ABT-627, an endothelin ET(A) receptor-selective antagonist, attenuates tactile allodynia in a diabetic rat model of neuropathic pain.
Tactile allodynia, the enhanced perception of pain in response to normally non-painful stimulation, represents a common complication of diabetic neuropathy. The activation of endothelin ET(A) receptors has been implicated in diabetes-induced reductions in peripheral neurovascularization and concomitant endoneurial hypoxia. Endothelin receptor activation has also been shown to alter the peripheral and central processing of nociceptive information. The present study was conducted to evaluate the antinociceptive effects of the novel endothelin ET(A) receptor-selective antagonist, 2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N, N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid (ABT-627), in the streptozotocin-induced diabetic rat model of neuropathic pain. Rats were injected with 75 mg/kg streptozotocin (i. p.), and drug effects were assessed 8-12 weeks following streptozotocin treatment to allow for stabilization of blood glucose levels (>/=240 mg/dl) and tactile allodynia thresholds (</=8.0 g). Systemic (i.p.) administration of ABT-627 (1 and 10 mg/kg) was found to produce a dose-dependent increase in tactile allodynia thresholds. A significant antinociceptive effect (40-50% increase in tactile allodynia thresholds, P<0.05) was observed at the dose of 10 mg/kg, i.p., within 0.5-2-h post-dosing. The antinociceptive effects of ABT-627 (10 mg kg(-1) day(-1), p.o.) were maintained following chronic administration of the antagonist in drinking water for 7 days. In comparison, morphine administered acutely at a dose of 8 mg/kg, i.p., produced a significant 90% increase in streptozotocin-induced tactile allodynia thresholds. The endothelin ET(B) receptor-selective antagonist, 2R-(4-propoxyphenyl)-4S-(1, 3-benzodioxol-5-yl)-1-(N-(2, 6-diethylphenyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxy lic acid (A-192621; 20 mg/kg, i.p.), did not significantly alter tactile allodynia thresholds in streptozotocin-treated rats. Although combined i.p. administration of ABT-627 and A-192621 produced a significant, acute increase in tactile allodynia thresholds, this effect was significantly less than that produced by ABT-627 alone. These results indicate that the selective blockade of endothelin ET(A) receptors results in an attenuation of tactile allodynia in the streptozotocin-treated rat.
Jarvis
M F
MF
Neurological and Urological Diseases Research and Metabolic Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6123, USA. michael.jarvis@abbott.com
Wessale
J L
JL
Zhu
C Z
CZ
Lynch
J J
JJ
Dayton
B D
BD
Calzadilla
S V
SV
Padley
R J
RJ
Opgenorth
T J
TJ
Kowaluk
E A
EA
D018712:Analgesics, Non-Narcotic / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D000077868:Atrasentan; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000150:complications*; D065128:Endothelin Receptor Antagonists; D006801:Humans; D008297:Male; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D011759:Pyrrolidines / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013237:Stereoisomerism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
C120508:A 192621; D018712:Analgesics, Non-Narcotic; D065128:Endothelin Receptor Antagonists; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D014662:Vasoconstrictor Agents; D000077868:Atrasentan