Descending control of spinal nociception that originates from the midbrain periaqueductal grey (PAG) is an important determinant of the pain experience. The current study investigated the role of different cyclooxygenase (COX) isoforms in regulating, at the level of the PAG, descending control of A- versus C-nociceptor evoked spinal reflexes. At 8 min intervals, either fast (7.5°C s^-1, 30-59°C) or slow (2.5°C s^-1, 30-57°C) rates of heating were applied to the hind paw dorsum to preferentially activate Aδ- or C-heat nociceptors, respectively (Yeomans et al., 1996a, b; McMullan et al., 2004) in propofol-anaesthetised (~30mg kg^-1 h^-1, i.v.) male Wistar rats (280-300g). Withdrawal EMG thresholds to fast or slow heat ramps were recorded from biceps femoris, before and after microinjection of substances into the PAG. Ketoprofen (100μg in 300nl), a non-selective COX inhibitor, had no significant effect on withdrawal thresholds to fast (ANOVA, p=0.6731; n=4) or slow (p=0.0973; n=4) heat ramps compared to vehicle when injected into dorsolateral/lateral regions of the PAG. However, it significantly increased (p<0.0001) withdrawal thresholds to fast (54.33±0.25 to 57.95±0.57°C, mean±s.e.m.; n=4) and slow (52.3±0.22 to 56.63±0.38°C; n=4) heat ramps when injected into the ventrolateral-PAG. The duration of this antinociceptive effect was longer for C-nociceptor (p<0.05 for all heat ramp trials between 1-41 and 57-65min post-injection, Bonferroni post-test) than A-nociceptor evoked responses (p<0.05 for trials between 17-25min post-injection). The COX-1 inhibitor SC-560 (50nM) produced similar effects to ketoprofen on both A-nociceptor (p<0.05 for trials between 17-25min post-injection; n=3) and C-nociceptor evoked responses (p<0.05 for trials between 1-65 and 81min post-injection; n=4), again with greater influence over C-nociceptor evoked responses. The COX-2 inhibitor NS-398 (5μM) had no significant effect on withdrawal thresholds to fast (p=0.4991; n=3) or slow (p=0.1918; n=4) heat ramps. Vehicle (70% DMSO, 30% physiological saline) had no significant effect on thresholds to fast or slow heat ramps in any PAG region. The data suggest that COX-1-derived products are tonically active in ventrolateral-PAG and play a role in setting the gain during acute nociceptive processing, with a greater influence over C- than A-nociceptor-evoked responses.