| Etomidate and propofol are widely used as intravenous anesthetics in clinic, however, the underlying mechanisms of their CNS actions are poorly known. Although some reports indicate that they have action sites in the spinal cord dorsal horn, it is still not clear whether their actions are specifically associated with anti-nociception or non-specifically relevant. As well known, both inhibitory amino acids (IAAs, e.g., GABA and glycine) and various endogenous opioid peptides exist as two major inhibitory systems in the CNS and exert their inhibitory actions via their receptors in the spinal cord dorsal horn. The former IAAs exert their actions via GABA receptors (e.g., GABAa, b, c) and glycine receptor, while the latter opioid peptides exert theirs actions via opioid receptors (e.g., mu-, delta-, kappa, and opioid receptor like 1, e.g., ORL1). Etomidate and propofol have been found to mainly increase GABAa receptor-mediated synaptic transmission as well as glycine receptor-mediated events. To see whether etomidate and propofol have anti-nociceptive effects in the spinal cord dorsal horn, we took two classes of opioid receptor ligands, morphine and nociceptin, as two positive controls and their vehicles (saline and DMSO) as negative controls to study their spinal actions by means of both behavioral surveys and in vivo electrophysiological extracellular single unit recordings in the dorsalhorn of spinal cord of rats. The results are as follows:1. Comparison of spinal effects of etomidate and propofol withmorphine and nociceptin 1.1 Effects on persistent spontaneous nociceptionS.c. injection of BV into the plantar surface of one hindpaw of rats immediately produced 1 h period of persistent spontaneous nociception (PSN) displaying as spontaneous flinching reflex. Intrathecal (i.t.) administration of both etomidate (0.04, 0. 08, 0. 5 umol) and propofol (0. 05, 0. 5, 5 umol) could suppress the bee venom (BV)-induced PSN dose-dependently, the results are similar to that of morphine (0.33, 3.3, 33 nmol) and nociceptin (3, 10, 30 nmol). To compare the efficacies of these four drugs, relative 55% inhibitory rate-produced doses were compared and the effective dose order is: morphine > nociceptin >etomidate > propofol. The antagonist of ORLl receptor CompB (30 nmol) could significantly reversed the inhibitory effect of i.t. NOC (10 nmol).When administered directly to the dorsal surface of the spinal cord, single dose of etomidate (0.5 umol) was also effective to suppress the increase in persistent spontaneous discharges of spinal dorsal horn wide-dynamic-range (WDR) neurons recorded. Similarly, three doses of propofol (0.05, 0.5, and 5 umol) could also produce dose-dependent suppression.Taken together, it is suggested that, similar to morphine and nociceptin, etomidate and propofol can also have anti-nociceptive effects in the spinal cord dorsal horn via inhibitory actions on WDR neuronal activities.1.2 Effects on thermal and mechanical hypersensitivityIn behavioral surveys, s.c. injection of BV produced a prolonged primary heat and mechanical hypersensitivity (hyperalgesia/allodynia) shown as a reduction in thermal paw withdrawal latency (PWTL) toradiant heat stimuli and mechanical paw withdrawal threshold (PWMT) to von Frey filament stimuli. Single effective dose of i.t. etomidate (0.08 umol), propofol (5 umol), morphine (3.3 nmol) and nociceptin (10 nmol) produced differential effects on BV-induced heat and mechanical hyperalgesia. When pre-treated, etomidate and morphine, but not propofol and nociceptin, were effective to prevent reduction in PWTL significantly, while when post-treated etomidate, morphine and propofol, but not nociceptin, were effective. For the effect on mechanical hypersensitivity, among the four drugs only morphine was effective.In in vivo electrophysiological recordings, s.c. injection of BV can induce increase in responsiveness of WDR neurons of rats to both radiant heat (45, 47, 49 and 53 C) and mechanical brush, press and pinch as shown in our previous reports. When applie...
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