Dr Maria Maiaru
Dr Stefania Mangione
Everything we study is immensely important clinically and where there is often a large unmet need. To isolate molecules that could be targeted therapeutically in the control of drug relapse would be a major achievement and therapeutic advance. To understand the molecular pathology of depression or ADHD would similarly open many doors to future therapeutic interventions. The symptoms of pain arising from nerve injury, neuropathic pain, such as allodynia (touch evoked pain), spontaneous pain, hyperalgesia (enhanced pain following injury), and of course cancer pain are difficult to control with currently available drugs.
We study a number of closely related diseases: Drug addiction, affective disorders, and pain mechanisms. At core these share the common problem of neural plasticity. For, while the nervous system is certainly plastic in its responses to the environment- it is not elastic. In other words the change in neural circuits that represent an attempt to compensate for drastic environmental change cannot easily be reset when kinder environmental pressures return. Genomics can be used to identify genes related to specific diseases and epigenetics can bring nervous system function in to line with environmental contingencies. In the field of pain, depression, ADHD and addiction new targets could lead to better treatments.
Our work has both provided a framework for understanding the underlying causes for these diseases, suggested mechanisms and provided a rational basis for some on-going pharmaceutical developments as well as suggesting new avenues of research. We were one of the very first groups to map the molecular changes that accompany pain and neuropathic pain states, develop molecular gene knockout models that throw light on the inter-relationship between opiate control of pain and addiction and suggest a rational basis for understanding and extending new therapies for depression and ADHD. We pioneered the use of genetic screens for identifying genes that drive regeneration in the adult central and peripheral nervous system. We have recently been targeting pharmacologically and anatomically defined neuronal populations; a very powerful approach that has further advanced our understanding of addiction, relapse into drug taking and anxiety states. All of these advances have been published and some are listed below.
Our objectives are:
• To understand how pain signaling is regulated at the level of the spinal cord and brain and to identify key new molecular targets that are involved in pain processing and therefore targets for analgesia. We wish to understand the ways in which pain can be regulated or de-regulated to create persistent pain states. There are strong indications that the brain is crucial for the regulation of spinal cord plasticity. It is critical that genomics is integrated with physiology and behaviour.
• To understand the underlying molecular pathology of drug addiction and depression and ADHD and identify areas of the brain associated with depression and anxiety and drug addiction.
Thus, our research investigates neuronal networks, mechanisms of activity-dependent plasticity and processes of trauma and disease- at the molecular, structural and behavioural levels. We believe that different diseases are characterized by different molecular signatures in the brain.
The Neurobiology of
Pain is a complex medical and social issue with a poorly defined relationship between injury and the subsequent pain state that can evolve. Pain also triggers aversive and threatening psychological feelings and patients in pain are likely to become depressed and anxious, have disturbed sleep patterns and generally have a poor quality of life similar in many ways to depressives. Damage to the nervous system can also produce neuropathic and central pain. One in seven people in the UK are thought to be taking medication for persistent pain of one sort or another.
Untreated pain has major social and economic impact in terms of lost employment and medical costs. The major clinical pains arise from surgery, trauma and disease and can be classified as pain from inflammation (rheumatism and arthritis), nerve injury (diabetic neuropathy, AIDS and post-herpetic neuralgia) and cancer. It has been reported that pain is poorly controlled in up to 4.2 million patients dying with cancer. One of the reasons for this is the clinical fear of producing an addicted state if opiates have been prescribed. Of patients who suffer pain, 33% had pain all or most of the time and 87% of those with pain rated it as moderate to severe [BMJ, 309 (1994) 1542-1546]. If post-operative pain relief improved either with new therapies or with better application of existing analgesics [British Journal of Anaesthesia, 78 (1997) 606-617], the cost of 9 million pain days (3 million operations with general anaesthetics per annum in the United Kingdom with an average 3 days of pain) would be reduced. Pain control is still in its infancy. Only 33% of patients with nerve injury gain pain control with existing drugs. 20% of people with cancer have movement-related or neuropathic pain, and perhaps one-third of visits to pain clinics are from patients with similar pain not due to cancer. It has been estimated that about 365 million days are lost per annum in the UK alone through pain related illness. This degree of disability has a huge economic toll in terms of loss of employment and disability payments but quality of life is equally compromised. Damage to the nervous system can result in both pain states and disability that at present has very little chance of being treated effectively. Our research has identified important contributions from brain pathways to the control of pain and most recently a role for a gene, MeCP2 in setting up pain states. Mutations in MeCP2 have been shown in humans to result in the devastating neurological disorder Rett Syndrome although it was unclear what the physiological functions of MeCP2 were in individual neurons. Working with the neurobiology of pain systems has therefore given us an exciting window into both the normal functions of MeCP2 in epigenetics, neuropathology and pain control.
Pain pathways in the brain
Brain areas involved in reward, pleasure and addiction
Addiction, and in particular opiate addiction is classified as a chronic relapsing disease and afflicts perhaps 50,000 people in the UK with a huge and disproportionate social cost.
We have identified a gene, the NK1 or substance P-preferring gene that is essential for the feelings of pleasure or euphoria caused by taking opiate drugs, like morphine and heroin. But what is remarkable is that ‘knocking out’ this one gene leaves the pain killing properties of morphine totally unchanged. And it also leaves the pleasurable effects of psychotropic drugs like cocaine, unaffected.
The gene codes for a protein that functions as a neurotransmitter receptor. This receptor is crucial for a special sort of signalling or ‘conversation’ that happens between neurones in particular parts of the brain. The receptor tells the nerve cell about the arrival of a particular messenger or neurotransmitter called substance P. This is the message that seems to be important for the pleasurable features of morphine to be felt.
