Orexins A and B (or Hypocretins 1 and 2) are two new neuropeptides synthesized by neurones in the lateral hypothalamus and recently characterized as ligands of two “orphan” receptors. They play important role(s) in wide variety of physiological functions including food intake, regulation of the neuroendocrine system, energy metabolism, control of blood pressure, body temperature, and the sleep-wake cycle. Additionally, widespread projections of their axons to superficial dorsal horn of the spinal cord and expression of both orexin-A and orexin-B receptors in dorsal root ganglion (DRG), lamina X surrounding the central canal and on C-fibres in the spinal cord led to the idea, and emerging evidence suggests that orexins modulate pain transmission. It is apparent from the evidence available that agonists specific for orexin-A and/or orexin-B receptors could represent a novel class of analgesic agents for the treatment of pain. The aim of this study was to investigate the effects of orexin-A and orexin-B on the excitability of cultured rat sensory neurones. Since the DRG contains cel bodies of primary sensory neurons that convey information about a wide variety of sensory signals including noxious stimuli, we have used isolated DRG cells as a nociceptive neuronal model. DRGs were removed from 1-2 day old neonatal rats after decapitation and DRG neurones were isolated by enzymatic and mechanical procedures. After establishing whole-cell mode of the patch clamp technique, resting membrane potentials were recorded under current clamp recording conditions. Brief application of orexin A induced dose-dependent biphasic subthreshold changes from resting membrane potential. The mean depolarisation of membrane potenatial was 0.6±0.2 mV (n=7), 2.2±0.4 mV (n=7), 6±0.7 mV (n=12) and 7.7±1.5 (n=7) after extracellular application of 20, 30, 100 and 200 nM orexin A, respectively. There were hyperpolarizing response to 100 nM (n=3) and 200 nM (n=2) orexin A application. The orexin A-induced depolarisations were not pertussis toxin-sensitive (100 nM, n=4). O considerable number of cells (11 out of 36 cells) were also non-responder to orexin A. Orexin B (100 nM) also caused reversible depolarisation of membrane potential in 3 out of 5 cells studied. Since both calcium activted chloride, nonselective cation and potassium conductances were active under our recording conditions it was difficult to interprete the obtained results. Results from this preliminary study warrants further investigations involving voltage clamp experiments and fluorescence calcium imaging to clarify the mechanism of actions of orexins in this model of nociceptive neurones. Keywords: Orexin A and B, pain, patch clamp, sensory neuron