Local antinociception induced by endothelin-1 in the hairy skin of the rat's back.
Subcutaneous injection of endothelin-1 (ET-1) into the glabrous skin of the rat's hind paw is known to produce impulses in nociceptors and acute nocifensive behavioral responses, such as hind paw flinching, and to sensitize the skin to mechanical and thermal stimulation. In this report, we show that in contrast to the responses in glabrous skin, ET-1 injected subcutaneously into rat hairy skin causes transient antinociception. Concentrations of 1 to 50 microM ET-1 (in 0.05 mL) depress the local nocifensive response to noxious tactile probing at the injection site with von Frey filaments for 30 to 180 minutes; distant injections have no effect at this site, showing that the response is local. Selective inhibition of ET(A) but not of ET(B) receptors inhibits this antinociception, as does coinjection with nimodipine (40 muM), a blocker of L-type Ca(2+) channels. Local subcutaneous injection of epinephrine (45 microM) also causes antinociception through alpha-1 adrenoreceptors, but such receptors are not involved in the ET-1-induced effect. Both epinephrine and ET-1, at antinociceptive concentrations, reduce blood flow in the skin; the effect from ET-1 is largely prevented by subcutaneous nimodipine. These data suggest that ET-1-induced antinociception in the hairy skin of the rat involves cutaneous vasoconstriction, presumably through neural ischemia, resulting in conduction block.


CONCLUSIONS
The pain-inducing effects of ET-1 have been well documented in glabrous skin of the rat, a frequently used test site. The opposite behavioral effect, antinociception, occurs from ET-1 in hairy skin and is correlated with a reduction in blood flow. Vasoactive effects are important in assessing mechanisms of peripherally acting agents.
Shrestha
Saurav
S
Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Gracias
Neilia G
NG
Mujenda
Florence
F
Khodorova
Alla
A
Vasko
Michael R
MR
Strichartz
Gary R
GR
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000627:therapeutic use*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000627:therapeutic use*; D004837:Epinephrine / Q000494:pharmacology; D006197:Hair; D008297:Male; D009292:Narcotic Antagonists; D009553:Nimodipine / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D012867:Skin / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D013618:Tachyphylaxis
D000316:Adrenergic alpha-Agonists; D018712:Analgesics, Non-Narcotic; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D009292:Narcotic Antagonists; D044022:Receptor, Endothelin A; D011957:Receptors, Opioid; D009553:Nimodipine; D004837:Epinephrine