For the love of paradox: from neurobiology to pharmacology

Bond, Richard A.; Giles, Heather

Behavioural Pharmacology:
doi: 10.1097/FBP.0b013e328348ec6f
Review Articles

The acute and chronic effects of certain drugs can often be opposite. For example, in congestive heart failure acute administration of β-adrenoceptor agonists results in beneficial improvement in symptoms of the disease, but their chronic use increases mortality. Conversely, certain β-adrenoceptor antagonists/inverse agonists (β-blockers) initially cause a detrimental response by decreasing cardiac contractility in congestive heart failure, whereas chronic treatment with the same β-blockers improves contractility and survival. Furthermore, this time-dependent reversal of outcomes occurs in nonpharmacological interventions, such as exercise, and can even be observed in the response of plants to pruning or other stressors, with the results being a different short-term versus long-term effect. Here, we review some of these phenomena with a special emphasis on the temporal dissociation of pharmacological effects. Although Francis Colpaert used this knowledge to lead a drug discovery project for an analgesic compound that initially produced hyperalgesia, we focused on examples outside the central nervous system.

Author Information

Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, Texas, USA

Correspondence to Richard A. Bond, PhD, Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Room 521, Building Science and Research 2, Houston, TX 77204-5037, USA E-mail: RABond@UH.Edu

Received March 22, 2011

Accepted April 17, 2011

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Given that this special issue is dedicated to the life and work of Francis Colpaert, we include a brief description of our personal experience with Francis, the scientist and more importantly, Francis, the man.

In 2002, Adrian Newman-Tancredi and we attended a conference on inverse agonism in S'Agaro, Spain. After Adrian heard my talk on the counterintuitive use of β-adrenoceptor-inverse agonists (a subset of β-blockers), he approached me and said that I should contact his boss, Francis Colpaert. Adrian said Francis was also thinking counterintuitively and was even applying it to drug discovery. Francis and I began a very enjoyable extensive email discussion on the paradox, with the discussion often turning into philosophical arguments. As a result of these emails, about a year later Francis decided to stop by and meet us in Houston on his way to San Antonio. We spent a lovely couple of days and it very much cemented our friendship, likely due to our love for food and wine, as much as our love of paradox. Anyway, we stayed in email and phone contact for the next few years. Even when months had gone by in between contacts, it was as if we had just communicated the day before. Next, we saw each other at a conference in Hamburg, where we were both speakers in a session appropriately titled, ‘Paradoxical Pharmacology’. Of course, we did manage, among other things, to fit in a nine-course degustation dinner with matching wines at one of the city's top restaurants. The following year, we visited his home outside Toulouse, ‘Mirabel,’ where we met Anne, his partner of more than 20 years; we had an absolutely wonderful time. Francis' constant joy of life was contagious. We stayed in email/phone contact for a few months, mainly about science, but also about the ups and downs of Francis' life in the pharmaceutical industry.

In March of last year, we decided to call Francis because it had been months since we had communicated. It was then he told me about his recent diagnosis of pancreatic cancer. With help from a friend and colleague, Richard managed to get in touch with the Head of GI oncology (Jim Abbruzzese) at arguably the world's best cancer institute, MD Anderson Cancer Center, Houston, Texas, USA. Jim was absolutely wonderful, and although he advised Francis not make the trip to MD Anderson, he would always offer support and treatment options and regimens for Francis to discuss with his oncologists. We returned to Mirabel in July and Francis looked a bit thinner, but was still full of life when he was not exhausted. By this time, we knew Francis' first treatment regimen had failed to stop the tumor growth or metastasis. Jim Abbruzzese then recommended a regimen that included a drug approved in Europe for some cancers, but was still in clinical trials for pancreatic cancer and was not available in France. Heather managed to get the company to review Francis' case and to agree to provide Francis with the drug. Although no drug yet discovered is very effective in this disease, it did provide hope. We went back to Mirabel 7 weeks later, and now Francis did look very poorly; but still, his agile brain and lovely smile provided us all with much to enjoy during that last visit. It was distressing that the French system was so slow in obtaining the drug. The drug finally arrived about 2 weeks later (2 months after the company offered to provide it.) Ironically, it arrived the day Francis died.

Although all of the last 8 months of his life seemed filled with sad and tragic events, Francis remained as full of life as possible; indeed, to me it often seemed miraculous that he could enjoy so much the times when he was alert enough to engage in discussions, or when he was hungry enough to have something substantial to eat. Francis' joy of life was simply incredible, and this is what we remember. A life too short but filled with enough passion to fuel all who knew him. It is a true privilege to have had him as a friend.

