Sensory fibers resistant to the actions of tetrodotoxin mediate nocifensive responses to local administration of endothelin-1 in rats.
Endothelin-1 (ET-1) applied to the sciatic nerve or injected into the plantar hindpaw of rats induces pain behavior (ipsilateral hindpaw flinching) and selective excitation of nociceptors by activation of endothelin-A (ET(A)) receptors. To determine the pharmacological profile of the sensory fibers that mediate this pain behavior, we administered lidocaine (LID, a non-selective conduction blocker) or tetrodotoxin (TTX) prior to ET-1. LID (1 or 2%, 0.1 ml) was injected percutaneously into the sciatic notch, or TTX (10 microM, 4 microl) was injected into the sciatic nerve prior to the more distal application of ET-1 (400 microM, 40 microl) onto the sciatic nerve or subcutaneously into the plantar hindpaw (400 microM, 10 microl). LID inhibited ET-1-induced flinching in a dose-dependent manner; the mean total number of flinches was reduced by 39% for 1% LID and by 87% for 2% LID. In contrast, TTX failed to inhibit flinching behavior induced by sciatic nerve application of ET-1 despite a similar magnitude of motor and sensory blockade as that observed with 2% LID. Partial blockade of flinching behavior by intraneural TTX (mean total flinches were reduced by 51%) was observed after subcutaneous injection of ET-1. Unexpectedly, ET-1 prolonged the actions of 1% LID and, even when applied alone, produced clear signs of motor and sensory conduction block. These results are evidence that ET-1-induced pain is transmitted to the central nervous system via sensory fibers using tetrodotoxin-resistant sodium channels, and that ET-1 has analgesic actions that exist despite the activation of local pain pathways.
Department of Anesthesiology, Perioperative and Pain Medicine, Children's Hospital, Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA 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.
Constance S
CS
Houck
Alla
A
Khodorova
Amy M
AM
Reale
Gary R
GR
Strichartz
Gudarz
G
Davar
D000818:Animals; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000633:toxicity*; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D010146:Pain / Q000139:chemically induced* / Q000503:physiopathology; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects / Q000502:physiology; D013779:Tetrodotoxin / Q000633:toxicity*
D019332:Endothelin-1; D013779:Tetrodotoxin