Sydney University Neuroscience

Research Themes:

R Bandler & K Keay

Shock, Injury and Pain Research at the Laboratory of Neural Structure and Function Integration of central events precipitating circulatory shock Sudden hypotensive (vasodepressor) episodes are characteristic of the response to severe blood loss (hypovolemia), deep somatic or visceral pain and certain social stressors. Using the ventrolateral PAG region as an entry point into central sympathoinhibtory circuits we have utilised both anatomical and physiological approaches to define the neural networks which mediate the shock-like responses to a range of specific vasodepressor stimuli. We have shown that the shocklike response to progressive blood loss can be blocked by inactivation of the caudal midline medulla, one of the major output targets of the ventrolateral PAG. In contrast however, blockade of this region has little effect on the vasodepression evoked by noxious activation of cardiopulmonary receptors nor by vlPAG activation. Thus although we have shown previously that the ventrolateral periaqueductal gray (vlPAG), is selectively activated by a wide range of stimuli evoking vasodepression the projections to the caudal midline medulla may only mediate vasodepression to a select few of these stimuli. Our findings suggest that the vlPAG is a useful entrypoint in investigating the central circuits mediating sympathoinhibition and that the cicuits by which haemorrhage and deep pain evoke shock may well be different. fMRI imaging of circuits mediating the shock response Brain areas controlling blood pressure and heart rate have been visualized for the first time in humans, using functional magnetic resonance imaging (fMRI) techniques. The use of fMRI technology has made it possible to determine, in a noninvasive way, human brain sites activated during specific challenges which evoke rapid and sustained changes in blood pressure and heart rate. Discrete regions of activation both in higher (forebrain) and lower (brainstem) brain regions were observed as blood pressure increased and heart rate fell in response either to: (i) immersion of one hand in cold water; (ii) during application of a cold compress to the forehead; or (iii) abdominal straining. The discrete lower brainstem regions activated during the cardiovascular challenges in this study are consistent with the results of earlier physiological and anatomical studies undertaken in animals. An unexpected finding, however, was the prominence of lateralised activation in discrete higher (forebrain) brain regions. This finding suggests that, in humans, specific higher brain regions participate significantly in the regulation of even very basic cardiovascular adjustments.

The transition from acute injury to chronic pain The upper cervical spinal cord is a major target for primary nociceptive afferents from the head and neck, and also receives nociceptive information from the rest of the body, via propriospinal input from lower segments. In addition, striking clinical findings that commissural myelotomy in the upper cervical spinal cord can provide relief from chronic pain places these spinal segments in a unique position with regards to pain processing circuitry. The aims of our current experiments are to determine whether specific populations of upper cervical spinal neurons play a role in the transition from acute to chronic pain following injury. Determining the functional characteristics of activated upper cervical neurons during different phases of the injury response using the technique of extracellular unit recordings of antidromically-identified spinal neurons will be used, along with juxtacellular neuronal labelling (biotinamide) to morphologically identify each neuron and its dendritic and axonal processes. Our collaboration with Vaughan and Christie it is hoped will allow us to elucidate the the synaptic mechanisms underlying relevant signal transduction cascades in whole cell recordings from cervical spinal cord slices taken at different phases of the injury response. Organization and nociceptive properties of spinal and NTS afferents to vasodepressor regions of the brainstem To identify sources and sensory properties of spinal afferents to different vasodepressor regions of the brainstem, experiments were carried out using the combinination of retrograde tracing and the immuno-histochemical detection of the immediate early gene, c-fos. Injection of retrograde tracer into physiologically identifed sites in brainstem depressor regions revealed a substantial spinal input the largest componant of which arises from the upper cervical segments. We are currently investigating whether noxious stimulation of deep somatic and visceral structures prefentially activates spinal projections to vasodepressor regions.

LEFT: Photomicrograph of single, Fos-immunoreactive (*) and double-labelled (arrowhead) vlPAG neurons. For double-labelled neurons it can be seen that the cell cytoplasm contains retrogradely transported rhodamine microbeads (red) from the RVLM, whereas the nucleus contains Nickel-enhanced DAB reaction product (black) indicating Fos-immunoreactivity. Single, Fos-immunoreactive neurons contained the nuclear DAB reaction product, but no rhodamine microbeads in the cytoplasm. RIGHT: Serial coronal sections through the PAG of the rat showing the location of: Top Row: Fos immunoreactive neurons in anaesthetised control animals; Middle Row: Fos immunoreactive neurons following noxious stimulation (formalin injection) of the deep neck muscles and; Bottom Row: “double-labelled” (rhodamine containing and Fos-immunoreactive) neurons following noxious stimulation of the deep neck muscles. The number below each section represents the level caudal to bregma.

The neural substrates of labour pain Labour can be divided into two stages. The first stage begins with active uterine contractions and ends with full cervical dilatation. The pain experienced during this phase is predominantly a visceral pain. The second stage begins at full cervical dilatation and ends with foetal delivery. Pain during this stage arises from vaginal and perineal distension and is predominantly a deep somatic pain. The broad aim of this series of experiments is to identify the neural substrates in which labour pain is represented but more specifically to determine whether an ”escapable” yet deep pain activates similar neural circuitry to that activated by chronic deep pain. We have recently characterised the pattens of neuronal activity and some of the neurochemical changes associated with pain evoked by uterine contraction and cervical dilatation. Our current aim is to compare these patterns with those evoked by pain characteristic of the second stage of labour, produced by vaginal and perineal distension. These experiments will define the discrete neuronal populations involved in the different types of pain associated with the first and second stages of parturition. The selective modulation of first and second phase labour pain using novel analgesic manoeuvres is the ultimate aim of this series of experiments. back

P Siddall
Functional anatomy and pharmacological management of pain states in humans.

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