Increasing efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA). To test whether the ERSNA-induced increases in ARNA involved norepinephrine activating -adrenoceptors on the renal sensory nerves, we examined the effects of renal pelvic administration of the 1- and 2-adrenoceptor antagonists prazosin and rauwolscine on the ARNA responses to reflex increases in ERSNA (placing the rat's tail in 49°C water) and renal pelvic perfusion with norepinephrine in anesthetized rats. Hot tail increased ERSNA and ARNA, 6930±900 and 4870±670%·sec (area under the curve ARNA vs time). Renal pelvic perfusion with norepinephrine increased ARNA 1870±210%·sec. Immunohistochemical studies showed that the sympathetic and sensory nerves were closely related in the pelvic wall. Renal pelvic perfusion with prazosin blocked and rauwolscine enhanced the ARNA responses to reflex increases in ERSNA and norepinephrine. Studies in a denervated renal pelvic wall preparation showed that norepinephrine increased substance P release, from 8±1 to 16±1 pg/min, and PGE₂ release, from 77±11 to 161±23 pg/min, suggesting a role for PGE₂ in the norepinephrine-induced activation of renal sensory nerves. Prazosin and indomethacin reduced and rauwolscine enhanced the norepinephrine-induced increases in substance P and PGE₂. PGE₂ enhanced the norepinephrine-induced activation of renal sensory nerves by stimulation of EP4 receptors. Conclusion: interaction between ERSNA and ARNA is modulated by norepinephrine which increases and decreases the activation of the renal sensory nerves by stimulating 1- and 2- adrenoceptors, respectively, on the renal pelvic sensory nerve fibers. Norepinephrine-induced activation of the sensory nerves is dependent on renal pelvic synthesis/release of PGE₂.