Novel signalling pathways regulating nociception

Pain is something that everyone experiences at some point in their lives, and for many it is a constant burden which prevents them from engaging in a normal lifestyle. Most pain is experienced or "sensed" by the brain as a result of signals sent to it from nerves throughout the rest of the body. Thus a nerve with endings in a fingertip can relay information to the brain that the individual has touched a hot surface. This allows the body to withdraw the finger before too much damage is inflicted. Unfortunately, in some conditions (e.g. chronic pain) the activity of these distal nerves may become spontaneous leading to debilitating conditions whereby pain is experienced over long periods of time without any external stimulation. Such pain is very hard to treat but even harder to bear. Therefore, a major aim for researchers is to develop means of pain relief that would enable patients to have a normal, active lifestyle. Currently available approaches are effective in preventing some types of pain, but generally are poor in treating chronic pain and, in addition, often have major downsides (e.g. addiction, concomitant loss of sensation, paralysis). Our project is designed to investigate the usefulness of a new approach to the treatment of pain, which can bypass many of the problems associated with current therapies.

As is the case with some current approaches, our plan is to focus on the signals which are relayed from the ends of pain-sensing nerves to the brain. These signals are brief electrical impulses which pass along the sensing nerves and the level of pain sensed by the brain depends on the number and frequency of these impulses. The impulses arise from the synchronised activity of a group of proteins located in the outer layer or boundary of the nerve. These proteins allow passage into and out of the nerve of specific, electrically charged atoms, and the flow of this charge is sufficient to trigger similar activity in adjacent parts of the nerve boundary - in this way an electrical "wave" propagates from nerve ending all the way to the brain. It is a very rapid process, initiated normally by something like a hot surface, or a sharp object but in some diseases these impulses can be generated without external stimulation causing pathological pain. There are drugs currently available which can stop these impulses completely: local anaesthetics, for example, can block one of the proteins responsible for the electrical waves and are commonly used for minor surgery and dental treatment. These are extremely effective in blocking pain, but they block all sensation, leaving the patient numb for some time. Numbness is a problem in itself: not only is it uncomfortable, but one can damage a numbed region without realising it.

Our novel approach to the control of pain is to target two alternative proteins which control the formation of electrical impulses in peripheral nerves. Regulating their activity will, instead of blocking impulses in an all-or-nothing manner (as is the case with local anaesthetics), cause a more subtle yet effective dampening of activity so that the individual will feel relief from pain without much numbness. Through the control of these proteins, nerves will be less able to generate the impulses associated with pain, but no block of the impulses will be imposed. We plan to regulate these two proteins in a co-ordinated manner by interfering with chemical events within the nerves which normally regulate their activity - by blocking or enhancing such events, we can "tune" the protein activity - and hence control the activity of the nerve, without stopping its activity altogether. Our ideas will be tested and refined at the level of individual nerve cells, and then developed for testing in controlled experiments involving pain sensation in living animals. Only through such a strategy can we develop this new approach to treatment of pain in patients and reduce the problems associated with current treatments.

Although effective treatments for some types of pain are available, they are non-ideal: drugs targeting the CNS are often associated with issues such as addiction and tolerance. Those currently available which target peripheral sensory neurones can lead to complete sensory loss, and can also affect motor neurones. We suggest exploring alternative targets within peripheral nociceptive pathways which could normalize rather than block afferent sensory activity. Our programme of study will therefore focus on a novel paradigm (discovered by the applicants) concerning regulation of two specific ion channels expressed in sensory neurons, the M-type K+ channel and the T-type Ca2+ channel. Both regulate sensory neuron excitability by setting the resting membrane potential and firing threshold without directly driving action potential propagation. Our current research indicates that both these channels are physiologically modulated by endogenous reactive oxygen species and gasotransmitters, particularly carbon monoxide (CO). We will build upon substantial pilot studies to characterise the intracellular signalling network through which M- and T-type channels are regulated by gasotransmitters and ROS, and to identify physiological triggers through which such pathways can control channel activity. This will be achieved using a multidisciplinary approach involving patch-clamp electrophysiology and confocal imaging, supported by genetic and pharmacological interventions. Finally we shall investigate the contribution of such regulation to the control of afferent sensory activity both in vitro and in vivo using established behavioural tests and models of acute and chronic pain. Our results will provide a novel approach to pain management in which sensory nerve activity can be normalised rather than fully inhibited, thus providing pain relief without sensory blockade.

According to our hypotheses, and supported by our significant pilot (and recently published) data, we believe our studies will lead to the development of improved, novel means by which both acute and chronic pain can be controlled; these new means will reduce side effects of analgesia (e.g. loss of sensation). With this in mind, the ultimate impact of this research will be with patients suffering from acute or chronic pain. Such benefit is long-term and will require exploitation of the new information which will be gained as a direct result of our studies. A more immediate impact will affect those active in the field of pain physiology and its treatment i.e. other academic and industrial researchers, including those involved with drug design, as well as research-active clinicians.

At a fundamental level and in the short-term, our research will be of interest and benefit to other researchers, including cell biologists and neurobiologists with an interest in signalling pathways involving the regulation of ion channels. Given the diverse biological roles of gasotransmitters as well as reactive oxygen and nitrogen species, our findings in sensory neurones will inform ongoing research in other fields, including research into cardiovascular disease and cancer. We believe our work will lead to the identification of signalling pathways and mechanisms which can be targeted for therapeutic benefit - indeed, we aim to exploit any opportunities ourselves, but such findings will also appeal, in the short to mid-term, to other academics and pharmaceutical companies since pain treatment is a widely recognised major clinical need.

In the mid- to long-term, as part of the translation development of our findings, we anticipate that any therapeutically useful approaches arising (based on regulation of the specific ion channels which are the focus of our work) will inform clinical trials aimed at resolving pain complaints in a more practical and patient-friendly manner. In addition, our findings can be used to support the activities and campaigns of charitable organizations such as the British Pain Society (BPS), which promotes education, training, research and development in all fields of pain and its treatment.

In the long term, our research will be of primary importance to patients suffering from acute or chronic pain for whatever reason. The BPS estimates that some 10 million individuals in the UK suffer pain on a daily basis, resulting in a major impact on life quality and the ability to function normally without distress. Any form of practical pain relief arising from our studies will therefore have significant impact on this large fraction of the population in terms of improving quality of life and ability to contribute to society through practical activity, including working. Indeed, the benefit to individuals will collectively have a major national impact: in the UK, millions of working days are lost due to pain-related absences. The BPS estimates a national cost of approximately £5 billion annually. Enabling individuals to return to work more promptly, or indeed to avoid absences, through the development of new approaches to pain control, will have a tremendous positive impact on national economy and, therefore, the nation's international competitiveness, which in turn will further enhance individuals' quality of life.

Development of new therapies from fundamental scientific observations concerning the physiological regulation of specific molecular targets in sensory neurones is a long-term project, involving years of effort in the research laboratory, drug development industry and clinical trial arena. Such investment of time and effort must reflect the social and economic importance of the issues being addressed. Given the widespread prevalence of pain within the population, and its enormous economic and social impact on the nation, such investment must be considered worthwhile.