Modification of antiallodynic and antinociceptive effects of morphine by peripheral and central action of fluoxetine in a neuropathic mice model

Abstract

We have previously reported that serotonin concentration was reduced in the brain of mice with neuropathic pain and that it may be related to reduction of morphine analgesic effects. To further prove this pharmacological action, we applied fluoxetine, a selective serotonin reuptake inhibitor, to determine whether it suppressed neuropathic pain and examined how its different administration routes would affect antinociceptive and antiallodynic effects of morphine in diabetic (DM) and sciatic nerve ligation (SL) mice, as models of neuropathic pain. Antiallodynia and antinociceptive effect of drugs were measured by using von Frey filament and tail pinch tests, respectively. Fluoxetine given alone, intracerebroventicularly (i.c.v., 15 microg/mouse) or intraperitoneally (i.p., 5 and 10 mg/kg) did not produce any effect in either model. However, fluoxetine given i.p. enhanced both antiallodynic and antinociceptive effects of morphine. Administration of fluoxetine i.c.v., slightly enhanced only the antiallodynic effect of morphine in SL mice. Ketanserine, a serotonin 2A receptor antagonist (i.p., 1 mg/kg) and naloxone, an opioid receptor antagonist (i.p., 3 mg/kg), blocked the combined antinociceptive effect of fluoxetine and morphine. Our data show that fluoxetine itself lacks antinociceptive properties in the two neuropathy models, but it enhances the analgesic effect of morphine in the periphery and suggests that co-administration of morphine with fluoxetine may have therapeutic potential in treatment of neuropathic pain.

Modification of morphine analgesia by venlafaxine in diabetic neuropathic pain model

“…Our results are consistent with a previous finding where the selective serotonin reuptake inhibitor (SSRI), fluoxetine, enhanced antinociceptive and antiallodynic effects of morphine in diabetic and sciatic-nerve-ligated mice [24]. Other reports also revealed that acute co-administration of serotonin and noradrenaline reuptake inhibitors (milnacipram and venlafaxine) and a tricyclic antidepressant (doxepin) with tramadol potentiated the antihyperalgesic effect of tramadol in the CCI model of neuropathic pain [17,26,28].…”

“…Mechanical hyperalgesia, observed after three weeks of diabetes, showed a reduced sensitivity to morphine-induced antinociception. This is consistent with numerous earlier reports of a significant reduction in the antinociceptive potency of morphine that was associated with hyperglycemic state in diabetes [4,5,24]. Alteration in the µ-opioid receptor function, an increase in the levels of interleukin-1b, and accumulation of morphine-3-glucuronide were reported in diabetic rats [9].…”

Mechanisms of morphine–venlafaxine interactions in diabetic neuropathic pain model

“…(5 mg/kg, ip) and MRF (5 mg/kg, sc) was inhibited by ketanserin and NLX in sciatic nerve ligation mice [10]. Our results suggested that both serotonin and noradrenaline mechanisms play a significant role in pain modulation after acute administration of MRF with VFX in STZ-induced neuropathic pain model.…”

“…Sounvoravong et al [10] revealed that ketanserine, a serotonin 2A receptor antagonist, and NLX blocked the combined antinociceptive effect of fluoxetine, a selective serotonin reuptake inhibitor, and MRF in neuropathic pain model.…”

Monoaminergic Antidepressants in the Relief of Pain: Potential Therapeutic Utility of Triple Reuptake Inhibitors (TRIs)

“…Interestingly, the effects of fluoxetine are completely blunted in 5-HT depleted animals [227,233] suggesting that SSRIs-induced antinociception involves serotonergic pathways. In addition, fluoxetine but also fluvoxamine, paroxetine and sertraline significantly potentiated the analgesic effect of morphine [234-239] (Table 3). Although these effects were blocked by naloxone, fluoxetine did not alter the binding of [ 3 H]-naloxone demonstrating the lack of affinity of this SSRI for opioid receptors [239].…”