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Studies on serotonin involvement in nucleus raphe inhibition and morphine depression of spinal cord neurones

University of British Columbia

It is not clear whether 5-hydroxytryptamine (5-HT) mediates, at least partly, the nucleus raphe magnus (NRM) stimulation-produced inhibition of deep dorsal horn wide dynamic range (WDR) neuronal nociceptive activity. The role of 5-HT in the NRM phasic inhibition is suggested by the presence of 5-HT in some of the descending fibres from the NRM, the release of 5-HT into spinal perfusates upon NRM stimulation and the fact that the iontophoretic application of 5-HT in the spinal cord depresses the nociceptive activity of the deep dorsal horn WDR neurones. However, systemic administration or iontophoretic application of methysergide, a putative 5-HT antagonist in the spinal cord did not reduce the NRM phasic inhibition of the deep dorsal horn WDR neurones. Experiments were therefore performed to determine whether 5-HT mediates the NRM phasic inhibition of WDR neurones by comparing the inhibition of the neuronal nociceptive activity to the NRM stimulation before and after administering the selective 5-HT uptake blocker, fluoxetine (6.0 mg/kg, i.v.), or the monoamine oxidase inhibitor, pargyline (30.0 mg/kg, i.v.). The NRM phasic inhibition following the drug treatment with fluoxetine or pargyline was decreased. Thus, 5-HT does not mediate but appears to reduce the NRM phasic inhibition of the deep dorsal horn WDR neurones. Fluoxetine administration did not affect the noxious heat-evoked activity of the dorsal horn WDR neurones. This lack of effect of fluoxetine on neuronal nociceptive activity probably reflects a lack of 5-HT involvement in the tonic control of dorsal horn WDR neuronal nociceptive activity, as suggested by some authors. Pargyline treatment produced an increase in the heat-evoked activity of the dorsal horn neurones studied. The mechanism responsible for this effect is not known. Experiments were performed to re-examine the effect of morphine on the NRM phasic inhibition of spinal cord nociceptive transmission. A controversy exists as to whether morphine elicits a supraspinal attenuation of spinal nociceptive transmission. Some investigators claim that morphine activates a NRM descending inhibition since microinjection of the drug into this nucleus produces a decrease in the nociceptive activity of the spinal cord dorsal horn WDR neurones. However, systemic morphine failed to enhance the NRM phasic inhibition of the dorsal horn WDR neurones. To test the hypothesis that morphine activates a descending serotonergic inhibitory system from the NRM impinging on the deep dorsal horn WDR neurones, morphine and fluoxetine were given concurrently. However, with this treatment a decrease in the NRM phasic inhibition was observed which was greater than seen with fluoxetine alone. Thus, these experimental results do not favour the above hypothesis. Morphine also suppressed the noxious heat-evoked activity of the deep dorsal horn WDR neurones. When this drug was administered concurrently with fluoxetine, the observed decrease in the nociceptive activity of the WDR neurones was not statistically different from that observed with morphine alone. This finding suggests that 5-HT does not mediate morphine's suppressive effect on the deep dorsal horn WDR neurones and is against the hypothesis that 5-HT is intimately involved in mediating morphine inhibition of spinal cord nociceptive transmission.

Text

2010-06-20

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http://hdl.handle.net/2429/25902

Pharmaceutical Sciences

University of British Columbia

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