DEPRESSION OF NMDA-RECEPTOR-MEDIATED SYNAPTIC TRANSMISSION BY 4 ALPHA(2)-ADRENOCEPTOR AGONISTS ON THE IN-VITRO RAT SPINAL-CORD PREPARATION

1. alpha(2)-Adrenoceptor agonists have a spinal site of analgesic acti on. In the current study the synaptic depressant actions of xylazine, detomidine, romifidine and dexmedetomidine have been compared on segme ntal reflexes containing NMDA receptor-mediated components in the neon atal rat hemisected spinal cord preparation in vitro. 2 Reflexes were evoked in the ventral root following either supramaximal electrical st imulation of the corresponding ipsilateral lumbar dorsal root to evoke the high intensity excitatory postsynaptic potential (e.p.s.p.) invol ving all primary afferent fibres, or low intensity stimulation to evok e the solely A fibre-mediated low intensity e.p.s.p. The high intensit y e.p.s.p. contains a greater NMDA receptor-mediated component. 3 Xyla zine, romifidine, detomidine and dexmedetomidine all depressed both th e high intensity e.p.s.p. and the low intensity e.p.s.p. giving respec tive EC50 values of 0.91+/-0.2 mu M (n=12), 23.4+/-3 nM (n=12), 37.7+/ -7 nM (n=8) and 0.84+/-0.1 nM (n=4) for depression of the high intensi ty e.p.s.p. and 0.76+/-0.1 mu M (n=12), 22.0+/-3 nM (n=12), 24.9+/-6 n M (n=4) and 2.7+/-0.6 nM (n=4) for depression of the low intensity e.p .s.p., respectively. Unlike the other three drugs, the two values for dexmedetomidine, showing a greater selectivity for the high intensity e.p.s.p., are significantly different. 4 Each of these depressant acti ons was reversed by the selective alpha(2)-adrenoceptor antagonist ati pamezole (1 mu M). 5 In contrast to previous reports of the actions of alpha(2)-adrenoceptor agonists on the in vitro spinal cord preparatio n, at concentrations ten fold higher than the above EC50 values xylazi ne, romifidine, detomidine and dexmedetomidine depressed the initial p opulation spike of motoneurons (MSR). This depression was not reversed by atipamezole. 6 Comparison of the rank order of the present EC50 va lues for depression of the high intensity e.p.s.p. with potency ratios from in vivo analgesic tests in previous studies show a close correla tion between the present in vitro tests and analgesic potency. There i s no correlation between the present data and previously obtained affi nities of the agonists at non-adrenergic imidazoline binding sites. 7 The current findings therefore suggest that xylazine, romifidine, deto midine and dexmedetomidine are exerting their central analgesic action s at the spinal level principally through alpha-(2)-adrenoceptors. All four agonists showed the same profile of selective depression of the NMDA receptor-mediated component of reflexes similar to that reported previously for clonidine. However dexmedetomidine, unlike the other li gands, selectively depressed the high intensity e.p.s.p.