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

BACKGROUND AND PURPOSE

The 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 APPROACH

C-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 RESULTS

Milnacipran 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-HT_1/2 receptor antagonist, and yohimbine or idazoxan, α₂-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 IMPLICATIONS

Milnacipran 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.     

Milnacipran Remediates Impulsive Deficits in Rats with Lesions of the Ventromedial Prefrontal Cortex

Background:

Deficits in impulse control are often observed in psychiatric disorders in which abnormalities of the prefrontal cortex are observed, including attention-deficit/hyperactivity disorder and bipolar disorder. We recently found that milnacipran, a serotonin/noradrenaline reuptake inhibitor, could suppress impulsive action in normal rats. However, whether milnacipran could suppress elevated impulsive action in rats with lesions of the ventromedial prefrontal cortex, which is functionally comparable with the human prefrontal cortex, remains unknown.

Methods:

Selective lesions of the ventromedial prefrontal cortex were made using quinolinic acid in rats previously trained on a 3-choice serial reaction time task. Sham rats received phosphate buffered saline. Following a period of recovery, milnacipran (0 or 10mg/kg/d × 14 days) was orally administered 60 minutes prior to testing on the 3-choice task. After 7 days of drug cessation, Western blotting, immunohistochemistry, electrophysiological analysis, and morphological analysis were conducted.

Results:

Lesions of the ventromedial prefrontal cortex induced impulsive deficits, and repeated milnacipran ameliorated the impulsive deficit both during the dosing period and after the cessation of the drug. Repeated milnacipran remediated the protein levels of mature brain-derived neurotrophic factor and postsynaptic density-95, dendritic spine density, and excitatory currents in the few surviving neurons in the ventromedial prefrontal cortex of ventromedial prefrontal cortex-lesioned rats.

Conclusions:

The findings of this study suggest that milnacipran treatment could be a novel strategy for the treatment of psychiatric disorders that are associated with a lack of impulse control.     

Milnacipran enhances the control of impulsive action by activating D1-like receptors in the infralimbic cortex

Rationale

Elevated impulsivity is often observed in patients with depression. We recently found that milnacipran, an antidepressant and a serotonin/noradrenaline reuptake inhibitor, could enhance impulse control in rats. However, the neural mechanisms underlying the effects of milnacipran on impulsive action remain unclear. Milnacipran increases not only extracellular serotonin and noradrenaline but also dopamine specifically in the medial prefrontal cortex, which is one of the brain regions responsible for impulsive action.

Objectives

Our goal was to identify whether D₁- and/or D₂-like receptors in the infralimbic cortex (IL), the ventral portion of the medial prefrontal cortex, mediates the milnacipran-enhanced impulse control in a three-choice serial reaction time task.

Methods

The rats were bilaterally injected with SCH23390, a selective D₁-like receptor antagonist (0.3 or 3 ng/side) or eticlopride, a selective D₂-like receptor antagonist (0.3 or 1 μg/side) into the IL after acute intraperitoneal administration of milnacipran (10 mg/kg).

Results

Intra-IL SCH23390 injections reversed the milnacipran-enhanced impulse control, whereas injections of eticlopride into the IL failed to block the effects of milnacipran on impulsive action.

Conclusions

This is the first report that demonstrates a critical role for D₁-like receptors of the IL in milnacipran-enhanced control of impulsive action.     

Proof of concept study: does fenofibrate have a role in sleep apnoea syndrome?

Abstract

Objective:

To investigate the effect of fenofibrate on sleep apnoea indices.     

Management of gastro-oesophageal reflux disease in primary care: a European observational study

Abstract

Objective:

To describe the management of gastro-oesophageal reflux disease (GERD) in primary care, as part of the RANGE (Retrospective ANalysis of GERD) study.     

Acute back pain: benefits and risks of current treatments

Abstract

Objective:

To review the efficacy and safety of current treatments for acute low back pain.     

Advantages and challenges of oestrogen-free hormonal contraception

Abstract

Background:

Not all women tolerate hormonal contraceptives containing oestrogens.     

Work productivity loss in patients with dry eye disease: an online survey

Abstract

Objective:

To assess the impact of dry eye disease (DED) on productivity.     

