| Etomidate(ETO), a carboxylated imidazole, has been used clinically to produce a rapid induction anesthesia of short duration via intravenous administration. Its use is associated with a rapid onset and recovery. No significant adverse effects of ETO have been demonstrated on the cardiovascular system or respiratory system (Kay, 1976; Marquardt et al., 1977; Criado et al., 1980). Accumulating evidence suggests that ETO shows highly specific interactions with the GABAA receptors in the cultured hippocampal neurons, expression system (Yang et al., 1996; Belelli et al., 2003) and transfected mouse fibroblast cells (Tomlin et al., 1998). Furthermore, the ETO actions on GABAa receptors areenantioselective and it has higher selectivity in vitro for (32- and B3-containing receptors than B1 subunit-containing receptors (Thompson et al, 1996; Hill-Venninge et al, 1997; Belelli et al, 1997). In our previous studies, it has been found that intrathecal (i.t.) administration of ETO at sub-anesthetic doses produces a remarkable depressive effect on the spontaneous flinching reflex induced by the chemical irritants in adult rats, as well as on the c-Fos expression in the superficial and deep spinal dorsal horn (Chen et al., 1999; 2002; Sun et al., 1999; 2001). Electrophysiological studies have also shown in the rat spinal dorsal horn that i.t. ETO inhibits the increase of spontaneous firing of wide-dynamic-range (WDR) neurons induced by subcutaneous (s.c.) injection of chemical irritants into the receptive field (Chen et al., 1999). It is, therefore, suggested that the spinal dorsal horn might be an important site for ETO to modulate the neuronal response to noxious stimuli. So far, little attention has been paid to the spinal cellular and molecular mechanisms of ETO. It has been well known that the superficial dorsal horn, especially substantia gelatinosa (SG, lamina II of Rexed) of the spinal cord plays an important role in the modulation of nociceptive transmission from the periphery to the CNS. Neurons in spinal deep dorsal horn include ascending projecting cells and spinal interneurons mediating spinally organized nociceptive flexion reflex (Willis and Coggeshall, 1991), so spinal deep dorsal horn is also an important target for analgesia. In this study, we used the whole-cell recording technique to investigate the spinal cellular and molecular mechanisms of ETO in adult rat spinal slices. The results are as follows:1. The effect of ETO on membrane current of SG neurons in the adult rat spinal dorsal horn under voltage clampSuperfusion of ETO could induce an outward current on SG neurons of spinal dorsal horn at a holding potential of 0 mV; this action was dose-dependent in concentration range of 10-1000 uM with an EC50 value of 258 uM and Hill coefficient of 1.2. The outward current induced by 500 uM of ET was 78 +8 pA(n=41). The reversal potential of ETO-induced current was close to the equilibrium potential for Cl- (n = 4). ETO-induced current could be inhibited completely by pretreatment of picrotoxin, a Cl" channel blocker (100 uM; n=5). The ETO-induced current was not affected by tetrodotoxin (TTX; 1 uM; n = 5), a Na+ channel blocker,. When examined using some inhibitors with respect to inhibitory neurotransmitter receptor, the ETO-induced current was depressed in amplitude by bicuculline, a GABAa receptor antagonist, (10 uM; n=6; by 80 +5%), but not by strychnine, a glycine receptor antagonist, ( 1 uM; n=6). ETO in lower concentration (50 uM) can potentiate the outward current induced by exogenous GABA (2 mM; n=7) in SG neurons, but did not affect the outward current induced by exogenous glycine (1 mM; n=6), in the SG neurons.From the above results, we conclude that ETO exerts a GABA-mimetic action in higher concentration by inducing an inward CV flow by activating GABAA receptor directly in SG neurons, which resulted in hyperpolarization of membrane of SG neurons. In lower concentration, ETO exerts a GABA-modulatory action via potentiating action of exogenous GABA in spinal SG neuron... |
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