INTRATHECAL ALPHA(2)-ADRENERGIC AGONISTS STIMULATE ACETYLCHOLINE AND NOREPINEPHRINE RELEASE FROM THE SPINAL-CORD DORSAL HORN IN SHEEP - AN IN-VIVO MICRODIALYSIS STUDY

Background: Intrathecal injection of clonidine and dexmedetomidine pro duce behavioral analgesia by an alpha(2)-adrenergic mechanism. Functio nal and anatomic studies suggest that this analgesia is mediated by ch olinergic activation. This hypothesis was directly tested by measuring extracellular acetylcholine concentrations in spinal cord interstitia l fluid by means of microdialysis after intrathecal injection of these alpha(2)-adrenergic agonists in sheep. Methods: Twelve sheep with chr onically Implanted thoracic intrathecal catheters were anesthetized wi th halothane. Multiple 200-mu m-diameter dialysis fibers were inserted surgically at a mid-thoracic level through the dorsal horn and perfus ed with artificial cerebrospinal fluid. After baseline sampling, eithe r clonidine (100 mu g), dexmedetomidine (100 mu g), or saline were inj ected intrathecally. Microdialysis samples were analyzed by high-press ure liquid chromatography for acetylcholine and norepinephrine. Result s: Both alpha(2)-adrenergic agonists increased acetylcholine in microd ialysate, whereas intrathecal saline had no effect. Analysis of the ra w data showed that all groups differed significantly, with greater lev els of acetylcholine following administration of dexmedetomidine than clonidine or saline. Unexpectedly, intrathecal clonidine also increase d microdialysate norepinephrine levels. Conclusions: These data are co nsistent with previous experiments measuring acetylcholine concentrati ons in cerebrospinal fluid and support analgesia from alpha(2)-adrener gic agonists mediated in part by cholinergic activation. In addition, the increase in norepinephrine concentrations after intrathecal admini stration of clonidine suggest stimulation of norepinephrine release by this agent.