Secrets of the opium poppy revealed

https://doi.org/10.1016/j.neuropharm.2004.06.016Get rights and content

Abstract

Studies concerning drugs of abuse have made major contributions in defining the circuitry, as well as cellular and molecular substrates that underlie certain behaviors. Opiate drugs for example, have revealed important insights concerning pain perception and reward. Up to the late 1960s, opiate drugs were suspected to work by mysteriously perturbing lipid membrane structure. We now know the following: the sequence and neuroanatomy of the G-protein coupled receptors that mediate opiate effects; that many proteins interact with opioid receptors such as G-protein sub-unit combinations, G-protein receptor kinases, arrestins and calmodulin; that many signaling molecules are modulated by opioid receptors, including ion channels, kinase cascades and adenyl cyclase. More than 20 different peptides, excised from three precursor proteins by specific proteases, have been shown to be endogenous ligands for opioid receptors. Revealing the molecules of the endogenous opioid system has inspired efforts for developing new opioid analgesics with the hope of minimizing abuse potential. This article will detail the current rationale for searching for less-addictive opiate analgesics and speculate on the future of drug abuse research in furthering our understanding of neural plasticity and the underpinnings of addictive behavior.

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.

References (33)

  • H. Akil et al.

    Endogenous opioids: biology and function

    Annu. Rev. Neurosci

    (1984)
  • A.C. Charles et al.

    Coexpression of delta-opioid receptors with micro receptors in GH3 cells changes the functional response to micro agonists from inhibitory to excitatory

    Mol. Pharmacol

    (2003)
  • S. Eitan et al.

    Brain region-specific mechanisms for acute morphine-induced mitogen-activated protein kinase modulation and distinct patterns of activation during analgesic tolerance and locomotor sensitization

    J. Neurosci

    (2003)
  • C.J. Evans et al.

    Cloning of a δ opioid receptor by functional expression

    Science

    (1992)
  • C.J. Evans et al.

    Opiate drugs: ‘guilt by association’

    Mol. Psychiatr

    (2000)
  • S.G. Grant

    Synapse signalling complexes and networks: machines underlying cognition

    Bioessays

    (2003)
  • Cited by (38)

    • Ultrastructural evidence for mu and delta opioid receptors at noradrenergic dendrites and glial profiles in the cat locus coeruleus

      2021, Brain Research
      Citation Excerpt :

      In basal conditions, cellular function requires a minimum number of receptors located on plasmalemmal sites, with most receptors situated within the cytoplasm. In addition, the internalization of G-protein coupled receptors depends on the rate constants for both endocytosis and recycling (Evans, 2004; Koenig and Edwardson, 1997). As a result, the percentage of receptors found on the plasma membrane varies in response to the physiological status of the neuron (Cahill et al., 2001).

    • Opioid addiction: Who are your real friends?

      2017, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      This is supported by the fact that adult rodents living in enriched environments were found to be more sensitive to the aversive properties of kappa agonists, as compared to individually-housed animals (Smith et al., 2003). Additionally, as discussed above, the differences in the effects of EE on various opioids could be because of biased agonism (Evans, 2004; Kelly et al., 2008a; Pradhan et al., 2012a; Barwatt et al., 2013; Emery et al., 2016; Emery et al., 2015) or PAMs (Burford et al., 2015; van der Westhuizen et al., 2015). Thus, more studies need to determine if that phenomenon is unique to heroin (or mice) or can be generalized to other opioids (and rats).

    • Opioid pharmaceuticals and addiction: The issues, and research directions seeking solutions

      2010, Drug and Alcohol Dependence
      Citation Excerpt :

      The current view of the receptor is a component of a dynamic protein complex within the membrane. The receptor is capable of orchestrating the interaction of many different proteins and the final complexes formed dependent upon; the available proteins for interacting with the receptor, the history of the local environment of the receptor, and the ligand occupying the receptor (Evans, 2004). The signaling cascades that are activated depend upon the complex formed, which also dictates the trafficking and desensitization mechanisms of the receptor (Kelly et al., 2008).

    View all citing articles on Scopus
    View full text