Inflammation induces an up-regulation of neuropeptide tyrosine (NPY) and its receptors in the dorsal horn, suggesting an important role in nociceptive transmission. Our initial studies revealed that NPY dose-dependently increased hotplate response latency, and to a lesser degree, thermal paw withdrawal latency (PWL); these effects occurred at doses that affect neither motor coordination (as assessed by the rotarod test) nor paw skin temperature. We next evaluated the behavioral effects of intrathecal administration of NPY and NPY antagonists with the aim of assessing the contribution of NPY to correlates of persistent nociception associated with the unilateral plantar injection of carrageenan or complete Freund's adjuvant (CFA). NPY robustly and dose-dependently increased PWL on the side ipsilateral to carrageenan injection, with only a small effect on the contralateral side. Similarly, NPY (30 microg) produced a large and long-lasting increase in PWL on the side ipsilateral to CFA injection (140% change), with only a small effect on the contralateral side (25% change). The ipsilateral effect of NPY was completely inhibited with the potent Y1 antagonist, BIBO 3304 (3 microg), but not the Y2 antagonist, BIIE 0246. When administered alone, BIBO 3304 (but not BIIE 0246) slightly decreased thermal PWL on the side ipsilateral (25% change), but not contralateral, to CFA injection; this suggests that inflammation strengthens inhibitory NPY tone. We conclude that spinal Y1 receptors contribute to the inhibitory effects of NPY on thermal hypersensitivity in the awake rat. Further studies are necessary to determine whether enhanced release of NPY and Y1-mediated inhibition of spinal nociceptive transmission ultimately results in a compensatory, adaptive inhibition of thermal hypersensitivity in the setting of inflammation.