ABT-627, an endothelin ETA 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 neuro pathy. The activation of endothelin ETA receptors has been implicated in di abetes-induced reductions in peripheral neurovascularization and concomitan t endoneurial hypoxia. Endothelin receptor activation has also been shown t o alter the peripheral and central processing of nociceptive information. T he present study was conducted to evaluate the antinociceptive effects of t he novel endothelin ETA receptor-selective antagonist, 2 R-(4-methoxyphenyl )-4S-(1,3-benzodioxol-5-yl)-1-( N,N-di(n-butyl)aminocarbonyl-methyl)-pyrrol idine-3R-carboxylic acid (ABT-627), in the streptozotocin-induced diabetic rat model of neuropathic pain. Rats were injected with 75 mg/kg streptozoto cin (i.p.), and drug effects were assessed 8-12 weeks following streptozoto cin treatment to allow for stabilization of blood glucose levels (greater t han or equal to 240 mg/dl) and tactile allodynia thresholds (less than or e qual to 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 thresho lds. A significant antinociceptive effect (40-50% increase in tactile allod ynia thresholds, P < 0.05) was observed at the dose of 10 mg/kg, i.p., with in 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 a ntagonist in drinking water for 7 days. In comparison, morphine administere d. acutely at a dose of 8 mg/kg, i.p., produced a significant 90% increase in streptozotocin-induced tactile allodynia thresholds. The endothelin ETB receptor-selective antagonist, 2 R-(4-propoxyphenyl)-4S-(1,3-benzodioxol-5- yl)-1 -( N-(2,6-diethylphenyl)aminocarbonyl-methyl)pyrrolidine-3R-carboxyli c acid (A-192621; 20 mg/kg, i.p.), did not significantly alter tactile allo dynia thresholds in streptozotocin-treated rats. Alhough combined i.p. admi nistration of ABT-627 and A-192621 produced a significant, acute increase i n tactile allodynia thresholds, this effect was significantly less than tha t produced by ABT-627 alone. These results indicate that the selective bloc kade of endothelin ETA receptors results in an attenuation of tactile allod ynia in the streptozotocin-treated rat. (C) 2000 Elsevier Science B.V. All rights reserved.