We and others previously reported that the antinociceptive effect of clonidine, measured by the hot plate method, was greater in spontaneously hypertensive rats (SHRs) than in Wistar-Kyoto rats (WKYs). In the present study, we found that the difference in clonidine-induced analgesia between these two strains was abolished after lesioning the presynaptic noradrenergic neurons with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4). Previous studies indicated that clonidine increases tissue norepinephrine (NE) content by inhibiting NE release. We found that the basal NE concentration in locus coeruleus (LC), as measured by HPLC-ECD, was not different between WKYs and SHRs. Systemic application of clonidine (0.69 mg/kg, I.P.) significantly increased the tissue content of NE in the SHRs, but not in WKYs. Using pressure microinjection and high-speed chronoamperometric recording techniques, we found that local application of KCl to the LC brain slices increased extracellular NE levels in both strains. Perfusion of slices with clonidine (1 microM) selectively attenuated KCl-evoked NE release in SHRs, suggesting that clonidine-induced presynapitc inhibition is more effective in SHRs than in WKYs. In conclusion, our data indicate that SHRs possess augmented sensitivity to clonidine to inhibit presynaptic NE release, which may be responsible for the enhanced antinociceptive effect of clonidine in this strain.