Clinical and Experimental Pharmacology and Physiology (2008) 35, 447– 453 doi: 10.1111/j.1440-1681.2008.04913.x Blackwell Publishing Asia Original Articles Intraspinal control of sympathetic and motor outflow AK Goodchildet al. CONTROL OF SYMPATHETIC, RESPIRATORY AND SOMATOMOTOR OUTFLOW BY AN INTRASPINAL PATTERN GENERATOR Ann K Goodchild, Bart T M van Deurzen, Cara M Hildreth and Paul M Pilowsky Macquarie University Neuroscience Centre, Australian School of Advanced Medicine, Macquarie University, New South Wales, Australia SUMMARY 1. Sympathetic and somatic motor outflow results from the summation of excitatory and inhibitory inputs arising from intra- and supra-spinal origins. Here we determined the contri- bution of intra- and supra-spinal GABAergic inputs, utilizing GABA-A receptors, in producing sympathetic and somatic motor outflow. 2. Spinal GABA-A receptor blockade, with bicuculline or picrotoxin injected intrathecally at T9, increased the level and lability of arterial pressure, sympathetic (splanchnic and cervical sympathetic) and motor (phrenic) nerve activity. Bursts of activity occurring irregularly, at low frequency were seen in all nerves. 3. C1 spinal transection abolished phrenic nerve activity and reduced sympathetic nerve activities and arterial pressure. Intrathecal bicuculline-induced bursting in sympathetic and motor (phrenic, sciatic and brachial) nerves was similar to that seen prior to C1 transection. Thus supraspinal control of sympathetic and somatomotor outflow is not dependent on GABA-A receptors. 4. Bicuculline-induced effects on phrenic nerve activity were eliminated after C8 spinal cord transection and regular phrenic rhythm resumed indicating that bicuculline was not acting directly on phrenic motoneurons. 5. Bicuculline evoked similar bursting characteristics in both sympathetic and motor nerves attributable to increased excita- bility of spinal cord neurons. The bursting patterns evoked were often coincident in sympathetic and motor nerves suggesting a common site of origin. 6. These data suggest there is intraspinal coupling between multiple sympathetic and motor outflows in the adult rat spinal cord in vivo. Cervicothoracic spinal cord generator/s perhaps in the form of interneuronal networks, utilizing GABA-A and glutamate receptors, can simultaneously drive functionally independent nerves. Key words: intraspinal pattern generator, sympathetic, somatomotor, respiratory. INTRODUCTION The summed contribution of multiple excitatory and inhibitory inputs to sympathetic preganglionic and somatic motor neurons determines their final outputs. It is plausible to suggest that altering the balance of these inputs to sympathetic preganglionic neurons (SPN) may contribute to conditions such as hypertension. Neuro- transmitters mediating inhibitory effects include glycine and GABA, 1,2 as well as peptides such as enkephalin 3 and amines such as noradren- aline and serotonin. 4,5 Here we focus on the GABAergic inhibition of sympathetic and motor nerve activity at the level of the spinal cord. Anatomical, physiological and pharmacological evidence indi- cates that GABA inhibits SPN and motoneurons. GABA immuno- reactive terminals innervate SPN 6 and motoneurons; 7 GABA receptors including GABA-A receptors are found on SPN 8 and motoneurons. 9,10 Iontophoresis of GABA or bicuculline, a GABA-A receptor antag- onist, onto identified SPN reduces or increases their activity, respectively. 1,11 GABAergic innervation of SPN and motoneurons originate both intra- and supra-spinally. 11–17 We previously demonstrated that spinal GABAergic pathways are not involved in the sympathetic baroreflex; 18 nevertheless, they do provide a tonic inhibition of the sympathetic nervous system. 18,19 Viral labelling studies indicate that spinal interneurons control sympathetic outflow. 20 Specifically GAD67 positive presympathetic neurons exist in and around the central autonomic area which, when activated, can inhibit SPN. 16 Similarly, electrical stimulation of the dorsolateral funiculus or ventrolateral medulla evokes fast inhibitory post synaptic potentials in SPN which can be blocked in 37 per cent of cases by bicuculline. 11,21 In the present study, we quantified the contribution of supra- and intraspinal GABAergic inputs to sympathetic outflow by comparing the effects of spinal GABA-A receptor blockade before and after spinal cord transection. Spinal pattern generators are activated by a variety of stimuli and produce a bursting activity in motor outputs. 22–25 There is some evidence for coupling between sympathetic and somatic motoneurons at the spinal level in the in situ perfused trunk-hindquarters adult mouse preparation. 26 Consequently, we determined whether or not such coupling exists in the adult rat in vivo and, if so, the potential location of this coupling. We measured multiple sympathetic and motor outputs and determined whether or not they were activated coincidently by GABA-A receptor inhibition, both before and after transection at different levels of the spinal cord. The role of glutamate receptors in the coordinated Correspondence: A/Professor Ann Goodchild, Macquarie University Neuroscience Centre, Australian School of Advanced Medicine, Dow Corning Building, 3 Innovation Rd, Macquarie University, New South Wales 2109, Australia. Email: ann.goodchild@vc.mq.edu.au Presented at the IVth Franco-Australian Meeting on Hypertension, Northern Territory, Australia, September 2007. The papers in these proceed- ings have been peer reviewed. Received 10 October 2007; revision 18 December 2007; accepted 21 December 2007. © 2008 The Authors Journal compilation © 2008 Blackwell Publishing Asia Pty Ltd