Effects of milnacipran, a 5‐HT and noradrenaline reuptake inhibitor, on C‐fibre‐evoked field potentials in spinal long‐term potentiation and neuropathic pain

Abstract

Keywords5-HT and noradrenaline reuptake inhibitor; spinal cord; long-term potentiation; neuropathic pain; C-fibre-evoked field potential; in vivo electrophysiology ------------------------------- BACKGROUND AND PURPOSEThe analgesic action of 5-HT and noradrenaline reuptake inhibitors (SNRIs) on nociceptive synaptic transmission in the spinal cord is poorly understood. We investigated the effects of milnacipran, an SNRI, on C-fibre-evoked field potentials (FPs) in spinal long-term potentiation (LTP), a proposed synaptic mechanism of hypersensitivity, and on the FPs in a neuropathic pain model. EXPERIMENTAL APPROACHC-fibre-evoked FPs by electrical stimulation of the sciatic nerve fibres were recorded in the spinal dorsal horn of anaesthetized adult rats, and LTP was induced by high-frequency stimulation of the sciatic nerve fibres. A rat model of neuropathic pain was produced by L5 spinal nerve ligation and transection. KEY RESULTSMilnacipran produced prolonged inhibition of C-fibre-evoked FPs when applied spinally after the establishment of LTP of C-fibre-evoked FPs in naïve animals. In the neuropathic pain model, spinal administration of milnacipran clearly reduced the basal C-fibre-evoked FPs. These inhibitory effects of milnacipran were blocked by spinal administration of methysergide, a 5-HT1/2 receptor antagonist, and yohimbine or idazoxan, a2-adrenoceptor antagonists. However, spinal administration of milnacipran in naïve animals did not affect the basal C-fibre-evoked FPs and the induction of spinal LTP. CONCLUSION AND IMPLICATIONSMilnacipran inhibited C-fibre-mediated nociceptive synaptic transmission in the spinal dorsal horn after the establishment of spinal LTP and in the neuropathic pain model, by activating both spinal 5-hydroxytryptaminergic and noradrenergic systems. The condition-dependent inhibition of the C-fibre-mediated transmission by milnacipran could provide novel evidence regarding the analgesic mechanisms of SNRIs in chronic pain. AbbreviationsCNS, central nervous system; FP, field potential; HFS, high-frequency stimulation; LTP, long-term potentiation; SNL, spinal nerve ligation; SNRI, 5-HT and noradrenaline reuptake inhibitor; SSRI; selective serotonin reuptake inhibitor BJP British Journal of Pharmacology

No evidence of potentiation of buprenorphine by milnacipran in healthy subjects using a nociceptive test battery

“…In animal studies, milnacipran inhibited C-fibremediated nociceptive synaptic transmission in the spinal dorsal horn after the establishment of spinal long-term potentiation in a neuropathic pain model (Ohnami et al, 2012). Furthermore, it has been shown that milnacipran reduces thermal and mechanical allodynia in a rat model of neuropathic pain (chronic constriction injury of the sciatic nerve) (Berrocoso et al, 2011).…”

“…It has been demonstrated that milnacipran, a serotonin-noradrenaline reuptake inhibitor (SNRI), inhibits C-fibre-mediated nociceptive synaptic transmission in the spinal dorsal horn after the establishment of spinal long term potentiation in a neuropathic pain model, by activating both spinal serotonergic and noradrenergic systems (Ohnami et al, 2012). The inhibition of the C-fibre-mediated transmission by milnacipran could provide new evidence regarding the analgesic mechanism of SNRIs in chronic pain.…”

Supraspinal Projection of Serotonergic and Noradrenergic Pathways Modulates Nociceptive Transmission in the Lower Urinary Tract of Rats

“…Focused on the mechanism of SNRI's effectiveness in chronic pain diseases, some evidence has been reported recently. SNRI inhibit C‐fiber‐mediated nociceptive synaptic transmission in the spinal dorsal horn via activation of spinal 5‐HT and NA systems . Further, SNRI inhibit glutaminergic N‐Methyl‐D‐Aspartate receptor activity in the spinal dorsal horn, which produce nociceptive effects .…”

“…SNRI inhibit C-fiber-mediated nociceptive synaptic transmission in the spinal dorsal horn via activation of spinal 5-HT and NA systems. 20 Further, SNRI inhibit glutaminergic N-Methyl-D-Aspartate receptor activity in the spinal dorsal horn, which produce nociceptive effects. 21 Thus, SNRI could be effective in chronic pain diseases, including IC/BPS.…”

Regulation of Pain in Fibromyalgia by Selective Serotonin and Serotonin Norepinephrine Reuptake Inhibition

“…However, Jones et al [42] showed using the carrageenan-induced pain model in the rat that dual serotonergic-noradrenergic reuptake inhibition by dual SNRIs, or combinations of SSRIs and SNRIs were efficacious in producing a synergistic analgesic response. More recently, Ohnami et al [43] showed that milnacipran inhibited C-fiber-mediated nociceptive synaptic transmission activity in the adult rat spinal dorsal horn in a model of neuropathic pain evoked by activation of 5-hydroxytryptaminergic and noradrenaline-mediated pathways. Taken together, the results of these studies using animal models of chronic pain indicated that inhibition of serotonin and norepinephrine reuptake was responsible for the modulating analgesic effect of this drug class on chronic pain.…”