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Received September 29, 2002
Accepted after revision March 20, 2003
1 Department of Biological Sciences, The University of Warwick, Coventry CV4 7AL, UK
2 Centre for Neurobiology and Behaviour, Columbia University, 1051 Riverside Drive, NY 10032 USA
3 Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QJ, UK
4 Netherlands Institute for Brain Research, Meibergdreef 33, Amsterdam, 1105 AZ, The Netherlands
5 GlaxoSmithKline Pharmaceuticals, Coldharbour Road, The Pinnack, Harlow, Essex CM19 5AD, UK
6 Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, UK
* To whom correspondence should be addressed. E-mail: dspanswick{at}bio.warwick.ac.uk.
The neuropeptides orexin A and B are synthesised by perifornical and lateral hypothalamic (LH) neurones and exert a profound influence on autonomic sympathetic processes. LH neurones project to spinal areas containing sympathetic preganglionic neurones (SPNs) and therefore may directly modulate sympathetic output. In the present study we examined the possibility that orexinergic inputs from the LH influence SPN activity. Orexin-positive neurones in the LH were labelled with pseudorabies virus injected into the liver of parasympathetically denervated animals and orexin fibres were found adjacent to the soma and dendrites of SPNs. Orexin A or B (10-1000 nM) directly and reversibly depolarised SPNs in spinal cord slices. The response to orexin A was significantly reduced in the presence of the orexin receptor 1 (OX1R) antagonist SB334867A at concentrations of 1-10 µM. Single cell reverse transcriptase-polymerase chain reaction revealed expression of mRNA for both OX1R and OX2R in the majority of orexin-sensitive SPNs. The orexin-induced depolarisation involved activation of pertussis toxin-sensitive G-proteins and closure of a K+ conductance via a protein kinase A (PKA)-dependent pathway that did not require an increase in intracellular Ca2+. Orexins also induced biphasic subthreshold membrane potential oscillations and synchronised activity between pairs of electrically coupled SPNs. Coupling coefficients and estimated junctional conductances between SPNs were not altered indicating synchronisation is due to activation of previously silent coupled neurones rather than modulation of gap junctions. These findings are consistent with a direct excitation and synchronisation of SPNs by orexinergic neurones that in vivo could increase the frequency and coherence of sympathetic nerve discharges and mediate LH effects on sympathetic components of energy homeostasis and cardiovascular control.
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