Post-operative pain facilitates rat C-fibre activity-dependent slowing and induces thermal hypersensitivity in a sex-dependent manner

Background: Postoperative pain is a common clinical problem that, in preclinical studies, has almost exclusively been studied in males. Altered C-fibre activity-dependent slowing (ADS) is a potential underlying mechanism, given it is altered after tissue inflammation and nerve injury, but this has not been explored post-incision. We therefore investigated the effect of hind-paw incision on C-fibre ADS in both sexes and the involvement of voltage-gated sodium channels (Na _V) as they contribute to ADS. We also assessed mechanical and thermal sensitivity post-incision in both sexes. Methods: Dorsal roots were isolated from hind-paw incision (2–4 days post-surgery) or naive (control) juvenile rats of both sexes. Compound action potential recordings were made to assess C-fibre ADS in response to ×40 stimuli at 2 and 10 Hz and repeated in the presence of 20 nM tetrodotoxin/vehicle. Data were quantified by the normalised change in latency (negative peak) and width (positive-to-positive peak) of the triphasic C-fibre response. Hind-paw mechanical withdrawal thresholds and thermal withdrawal latencies were measured pre- and post-incision. Results: Incision facilitates C-fibre ADS in both sexes, with more pronounced facilitation in females. Tetrodotoxin induces sex- and injury-dependent changes in C-fibre ADS that were distinct between latency and width measures. Hind-paw incision induced comparable mechanical hypersensitivity in both sexes but less peak heat hypersensitivity in females. Conclusions: Hind-paw incision induces sex-dependent changes in C-fibre activity-dependent slowing, which likely contribute to the observed sex difference in peak thermal hypersensitivity. This may reflect sex- and incision-induced differences in functional expression of Na _V channels that differs by C-fibre subtype.