Management of neuropathic pain after surgical and non-surgical trauma with lidocaine 5% patches: study of 40 consecutive cases

Abstract

Objective:

To determine the efficacy of lidocaine 5% patches in patients with PNCCP.     

Predictors of asthma control in everyday clinical practice in Switzerland

Abstract

Objective:

To identify predictors of improved asthma control under conditions of everyday practice in Switzerland.     

Long-term safety and efficacy of aliskiren and valsartan combination with or without the addition of HCT in patients with hypertension

Abstract

Objective:

To assess the long-term safety and antihypertensive efficacy of aliskiren/valsartan 300/320?mg combination.     

The use of the Asthma Control Test in general practice and its correlation with asthma control according to the GINA guidelines

Abstract

Background:

The GINA guidelines have redefined the primary goal of asthma treatment as achieving optimum control.     

Complexities in the pharmacologic management of osteoarthritis pain

Abstract

Objective:

To discuss challenges in the pharmacologic management of osteoarthritis (OA) pain.     

Association between hypoglycemia and inpatient mortality and length of hospital stay in hospitalized,insulin-treated patients

Abstract

Objective:

To assess the impact of hypoglycemia on clinical outcomes among hospitalized, insulin-treated patients.     

Long-term clinical and economic outcomes associated with angiotensin II receptor blocker use in hypertensive patients

Abstract

Objective:

To examine clinical and economic outcomes associated with angiotensin II receptor blockers (ARB).     

Utilization of duloxetine and celecoxib in osteoarthritis patients

Abstract

Objectives:

To describe utilization patterns of duloxetine and celecoxib and subsequent opioid use among patients with osteoarthritis.     

SERT and NET occupancy by venlafaxine and milnacipran in nonhuman primates: a PET study

Introduction

Serotonin and norepinephrine reuptake inhibitors (SNRIs) are antidepressants which have high affinity to both serotonin transporter (SERT) and norepinephrine transporter (NET). In studies in vitro, SNRIs have been reported to show a large variability in the affinity ratio between SERT and NET. For instance, the reported affinity ratio is about 30 for venlafaxine and 1.6 for milnacipran. In this study in nonhuman primates, we aimed to investigate the relationship between SERT and NET affinity by measuring the in vivo occupancy at both transporters of venlafaxine and milnacipran.

Methods

PET measurements with [¹¹C]MADAM and [¹⁸F]FMeNER-D₂ were performed in two female cynomolgus monkeys at baseline and after pretreatment with venlafaxine and milnacipran, respectively. Relationships between dose, plasma concentration, and transporter occupancy were evaluated by saturation analysis using a hyperbolic function. Binding affinity (Kd^plasma) was expressed by the dose or plasma concentration at which 50 % of the transporter was occupied.

Results

SERT and NET occupancy by venlafaxine and milnacipran increased in a dose and plasma concentration-dependent manner. The Kd^plasma ratio of SERT to NET was 1.9 for venlafaxine and 0.6 for milnacipran.

Conclusions

In this nonhuman primate PET study, the affinity in vivo for SERT and NET, respectively, was shown to be at a similar level for venlafaxine and milnacipran. Both drugs were found to produce balanced inhibition of SERT and NET binding. This observation is not consistent with previous in vitro binding data and illustrates the need to characterize antidepressants at in vivo condition.     

Prevention of episodic migraine with topiramate: a prospective 24-week,open-label,flexible-dose clinical trial with optional 24 weeks follow-up in a community setting

Abstract

Objective:

To explore efficacy and safety outcomes of topiramate for episodic migraine prevention in community practice.     

Comparative efficacy and acceptability of pharmacotherapeutic agents for anxiety disorders in children and adolescents: a mixed treatment comparison meta-analysis

Abstract

Objective:

to compare efficacy and acceptability of different pharmacotherapeutic agents for treating anxiety disorders in children and adolescents     

Assessing achievement and maintenance of glycemic control by patients initiating basal insulin

Abstract

Objective:

Describe characteristics of diabetic patients who initiated basal insulin and assess their glycemic control.