Depression of NMDA receptor-mediated synaptic transmission by four alpha2 adrenoceptor agonists on the in vitro rat spinal cord preparation.
1. Alpha2-adrenoceptor agonists have a spinal site of analgesic action. In the current study the synaptic depressant actions of xylazine, detomidine, romifidine and dexmedetomidine have been compared on segmental reflexes containing NMDA receptor-mediated components in the neonatal rat hemisected spinal cord preparation in vitro. 2. Reflexes were evoked in the ventral root following either supramaximal electrical stimulation of the corresponding ipsilateral lumbar dorsal root to evoke the high intensity excitatory postsynaptic potential (e.p.s.p.) involving all primary afferent fibres, or low intensity stimulation to evoke the solely A fibre-mediated low intensity e.p.s.p. The high intensity e.p.s.p. contains a greater NMDA receptor-mediated component. 3. Xylazine, romifidine, detomidine and dexmedetomidine all depressed both the high intensity e.p.s.p. and the low intensity e.p.s.p. giving respective EC50 values of 0.91+/-0.2 microM (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 intensity e.p.s.p. and 0.76+/-0.1 microM (n=12), 22.0+/-3 nM (n=12), 24.9+/-6 nM (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 actions was reversed by the selective alpha2-adrenoceptor antagonist atipamezole (1 microM). 5. In contrast to previous reports of the actions of alpha2-adrenoceptor agonists on the in vitro spinal cord preparation, at concentrations ten fold higher than the above EC50 values xylazine, romifidine, detomidine and dexmedetomidine depressed the initial population spike of motoneurons (MSR). This depression was not reversed by atipamezole. 6. Comparison of the rank order of the present EC50 values for depression of the high intensity e.p.s.p. with potency ratios from in vivo analgesic tests in previous studies show a close correlation between the present in vitro tests and analgesic potency. There is no correlation between the present data and previously obtained affinities of the agonists at non-adrenergic imidazoline binding sites. 7. The current findings therefore suggest that xylazine, romifidine, detomidine and dexmedetomidine are exerting their central analgesic actions at the spinal level principally through alpha2-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 ligands, selectively depressed the high intensity e.p.s.p.
Faber
E S
ES
Department of Pharmacology, School of Medical Sciences, University Walk, Bristol.
Chambers
J P
JP
Evans
R H
RH
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000187:drug effects; D066298:In Vitro Techniques; D009412:Nerve Fibers / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012018:Reflex / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects*
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D016194:Receptors, N-Methyl-D-Aspartate