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The observation that certain drugs require time to produce an effect, or that certain drugs lose effectiveness with time, is well established. The oldest example of this latter phenomenon is likely the thousands of year old observation that the analgesic effect of opioids wane with repeated administration for weeks or months. In general, we term this observation as tolerance, tachyphylaxis, or desensitization. However, in receptor pharmacology, the term ‘desensitization’ is most often used to signify either a loss of ability of the receptor to couple to its effector machinery or a loss of receptor numbers by either sequestration or degradation. With few exceptions, this loss of responsiveness is viewed as a detrimental property of prolonged drug treatment with an agonist. Francis Colpaert turned this idea on its head by hypothesizing that, perhaps if we administered high-efficacy agonists to a receptor that mediated a hyperalgesic effect, then desensitization of this system would lead to an analgesic effect. Indeed, this is the proposed mechanism of action of the high-efficacy serotonin 5-HT1A agonist, F-13640 (Bardin and Colpaert, 2004; Bardin et al., 2005).

As stated above, although we will very briefly discuss examples of what might be termed ‘paradoxical pharmacology’ produced by drugs acting in the central nervous system (CNS), we will focus on two apparently unrelated diseases of the periphery: congestive heart failure (CHF) and asthma. These diseases may appear dissimilar, but in both conditions, β-adrenoceptor agonists are acutely beneficial, but chronically detrimental. Conversely, the acute use of β-adrenoceptor-inverse agonists (a subset of ‘β-blockers’ capable of not only blocking agonist-induced receptor activation, but also inhibiting constitutive signaling by unoccupied β-adrenoceptors) is detrimental, but their chronic use has been proven to be beneficial in the treatment of CHF (Hall et al., 1995; Krum et al., 1995; Lechat et al., 1998; Bristow, 2000), and recent reports suggest that the same may be true in the treatment of asthma (Callaerts-Vegh et al., 2004; Hanania et al., 2008, 2010b; Lin et al., 2008; Nguyen et al., 2008, 2009; Bond, 2001, 2002; Bond et al., 2007; Parra and Bond, 2007; Dickey et al., 2010; Walker et al., 2010; Hanania et al., 2010a).

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Congestive heart failure

CHF is a disease of an impaired cardiac contractility usually caused as a result of ischemic damage to the heart muscle. The body's response to the resultant decrease in cardiac output is to ‘compensate’ by activating the sympathetic nervous system and the rennin–angiotensin system to increase cardiac output and circulating blood volume. As activation of these systems leads to a compensatory increase in cardiac output, initial drug development strategies were based on further enhancing cardiac output with the use of β-adrenoceptor agonists to increase cardiac contractility. However, clinical trials demonstrated that while the acute use of β-adrenoceptor agonists in CHF was associated with improved hemodynamics and decreased symptoms of CHF, prolonged administration of β-adrenoceptor agonists resulted in an increase in mortality (The Xamoterol in Severe Heart Failure Study Group, 1990; Weber et al., 1982). However, perhaps a more unexpected finding was that when administered chronically, certain β-blockers were shown to increase cardiac contractility and to decrease mortality in CHF (Hall et al., 1995; Krum et al., 1995; Lechat et al., 1998; Bristow, 2000). This was a truly remarkable reversal – chronic administration of acutely negative inotropic drugs, like the β-blockers/inverse agonists, carvedilol or metoprolol, resulted in an increase in cardiac contractility and in a decrease in mortality in CHF with chronic use. Thus, for what we believe to be the only time ever in pharmacological history, certain members of a class of drugs have moved from being contraindicated to drugs of choice in the disease for which they were contraindicated (Fig. 1, left panel).

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‘The universe is filled with things that happen once, but if it happens twice, it will happen a third time.’ Paulo Coelho, The Alchemist.

So was the total reversal in the chronic management of CHF an isolated event or an example of a more general principle? If one decides to answer this question, the disease that comes up as a logical choice is asthma (Fig. 1). Just as in CHF, the use of β-adrenoceptor agonists (in this case, agonists of the β2-adrenoceptor subtype) is beneficial. β2-adrenoceptor agonists are the most potent bronchodilators discovered and are an important component of the treatment regimen of all asthmatics, regardless of disease severity. However, their constant chronic use has been associated with detrimental effects, ranging from loss of bronchoprotection to increases in asthma-related deaths (Nelson et al., 2006; Bond et al., 2007), sufficient to cause the Food and Drug Administration to mandate severe restrictions in their use in asthmatics. In addition, just as was the case in CHF, β-adrenoceptor antagonists/inverse agonists are contraindicated in patients with asthma. Therefore, in asthma, the outcomes of using agonists acutely or chronically, or using antagonists acutely had shown a perfect correlation to CHF (Fig. 1). However, the effect of chronic use of β-blockers, had never been tested (Bond, 2001, 2002).

