Evaluation of selective NK1 receptor antagonist CI-1021 in animal models of inflammatory and neuropathic pain

CI-1021 ([(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3)Ph) is a sele ctive and competitive neurokinin-1 (NK1) receptor antagonist. This study ex amines its activity in animal models of inflammatory and neuropathic pain. In mice, CI-1021 (1-30 mg/kg, s.c.) dose dependently blocked the developmen t of the late phase of the formalin response with a minimum effective dose (MED) of 3 mg/kg. Two chemically unrelated NK1 receptor antagonists, CP-99, 994 (3-30 mg/kg) and SR 140333 (1-100 mg/kg), also dose dependently blocked the late phase, with respective MEDs of 3 and 10 mg/kg. PD 156982, a NK1 r eceptor antagonist with poor central nervous system penetration, failed to have any effect. However, when administered i.c.v., it selectively blocked the late phase of the formalin response. Chronic constrictive injury (CCI) to a sciatic nerve in the rat induced spontaneous pain, thermal and mechani cal hyperalgesia, and cold, dynamic, and static allodynia. CI-1021 (10-100 mg/kg) and morphine (3 mg/kg) blocked all the responses except dynamic allo dynia. Carbamazepine (100 mg/kg) was weakly effective against all the respo nses. Once daily administration of morphine (3 mg/kg, s.c.) in CCI rats led to the development of tolerance within 6 days. Similar administration of C I-1021 (100 mg/kg, s.c.) for up to 10 days did not induce tolerance. Moreov er, the morphine tolerance failed to cross-generalize to CI-1021. CI-1021 b locked the CCI-induced hypersensitivity in the guinea pig, with a MED of 0. 1 mg/kg, p.o. CI-1021 (10-100 mg/kg, s.c.) did not show sedative/ataxic act ion in the rat rota-rod test. It is suggested that NK1 receptor antagonists possess a superior side effect profile to carbamazepine and morphine and m ay have a therapeutic use for the treatment of inflammatory and neuropathic pain.