Atipamezole, an alpha 2 antagonist, augments opiate-induced muscle rigidity in the rat

Abstract

Atipamezole is a new, highly selective alpha 2-adrenoceptor antagonist currently undergoing clinical trials as an antagonist for dexmedetomidine, a potent alpha 2 agonist with sedative and analgesic properties. It has previously been demonstrated that dexmedetomidine, acting at central alpha 2 adrenoceptors, antagonizes opiate-induced muscle rigidity. However, the role of endogenous alpha 2-adrenergic systems in opiate-induced rigidity remains to be elucidated. The present study was designed to assess the effects of atipamezole on basal muscle tone and on alfentanil-induced muscle rigidity in the rat. Muscle tone was measured using gastrocnemius electromyography (EMG). After a 15-min baseline, saline or atipamezole (0.3 or 1.0 mg/kg) was administered, and 10 min later, saline or alfentanil (50, 150, or 300 μg/kg) was injected subcutaneously. Data were collected for an additional 60 min. Atipamezole (1.0 mg/kg) pretreatment (in the absence of alfentanil) produced a small increase in tonic EMG activity when compared with saline pretreatment. After saline pretreatment, significant muscle rigidity occurred in the two highest alfentanil dose groups. Atipamezole (0.3 and 1.0 mg/kg) augmented alfentanil-induced muscle rigidity. The ability of the alpha 2 antagonist to potentiate both basal muscle tone and alfentanil-induced rigidity suggests that endogenous adrenergic activity and/or direct alpha 2-adrenoceptor interaction with opioid receptors mediate opiate-induced muscle rigidity. These findings may be of clinical as well as basic neuropharmacological interest.