Our laboratory decided to test the hypothesis that chronic use of certain β-blockers may be beneficial in asthma management. Now, a decade after the initial experiments were run, and with the help of collaborators, we have provided considerable evidence, including two small (10 patients) studies in mild asthmatics (Hanania et al., 2008, 2010b) that chronic treatment with β-blockers/inverse agonists may result in positive outcomes in asthmatics, as would be predicted from the CHF experience (Hall et al., 1995; Krum et al., 1995; Lechat et al., 1998; Bristow, 2000). For those interested in further reading, all of the data in support of the use of chronic β-adrenoceptor-inverse agonists in asthma have recently been reviewed and potential mechanisms have been postulated (Dickey et al., 2010; Walker et al., 2010)

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Brief examples from treatment of central nervous system diseases

The CNS does have several examples of therapies that either appear paradoxical, or have an opposite effect, depending on the duration of the treatment. For example, the CNS stimulant, methylphenidate, is used in the treatment of hyperactivity disorders. Additional examples include the loss of analgesia with the chronic, constant use of opioids and, conversely, the production of analgesia by use of a serotonin 5-HT1A receptor agonist. Stimulation of this receptor can initially mediate hyperalgesia, but Francis Colpaert discovered that chronic use of the high-efficacy 5-HT1A agonist, F-13640, results in profound and persistent analgesia. He speculated that the agonist had induced long-term neuroadaptive changes in the 5-HT1A receptor (Colpaert, 2006; Deseure et al., 2007). There are also other examples in which desensitization has been hypothesized to be a mechanism of action for the beneficial effect of the drug, but the finding tends to be discovered retrospectively and not by deliberate drug design. For example, the delay in the therapeutic effect of antidepressants that block the uptake of neurotransmitters, such as serotonin and norepinephrine, has been hypothesized to be a consequence of the need to produce desensitization of some of the receptor subtypes for these neurotransmitters.

A further example of how duration of agonist administration can determine its effect, and consequently the disease for which it is indicated is gonadotropin-releasing hormone (GnRH). Pulsatile administration of GnRH is used to simulate physiological signaling of the GnRH receptor and can restore reproductive potential in men and women whose infertility is a result of anomalous endogenous GnRH production or release. In contrast, if GnRH is administered constantly through a depot injection or by using synthetic long-acting GnRH agonists, this chronic stimulation of the GnRH receptor results in GnRH receptor desensitization and loss of response from the reproductive hormone axis (Oliveira et al., 2010; Beyer et al., 2011).

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Nonpharmacological examples of short-term detrimental behaviors for a longer-term benefit – ‘no pain, no gain’.

Behaviors, such as exercise, also have opposing physiological effects (i.e. on muscle tissue) between a single acute event and repetitive chronic exercise. Other behaviors also use strategies that are detrimental in the short term to derive long-term beneficial effects. Examples of these behaviors include dieting, saving money, and disciplining children. Even with plants, the effects of pruning (a ‘treatment’) are different between the short-term and long-term results.

We, in fact, speculate that acceptance of the rule of ‘do no harm’ may be doing medicine and drug discovery a disservice. This disservice is most likely to occur in cases, in which decisions are made to discontinue a drug discovery project on the basis of negative or ‘harmful’ results of an acute experiment, when the project was aimed at treatment for a chronic disease or condition. The current model of drug discovery is in itself paradoxical. Most diseases targeted by the pharmaceutical industry are those for which regular, long-term treatment is required. However, the constant pressure for speed, efficiency, and cost effectiveness in the drug discovery process means that decisions to halt or to progress projects are often based on the results of short-term experiments.

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‘Paradox is truth standing on her head to attract attention.’ G.K. Chesterton

The identification of the phenomena of temporal differences in the effects of both agonists and antagonists in numerous drug classes has, at first observation, seemed extremely paradoxical. However, as scientists, our natural inclination is to ask the question ‘why’. Over the coming years, the mechanistic basis for such behavior will undoubtedly be revealed, and the paradox will be no more. An excellent example of this is perhaps the first and most studied example of a paradoxical approach in medicine, the use of vaccines. Clearly, injecting even attenuated pathogens as a preventative measure for a disease is somewhat counterintuitive and can certainly result in short-term discomfort for a long-term gain, but immunology has now clearly explained why the phenomenon works and it no longer even appears to us as paradoxical. Nevertheless for those of us, such as Francis Colpaert, who have felt compelled to challenge the dogma of the current treatment paradigms because we observed paradoxical behavior, the path has been long and challenging. Seemingly, ‘simple’ explanations of mechanism of action of a particular drug class become turned on their head and obtaining funding, and acceptance of paradigm-shifting ideas by peers, takes many years. For example, it took more than 20 years from the first study indicating the use of β-blockers in CHF to the first marketing approval for such an indication. As Sir James Black would remind us, ‘it took 18 months to create the dogma (of β-blockers being contraindicated in CHF), and more than 2 decades to reverse it’. It was the challenge of the paradox that fascinated Francis, and his curiosity, insightful science, and perseverance have resulted in a potential new treatment for pain: a fitting legacy from this special man.

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The authors thank Bhupinder Singh for his help and input in producing this manuscript. Some of the ideas contained in this manuscript have been supported by the National Institutes of Health (R.A.B.); the American Asthma Foundation (R.A.B.); and Inverseon Inc. (R.A.B. and H.G.).

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Conflicts of interest

R.A.B. and H.G. are shareholders in Inverseon Inc.

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β-blockers; asthma; congestive heart failure; Francis Colpaert; paradoxical pharmacology

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