Proceedings of The Physiological Society
University of Cambridge (2008) Proc Physiol Soc 11, PC110
Descending control produced by cyclooxygenase-1 inhibition in the periaqueductal grey targets dorsal horn neurones with strong C-fibre inputs.
J. L. Leith1, J. C. Martindale2, L. F. Donaldson1, B. M. Lumb1
1. Department of Physiology & Pharmacology, University of Bristol, Bristol, United Kingdom. 2. GlaxoSmithKline, Harlow, United Kingdom.
Descending control of spinal nociception that originates from the midbrain periaqueductal grey (PAG) is an important determinant of the pain experience. We have recently shown that cyclooxygenase-1 (COX-1) regulates activity at the level of the PAG and that COX-1 inhibition exerts a preferential effect on C- versus A-nociceptor-evoked withdrawal reflexes (Leith et al, 2007). The current study investigated whether this differential control of C- versus A-nociceptor-evoked activity may be mediated in the spinal dorsal horn. Extracellular recordings were made from wide dynamic range deep dorsal horn neurones (n=18) with receptive fields on the hindpaw dorsum in alphadolone/alphaxalone-anaesthetised (~20mg.kg-1.hr-1, i.v.) male Wistar rats (280-300g; n=18). At 8 minute intervals, either fast (7.5°C.s-1, 30-57°C) or slow (2.5°C.s-1, 30-55°C) rates of heating were applied to the receptive field to preferentially activate Aδ- or C-heat nociceptors respectively (Yeomans et al, 1996a; 1996b; McMullan et al, 2004). Neuronal responses were recorded for 30min before and 65min after administration of the COX-1 inhibitor SC560 (50nM; 300nl volume; n=14) or vehicle (phosphate-buffered saline; n=4) into the ventrolateral-PAG. Afferent input to each cell was characterised by percutaneous electrical stimulation of the receptive field at suprathreshold (1.5 and 3.0 times threshold) intensity for C-fibre activation and the degree of C-fibre input was quantified. SC560 significantly increased the firing threshold of neurones to both fast and slow heat ramps (to a peak of 127±3% and 145±11% of control threshold respectively, mean±S.E.M., ANOVA, both p<0.01, n=8-9; overall effect on firing threshold (measured as area under the curve (AUC) over the timecourse 0-65min) 186±25min.°C and 211±36min.°C respectively, mean±S.E.M., ANOVA, both p<0.01) compared to vehicle. Peak change in firing threshold post-SC560 and overall effect on firing threshold were not significantly different between fast and slow heat ramps (p=0.0911 and p=0.5791 respectively, t-test, n=8-9). A significant positive correlation was found between the change in firing threshold (both peak threshold and overall effect on firing threshold) produced by SC560 and the degree of C-fibre afferent input to the neurones (r=0.5795, p<0.05 and r=0.6625, p<0.01 respectively, Spearman’s rank correlation). The data show that COX-1 inhibition in the ventrolateral-PAG inhibits the responses of wide dynamic range dorsal horn neurones to A- and C-heat nociceptor stimulation and suggests that the degree of descending control from the PAG on individual neurones may be dependent on the extent of their C-fibre innervation.
Where applicable, experiments conform with Society ethical requirements