Endothelin ET(B) receptor antagonist reduces mechanical allodynia in rats with trigeminal neuropathic pain

Abstract

Trigeminal neuropathic pain, which is associated with marked orofacial mechanical allodynia, is frequently refractory to currently available drugs. Because endothelins (ETs) can contribute to nociceptive changes in animal models of inflammatory, cancer, and diabetic neuropathic pain, the present study evaluated the influence of ET(A) and ET(B) receptor antagonists on orofacial mechanical allodynia in a rat model of trigeminal neuropathic pain. Unilateral constriction (C) of the infraorbital nerve (ION) caused pronounced and sustained bilateral mechanical allodynia, evaluated by application of von Frey hairs to the vibrissal pad. Mechanical allodynia on postoperative days 12-15 after nerve injury was abolished for up to 90 mins by subcutaneous administration of 2.5 mg/kg morphine, but was fully refractory to intravenous (iv) administration of 10 mg/kg of the dual ET(A) plus ET(B) or selective ET(A) receptor antagonists, bosentan and atrasentan, respectively. In sharp contrast, iv administration of 20 mg/kg of the selective ET(B) receptor antagonist, A-192621, caused a net 61 +/- 15% reduction of mechanical threshold, lasting 2 hrs. Co-injection of atrasentan plus A-192621 did not modify ION injury-induced mechanical allodynia. Injection of 10 pmol ET-1 into the upper lip of naive rats caused ipsilateral mechanical allodynia lasting up to 5 hrs. Thus, ET(B) receptor-mediated mechanisms contribute to orofacial mechanical allodynia induced by CION injury, but, some-how, functional ET(A) receptors are required for expression of the antiallodynic effect of ET(B) receptor blockade.