Orexin containing neurons in the lateral hypothalamus project to all levels of the spinal cord including dorsal horn, intermediolateral cell column and ventral horn. This study was undertaken to determine the role of orexin receptors in the spinal cord. Experiments were conducted on anesthetized, vagotomised and artificially ventilated Sprague-Dawley rats (n = 17). Intrathecal injection of orexin A (OX-A) (20 nmol) caused increase in mean arterial pressure (MAP), heart rate (HR), splanchnic sympathetic nerve activity (sSNA) and phrenic nerve activity (PNA). But orexin receptor 1 antagonist, SB 334867 (200 nmol), was unable to affect the resting level of cardio-respiratory parameters when injected intrathecally. On the other hand SB 334867, injected 20 min before OX-A (20 nmol), significantly reduced but not abolished the effects of intrathecal OX-A. Pressor response, tachycardia and sympathoexcitation to intrathecal OX-A were attenuated by about 75% when administered after SB 334867 and respiratory effects were reduced by about 50%. These findings demonstrate that i) OX-A causes sympathetically mediated increase in MAP and HR and increases inspiratory drive, ii) both orexin 1 and 2 receptors mediate OX-A response in the spinal cord and iii) OX-A may not be active physiologically or may not be released under anaesthetic condition.