Nociceptive input to cerebellar pathways and its behavioural significance

All living creatures have to deal with pain - it's an unpleasant, but vital experience that safeguards animal welfare and ultimately, survival. Pain is a warning, a signal that you need to do something. Normally you have two choices: either move away and escape serious injury; or, if you're already hurt, you simply have to cope with the pain. Your brain recognises the difference between these two kinds of pain and works out the best bodily response. Escaping pain means that an animal has to rapidly get up and go. It has to run, jump, perhaps fly or swim to get away from the threat - this is an active response to escapable pain. To escape the pain animals have to move and movement requires increased muscular activity. When muscles go to work in an emergency they demand increases in blood pressure, heart rate and breathing to fuel them with extra oxygen and nutrients. In contrast, there is no escaping the pain of a stomach ache. When you move, the pain stays with you - all that can be done is to endure it, to try and cope with it. This is a passive response to inescapable pain. The best thing to do is to try and protect the injured tissues, which means 'lying low', keeping movement to a minimum - the opposite of an active response. To be effective, active and passive responses to pain are complex and they need body and brain to work together in a highly co-ordinated way. It is the body that responds to pain, but it is the brain that co-ordinates the respective changes in movement and in heart and lung functions. It is likely that escapable and inescapable pain is each controlled by its own separate connections within the brain. We have good evidence that this is the way that brain circuits control changes in blood pressure, but much less is known about the brain circuits that control changes in bodily movement in response to these different kinds of pain. The key aim of the present work is to find out whether different types of pain activate different circuits within the brain that control movement. In particular, we will focus on brain circuits leading to the cerebellum, the major controller of body movement in mammals. We will chart pain pathways within the brain that lead to the cerebellum and we will find out whether different pathways are activated by escapable pain (e.g. pain paths arising from the skin), as opposed to those activated by inescapable pain (e.g. pain paths arising from the guts). Also, by recording the electrical signals of individual brain cells, we will find out if painful and non painful signals are sent to the cerebellum by the same route. Pain also causes stress and anxiety, which affect the way in which an animal responds to, and copes with, pain. Stress activates parts of the brain that alter incoming pain signals, which in turn change the animal's response to pain. The final part of our study will see if the 'stress and anxiety' brain centres can alter the flow of information in pain pathways leading to the cerebellum.

Nociceptive inputs trigger action and, as such, they have fundamental roles in animal welfare and survival. They signal injury and alert an individual to escape, avoid or cope with the insult that caused the injury. Indeed the characteristic changes in behavioural activity associated with distress, including pain, are routinely used in the assessment of an animal's well being. Of course some pain can be escaped or avoided while others cannot. For instance, by increasing co-ordinated motor activity as part of active coping strategies, brief cutaneous insults can be escaped while, in marked contrast, deep or visceral pain is inescapable, and an appropriate response is quiescence and passive coping. An emerging concept is that the nociceptive inputs that elicit these different levels of escapability activate distinct pathways in the central nervous system to mediate the autonomic and behavioural changes that underlie either active or passive coping. An increasing body of evidence indicates that this is the case for autonomic control, however, much less is known about the organisation and modulation of nociceptive inputs to motor control centres. The current study will address this important gap in our understanding with respect to nociceptive input to the cerebellum; the largest motor structure in the mammalian brain. The twin aims of this proposal are to test the related hypotheses that (i) nociceptive inputs to the cerebellum associated with inescapable (visceral or C-nociceptor) or escapable (brief cutaneous or A delta-nociceptor) pain are mediated by anatomically distinct pathways, and (ii) that descending control mechanisms arising from the midbrain periaqueductal grey (PAG) exert differential control over these pathways. To test these hypotheses we will use two complementary in vivo approaches in anaesthetised rats: (i) functional anatomical studies, that combine retrograde transport of tract tracing substances with induction and visualisation of Fos protein to study activity in whole populations of neurones at several levels of sensory pathways leading to the cerebellum, and (ii) extracellular recording of single unit activity to characterise projection targets, peripheral inputs and descending control of individual spinal cord neurones. The main objectives to be achieved in the functional anatomical studies are: (1) To establish the spinal laminar distributions of whole populations of spino-olivary and post synaptic dorsal column projection neurones activated by A delta- as compared to C-nociceptors and those activated by cutaneous versus visceral nociceptors. And, (2) to determine the global pattern of activation of cerebellar-related circuits by nociceptive inputs with different behavioural significance at supraspinal levels e.g. neuronal activation at the level of the dorsal column nuclei, inferior olive and the cerebellum itself (cortex and nuclei). The main objective to be achieved in the electrophysiological studies is to functionally characterise within the spinal cord the responses and the descending control of individual neurones with projections to the inferior olive and/or dorsal column nuclei in terms of patterns of convergence of somatic (noxious and non-noxious inputs) and visceral inputs, and the degree of collateralisation of their ascending projections to the gracile nucleus and the inferior olive. The results of these studies will advance understanding of the role of the cerebellum, and of descending control of pre-cerebellar pathways, in determining motor responses to noxious inputs with different behavioural significance. The information gained will be an essential prerequisite for future studies that will aim to establish how plasticity in descending control contributes to alterations in motor function in chronic pain states.