The contribution of endothelin-1 (ET-1), acting via endothelin-A receptors (ET A ), on post-incisional pain was examined in a rat model of incision through the hairy skin of the lumbar dorsum. Postincisional 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 ET A was determined by pre-incisional, subcutaneous injection of the selective receptor antagonist BQ-123 at the incision site, 15 min or 24 hr 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 24h. 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 ET A in the immediate peri-operative period prevents the later development of central sensitization.
Incision of rat hairy skin changes pain responses, similar to pain in humans. Preincisional subcutaneous bupivacaine selectively suppresses and shortens allodynia for times far outlasting its local anesthesia, an effect largely from systemic actions.
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