Dexmedetomidine, acting through central alpha-2 adrenoceptors, prevents opiate-induced muscle rigidity in the rat

Abstract

The highly-selective alpha-2 adrenergic agonist dexmedetomidine (D-MED) is capable of inducing muscle flaccidity and anesthesia in rats and dogs. Intense generalized muscle rigidity is an undesirable side effect of potent opiate agonists. Although the neurochemistry of opiate-induced rigidity has yet to be fully elucidated, recent work suggests a role for a central adrenergic mechanism. In the present study, the authors determined if treatment with D-MED prevents the muscle rigidity caused by high-dose alfentanil anesthesia in the rat. Animals (n = 42) were treated intraperitoneally with one of the following six regimens: 1) L-MED (the inactive L-isomer of medetomidine), 30 μg/kg; 2) D-MED, 10 μg/kg; 3) D-MED, 30 μg/kg; 4) D-MED [30 μg/kg] and the central-acting alpha-2 antagonist, idazoxan [10 mg/kg]; 5) D-MED [30 μg/kg] and the peripheral-acting alpha-2 antagonist DG-5128 [10 mg/kg], or; 6) saline. Baseline electromyographic activity was recorded from the gastrocnemius muscle before and after drug treatment. Each rat was then injected with alfentanil (ALF, 0.5 mg/kg sc). ALF injection resulted in a marked increase in hindlimb EMG activity in the L-MED treatment group which was indistinguishable from that seen in animals treated with saline. In contrast, D-MED prevented alfentanil-induced muscle rigidity in a dose-dependent fashion. The small EMG values obtained in the high-dose D-MED group were comparable with those recorded in earlier studies from control animals not given any opiate. The high-dose D-MED animals were flaccid, akinetic, and lacked a startle response during the entire experimental period. The elimination of opiate rigidity by D-MED was completely blocked by the coadministration of the central alpha-2 antagonist, idazoxan, but only marginally by the peripheral alpha-2 antagonist, DG-5128. These results suggest that subanesthetic doses of the highly selective alpha-2 agonist dexmedetomidine may be clinically effective in preventing the muscle rigidity and augmenting the anesthesia produced by moderate to high doses of opiates. These effects appear to be due to the activation of central alpha-2 adrenoceptors. Selective alpha-2 adrenergic agonists show increasing clinical promise as anesthetic adjuvants.