Cutaneous endothelin-A receptors elevate post-incisional pain.
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. 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 ET(A) was determined by pre-incisional, subcutaneous injection of the selective receptor antagonist BQ-123 at the incision site, 15 min or 24h before surgery. Control incisions showed both primary tactile allodynia and hyperalgesia, and a weaker secondary hyperesthesia, peaking 3-4h 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 24h, but that of secondary hyperesthesia remained strong for at least 24h. Systemically delivered BQ-123 was without effect on any post-incisional hyperesthesia, and if the antagonist was locally injected 24h 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.
Mujenda
Florence H
FH
Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
Duarte
Adriana M
AM
Reilly
Erin K
EK
Strichartz
Gary R
GR
D000818:Animals; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D007839:Functional Laterality; D006941:Hyperesthesia / Q000188:drug therapy; D008297:Male; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000502:physiology; D010149:Postoperative Pain / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D010812:Physical Stimulation / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism*; D012867:Skin / Q000294:innervation / Q000378:metabolism*; D013997:Time Factors
D065130:Endothelin A Receptor Antagonists; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; C072247:cyclo(Trp-Asp-Pro-Val-Leu)