Brain areas involved in reward, pleasure and addiction
How does this discovery help us to understand drug addiction- particularly heroin addiction?
First, we have to understand how morphine works. There are two closely linked brain circuits in the brain: one that is concerned with the ‘wanting’ or ‘desire’ for a reward such as food or a drug and the other circuit that delivers the pleasure of ‘liking or having’ the desired object. We think that the brains own opiates –the endorphins- are closely involved in the second circuit, that is controlling the pleasure of eating when hungry or grooming. Morphine or heroin, hijack this brain circuit to generate euphoria- the high. In fact, the morphine experience is often described in terms of sexual pleasure.
Because ‘desiring’ and the pleasure of ‘having’, are controlled by different brain circuits, they can become separated. This generates the key paradox of addiction: wanting or craving for a drug can increase, while the pleasure of getting the drug can actually decrease dramatically.
So, when morphine is injected into the body, it overpowers and sends these same brain circuits into overdrive, generating the high. But now the brain begins to change to be able to deal with these regular and massive doses of morphine. The problem starts when these re-modeled brain circuits begin to drive demand for the drug and the person becomes dependent upon the drug. This is the addicted brain. Without the drug, the addict goes into withdrawal, which is painful and distressing. But even when this withdrawal period has been gone through, there is always the major problem of addiction, which is relapse back into drug taking.
We can start to look at the underlying biology of addiction and in fact other dysfunctional mental states such as depression-which can also be regarded as a chronic relapsing disease. In some ways depression and addiction do seem to be opposite sides of the same coin. There is pretty good evidence that the brain has changed in some way but in most cases we have no idea where in this enormous structure to look. I think that these results will direct us to particular parts of the brain, where we can describe and then perhaps devise therapies, to reverse some of the changes that have occurred in the brain. Now we can start to ask how particular brain circuits, that use this substance P signal, have changed during the process of addiction.
What are the clinical uses of SP antagonists?
So the discovery is important because it tells us, firstly, something new about addiction but also gives us a powerful new tool for separating the analgesic from the addictive properties of opiates in man. One of the problems about prescribing morphine is its of course its addictive qualities. This has been greatly exaggerated in the past as people in severe chronic pain on opiate medication, perhaps in the end stages of disease, never become dependent on the drug. But patients with intermittent or moderate pain, where there is a potential risk of dependency, could now receive opiate medication, in combination with a substance P antagonist drug, which would block the potentially dependency forming properties of morphine.
In addiction, which is defined as compulsive drug seeking and use, we also think drugs that antagonise the actions of substance P may be potentially important in reducing the severity of withdrawal symptoms and preventing relapse into drug taking-the great problem for all recovered addicts.
Relapse is thought to be the major problem associated with drug addiction. Basically the brain has been changed by the drug taking experience and is if you like primed ready to drive the ‘recovered’ addict into drug taking again.This is why addiction is now considered to be a chronic relapsing disease, like hypertension or diabetes- not an acute illness like a broken bone. The brain is certainly very plastic-it will change under pressure from the environment, but it is not so elastic. The brain does not ‘spring back into shape’ when the drug is removed from the circulation. Recovered addicts carry a trace of their addiction for many years.
As with most drug taking e.g. smoking, stress is a very potent trigger for relapse back into drug use. Drugs which block this substance P signalling system in the brain may be extremely useful in controlling relapse because they seem to block certain stress responses in the brain. Our recent research shows that substance P is crucially involved in orchestrating our response to danger in the world.
(adapted and revised from a BBC Radio 4 interview for the ‘Today’ Programme)
The Neurobiology of Depression
Depression is a major disease with huge worldwide incidence and has a major impact on the medical services. At any one time in the UK, 2.9million people have a diagnosis of depression. Like addiction, depression is also considered to be a chronic relapsing disease.
|Human Hippocampus||The Neurons are born throughout life in the hippocampus and antidepressants stimulate their production|
The hippocampus, an area of
the brain implicated in learning, memory and mood disorders, is one of the few
regions where neurogenesis occurs throughout life. Both the rate of neurogenesis
and the survival of new neurons can be influenced by environmental factors such
as stress, which drives neurogenesis down and environmental enrichment, which
increases both cell proliferation and survival. Recently, it was demonstrated
that chronic treatment with antidepressants drugs increased cell proliferation
in the hippocampus.This may have involved an increased local production of brain
derived neurotrophic factor (BDNF), a growth factor known to be up-regulated
following antidepressant treatment and to support
Antagonists of the NK1 receptor, the preferred receptor for the neuropeptide substance P, have been shown to have antidepressant activity in man and animals. To determine whether the lack of the NK1 receptor has any influence on hippocampal neurogenesis, we examined cell proliferation and survival in the hippocampus in NK1 gene knockout mice. We demonstrate here that there was a significant elevation of neurogenesis in the NK1R-/- mouse accompanied by an increased synthesis of BDNF. However, while the NK1 receptor represents a totally novel target for antidepressant drugs it is unclear to what extent this effect is through the modulation of monoaminergic pathways, the classical targets for antidepressant drugs. Other results indicated that, rather than acting independently, NK1 antagonists and those antidepressant drugs that modulate monoaminergic systems directly, co-operate to influence neurogenesis in the hippocampus perhaps through an increased release of BDNF. Most recently together with Dr Clare Stanford in the Department of Pharmacolgy, we have also shown that the NK1 knockout mouse is potentially an excellent model for ADHD (Attention deficit and hyperactivity disorder).
Page last modified on 07 mar 14 15:25 by Edward D Whitfield