Effects of spinal administration of amitryptiline, venlafaxine and fluoxetine on C-fibre and A-fibre evoked responses of dorsal horn neurones

Abstract

Antidepressants are among the most useful drugs used to relieve many different types of chronic pain including neuropathic pain, arthritis, low back pain, fibromyalgia and central pain. The modulation of nociception by antidepressants appears to be exerted at supraspinal sites through the activation of descending monoaminergic/opioid pathways to the dorsal horn. Nevertheless, spinal actions of antidepressants may also contribute to their analgesic effects. In this study, we have evaluated and compared the effects of spinally administered amitryptiline (tricyclic antidepressant), venlafaxine (noradrenaline/serotonin re-uptake inhibitor) and fluoxetine (selective serotonin re-uptake inhibitor) upon the responses of dorsal horn neurones. Extracellular recordings of electrically-evoked responses of single wide-dynamic-range (WDR) neurones were made in isofluorane anaesthetised rats (Sprague-Dawley, male, 2 months old). The effect of each dose of antidepressant (n = 5-7; cumulative doses: 10-20-40 ug/50 ll, i.t.) on Ab-, Ad- and C-fibre evoked responses and postdischarge responses was followed for 1 h Ab-fibre evoked responses of neurons were not altered by any of the antidepressants. However, Adfibre evoked responses were dose-dependently and highly inhibited by amitryptiline and venlafaxine (40 lg dose: 39.9 ± 12.6% and 34.4 ± 19.3% of control values, respectively) whereas fluoxetine was less effective (40 lg dose: 56.4 ± 12.9% of control). A similar pattern of inhibition was observed upon the C-fibre evoked responses (40 lg dose: 42.0 ± 15.3%, 34.6 ± 16.3% and 53.5 ± 14.7% of control, for amitryptiline, venlafaxine and fluoxetine, respectively). The evoked C-fibre mediated post-discharge responses were almost abolished with the highest dose of amitryptiline and venlafaxine (13.5 ± 4.6% and 6.8 ± 3.1% of control, respectively) while fluoxetine was devoid of effect. These results demonstrate that antidepressants inhibiting noradrenaline/serotonin re-uptake (amitryptiline and venlafaxine) exhibit greater spinal antinociceptive activity than those acting as selective serotonin re-uptake inhibitors (fluoxetine).