Do opioids evoke the release of serotonin in the spinal cord? An in vivo microdialysis study of the regulation of extracellular serotonin in the rat

Abstract This study investigated the regulation of serotonin (5-HT) and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the dorsal spinal cord of awake, freely moving rats, using microdialysis coupled to HPLC with electrochemical detection and tested the hypothesis that opioids exert their analgesic effect in part through the increased release of 5-HT in the dorsal horn. A dialysis tube was placed transversely at the L4 segment of the dorsal spinal cord and the basal concentration of 5-HT in the dialysate was characterized by infusion of a variety of substances through the dialysis probe: tetrodotoxin (TTX), KCl, imipramine, fluoxetine and amphetamine (AMPH). To evaluate the contribution of opioids, we also studied the effects of either systemic or intracerebroventricular (i.c.v.) injection of morphine or DAMGO. Extracellular concentrations of 5-HT and 5-HIAA were partially and reversibly reduced by TTX. In the presence of KCl, imipramine, fluoxetine or AMPH, 5-HT levels significantly increased. Under these conditions, extracellular 5-HIAA levels usually decreased. By contrast, the effects of opioids on 5-HT concentrations were highly variable. Low doses of morphine administered systemically increased 5-HT concentrations in only 3 of 6 rats. This was paralleled by a decrease in 5-HIAA. Higher doses of morphine, alone or in the presence of fluoxetine, did not change 5-HT concentrations. Intracerebroventricular injection of morphine or DAMGO increased the extracellular concentrations of 5-HT in only about one third of the animals. After intracerebroventricular opioid injection, extracellular concentrations of 5-HIAA either decreased by about 20% or did not change. These results demonstrate that the extracellular concentration of 5-HT in the dorsal spinal cord is partly derived from neuronal activity and that 5-HIAA levels are regulated differently from 5-HT. The fact that morphine and DAMGO evoked the release of 5-HT in some animals is consistent with the hypothesis that opioids exert their analgesic effects, at least in part, through serotonergic-mediated descending controls. However, since behavioral analgesia was produced in several animals in which an increase in 5-HT was not observed, our results suggest that evoked release of 5-HT in the spinal cord is not necessary for opioids to exert their analgesic action.