Chronic hypoxia (CH) produces carotid body (CB) sensitization manifested by exaggerated ventilatory responses to acute hypoxic tests. In the present work we have assessed the significance of adenosine, an excitatory neurotransmitter at the synapse between O₂-sensing chemoreceptor cells (ChC)-carotid sinus nerve (CSN) endings, on this sensitization process. We have used 4 groups of rats: control normoxic (CN) caffeine-treated normoxic (CafN), CH (12%O₂, 15 days) and caffeine-treated hypoxic (CafH). Caffeine was administered in the drinking water (1g/l). In comparison to CN, CafN rats exhibited: 1.Increased CA release in response to mild hypoxia (7%O₂); 2.a non-significant tendency increase CSN hypoxic chemosensory activity; and 3.an increased hypoxic ventilatory response. In comparison to CN, CH rats exhibited 1.CB sensitization evidenced by increased ventilatory hypoxic response and increased basal and hypoxic activity in the CSN 2.increase in the expression of TH and CA content, synthesis and release. 3.increase in basal and hypoxic of adenosine. 4.normal basal release and diminished hypoxia-induced release of ATP. In comparison to CH, CafH exhibited: 1.Equal ventilatory hypoxic response and decreased hypoxic CSN chemosensory activity; 2.Increased CA content, synthesis and release in response to mild hypoxia; 3.equal hypoxic adenosine release; 4.increased ATP release in response to hypoxia. In conclusion sustained inhibition of adenosine receptors inhibits hypoxic ventilatory response during CH being this effect compensated at central chemoreceptors. Our results suggest that adenosine can be one of the neurotransmitters involved responsible for the increased O₂ sensitivity during chronic hypoxia. Supported by: BFU2004-06394, CIBERCB06/06/0050, FISSPI042462, JCyLVA045/04, VA011C05 and CEPR/FCT. FCT (SFRH/BD/14178/2003) supports SV Conde.