The role of 5-HT1A-receptors in fentanyl-induced bulbospinal inhibition of a spinal withdrawal reflex in the rabbit

The sural to gastrocnemius withdrawal reflex is inhibited after injection of the OP3 (mu)-receptor-selective opioid fentanyl into the fourth ventricle of decerebrated rabbits. This effect is abolished by complete section of the spinal cord but not by the selective alpha(2)-adrenoceptor antagonist RX 821002 (Clarke RW, Parry-Baggott C, Houghton AK, Ogilvie J. The involvement of bulbo-spinal pathways in fentanyl-induced inhibition of spinal withdrawal reflexes in the decerebrated rabbit. Pain 1998;78;197-207). We have now investigated the role of 5HT(1A) receptors in mediating the descending inhibition activated by intraventricular fentanyl. In the control state, intraventricular fentanyl (330 mu g/kg) inhibited gastrocnemius reflex responses to a median of 34% of pre-drug levels. After intrathecal administration of the selective 5-HT1A receptor antagonist WAY-100635 (100 mu g), fentanyl reduced reflex responses to 83% of pre-fentanyl values, significantly less inhibition than in the control state. In a separate group of experiments, intravenous fentanyl (0.3-30 mu g/kg) depressed the sural-gastrocnemius reflex to 17% of pre-drug controls. This inhibition was not affected by intrathecal WAY-100635 (100 mu g), but combined administration of the 5-HT1A antagonist with RX 821002 (100 mu g) significantly reduced the effectiveness of i.v. fentanyl. After the highest dose reflexes were 37% of pre-fentanyl levels. These data show that the bulbospinal inhibition activated by fentanyl is mediated, at least in part, by activation of spinal 5-HT1A receptors. That blockade of these receptors failed to influence the inhibition induced by i.v. fentanyl might be taken to mean that the brain-stem action of fentanyl does not contribute significantly to the systemic actions of this opioid. A more probable explanation is that, in the preparation used in the present study, the bulbospinal and direct spinal actions of fentanyl occlude each other to produce an overall inhibition that is less than the sum of the two effects. (C) 2000 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.