would like to thank Camron Bryant for his suggestion and comments on the manuscript. Studies discussed in this article were supported by NIDA (DA05010), a Human Frontiers grant (01030586) and the Shirley and Stefan Hatos Neuroscience Research Foundation.
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