In order to elucidate the possible role of noradrenergic neurons of the nucleus locus coeruleus (LC) in stress responses, the effects of corticotropin-releasing factor (CRF) on LC neuronal activity were characterized. In halothane-anesthetized rats, intracerebroventricular administration of CRF was found to have two distinct actions: (1) A dose-dependent increase in spontaneous discharge activity was observed 3 min after peptide injection, with 1.0 and 3.0 µg CRF increasing activity by 7 ± 2 and 47 ± 12%, respectively; Ala14CRF (3.0 µg), an inactive analogue of CRF, had no effect on LC spontaneous discharge rates. These results confirm and extend previous studies of CRF activation of LC basal discharge activity; (2) additionally, CRF (1.0 and 3.0 µg) disrupted sensory responses of LC cells to sciatic nerve stimulation. As previously reported, responses of LC neurons to electrical stimulation of the sciatic nerve usually consisted of a brief activation beginning 20–40 ms after stimulus followed by a period of relatively suppressed activity lasting 100–200 ms. CRF attenuated both components. Responses plotted as normalized, cumulative histograms became more linear in the presence of CRF (1.0 and 3.0 µg), suggesting that discharge rates during phasic responses to sciatic stimulation were similar to spontaneous rates. Statistical comparison using the Kolmogorov-Smirnoff test or correlation coefficients demonstrated that both 1.0 and 3.0 µg CRF reduced response components, while 0.3 µg CRF and Ala14CRF (3.0 µg) had no effect. The degree of attenuation of LC sensory responses by CRF was not linearly related to the magnitude of CRF-in-duced increases in spontaneous discharge rate, suggesting that these are distinct effects of CRF. These actions of CRF on LC activity may represent an important mechanism in the central mediation of stre