Cutaneous endothelin-A receptors elevate post-incisional pain

The contribution of endothelin-1 (ET-1), acting via endothelin-A receptors (ETA), on post-incisional pain was examined in a rat model of incision through the hairy skin of the lumbar dorsum. Post-incisional mechanical hyperesthesia was evaluated by cutaneous trunci muscle reflexes (CTMR) of subcutaneous muscles responding to stimulation with von Frey filaments near the wound (primary responses) and at a distance, especially on the contralateral dorsum (secondary responses, involving spinal circuits). The role of ETA was determined by pre-incisional, subcutaneous injection of the selective receptor antagonist BQ-123 at the incision site, 15 min or 24 h before surgery. Control incisions showed both primary tactile allodynia and hyperalgesia, and a weaker secondary hyperesthesia, peaking 3-4 h after surgery and lasting at least 24 h. Primary allodynia, but not hyperalgesia, was dose-dependently suppressed by 15 min pre-incisional BQ-123. In contrast, both secondary allodynia and hyperalgesia were inhibited by local BQ-123. The suppression of primary allodynia by local antagonist disappeared in 24 h, but that of secondary hyperesthesia remained strong for at least 24 h. Systemically delivered BQ-123 was without effect on any post-incisional hyperesthesia, and if the antagonist was locally injected 24 h before surgery there was no difference on hyperesthesia compared to vehicle injected at that time. We conclude that ET-1, released from skin by incision, activates nociceptors to cause primary allodynia and to sensitize spinal circuits through central sensitization. Blockade of ETA in the immediate peri-operative period prevents the later development of central sensitization.