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The monoamine-mediated antiallodynic effects of intrathecally administered milnacipran, a serotonin noradrenaline reuptake inhibitor, in a rat model of neuropathic pain

Department of Anesthesiology, Gunma University, Maebashi, Gunma, Japan
Anesthesia & Analgesia (Impact Factor: 3.42). 05/2005; 100(5):1406-10, table of contents. DOI: 10.1213/01.ANE.0000149546.97299.A2
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ABSTRACT Antidepressants are often used to treat neuropathic pain. In the present study, we determined the antiallodynic effects of selective monoamine reuptake inhibitors in the spinal cord in a rat model of neuropathic pain. Mechanical allodynia was produced by tight ligation of the left L5 and L6 spinal nerves and determined by applying von Frey filaments to the left hindpaw. A serotonin noradrenaline reuptake inhibitor, milnacipran, a selective serotonin reuptake inhibitor, paroxetine, or a selective noradrenaline reuptake inhibitor, maprotiline, was administered intrathecally via a chronically implanted catheter. Milnacipran produced dose-dependent antiallodynic effects at doses between 3 microg and 100 microg. The effect lasted for 7 h after injection of 100 microg (P < 0.05). The antiallodynic effect of 30 microg of milnacipran was attenuated by intrathecal coadministration of 30 microg of yohimbine, an alpha(2)-adrenoceptor antagonist, 30 microg of methysergide, a serotonin receptor antagonist, or 30 microg of atropine, a muscarinic receptor antagonist (P < 0.01, respectively). Intraperitoneal administration of milnacipran had no antiallodynic effects at doses of 3 to 30 mg/kg. Antiallodynic effects were not produced by intrathecal administration of paroxetine (10 to 100 microg) or maprotiline (10 to 100 microg). These findings suggest that simultaneous inhibition of serotonin and noradrenaline reuptake in the spinal cord is essential to mediate antiallodynic effects. Milnacipran might be effective for suppression of neuropathic pain.

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    • "The stock solution of milnacipran, 5-HT receptor antagonists or alpha adrenoceptor antagonists was diluted in saline to specific concentrations in 10 μl and was intrathecally administrated over a period of 30 s followed by 10 μl saline at the same rate to flush the catheter. Each antagonist was mixed with milnacipran and they were simultaneously injected into the subarachnoid space through the catheter according to a previous study (Obata et al., 2005). To examine the effect of drugs, mechanical allodynia and thermal allodynia were evaluated at four time points: just before injection, and 0.5, 1 and 2 h after intrathecal administration of each drug. "
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    ABSTRACT: Milnacipran, a reuptake inhibitor of noradrenaline (NA) and serotonin (5-HT), elicits an antiallodynic effect in rats with neuropathic pain; however, the role of NA and 5-HT receptors in the induction of the antiallodynic effect of milnacipran remains unclear. Thus, we examined the effects of prazosin as an α1 adrenoceptor antagonist, yohimbine as an α2 adrenoceptor antagonist, metergoline as a 5-HT1, 5-HT2 and 5-HT7 receptor antagonist, cyanopindolol as a 5-HT1A/1B receptor antagonist, ketanserin as a 5-HT2 receptor antagonist, and ondansetoron as a 5-HT3 receptor antagonist on the antiallodynic effect of milnacipran in neuropathic rats with chronic constriction injury (CCI). The CCI rats expressed mechanical and thermal allodynia, which was attenuated by intrathecal injection of milnacipran. Yohimbine, but not prazosin, reversed the milnacipran-induced antiallodynic effect. The antiallodynic effect of milnacipran was also reversed by metergoline, ketanserin and ondansetron, while cyanopindolol reversed the antiallodynic effect on mechanical, but not thermal stimulation. Furthermore, c-Fos expression in lamina I/II of the spinal dorsal horn was enhanced by thermal stimulation and the enhanced expression of c-Fos was suppressed by milnacipran. This effect of milnacipran was reversed by yohimbine, metergoline, katanserin and ondansetron, but not prazosin. These results indicate that the effect of milnacipran on mechanical and thermal allodynia and c-Fos expression is elicited through the α2 adrenoceptor, but not α1 adrenoceptor, and 5-HT2 and 5-HT3 receptors; furthermore, the 5-HT1A/1B receptor is involved in mechanical allodynia, but not thermal allodynia.
    European Journal of Pharmacology 05/2014; 738. DOI:10.1016/j.ejphar.2014.05.022 · 2.68 Impact Factor
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    • "Antagonist studies were performed to test whether the effect of duloxetine in the POP model is mediated through the spinal ␣2-adrenergic receptors (idazoxan) or 5-HT 2A receptor subunits (ketanserin). According to a previous study [20], 5 ␮L of saline, 30 ␮g of idazoxan or 20 ␮g of ketanserin was i.t. administered 15 min before duloxetine injection (either i.t. or i.p.) followed by a 10 ␮L saline injection to flush the catheter. "
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    ABSTRACT: One promising strategy to prevent the chronicity of post-operative pain (POP) is to attenuate acute POP during the early phase by efficacious medications with fewer side effects. Duloxetine, one of the serotonin (5-HT)-norepinephrine (NE) reuptake inhibitors (SNRI), is used to treat a wide range of acute and chronic pain. However, its effect on POP has not been investigated. In the present study, we investigated the anti-hypersensitivity effect of duloxetine using a rat model of POP. The possible involvement of spinal 5-HT2A and α2-noradrenergic receptors were also evaluated by using antagonists for 5-HT2A (ketanserin) or α2-noradrenergic receptors (idazoxan). Finally, with the method of in vivo microdialysis, the increase in spinal NA and 5-HT levels after intraperitoneal (i.p.) delivery of duloxetine were investigated. The results showed that intrathecal (i.t.) or i.p. delivery of duloxetine produced an anti-hyperalgesic effect in a dose-dependent manner. The anti-hypersensitivity effect of duloxetine was partly attenuated by pretreatment with ketanserin or idazoxane. Microdialysis study revealed that 5-HT and NA concentrations at the spinal dorsal horn were increased, peaking at 30minutes after i.p. injection of 20mg/kg duloxetine. These findings indicate that duloxetine inhibits POP by increasing spinal NA and 5-HT levels and activating spinal 5-HT2A or α2-noradrenergic receptors.
    Neuroscience Letters 03/2014; 568. DOI:10.1016/j.neulet.2014.03.046 · 2.06 Impact Factor
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    • "SNRIs have limited affinities for other receptors and ion channels tested and exhibit acceptable safety profiles (Moret et al., 1985; Bymaster et al., 2001; Lee and Chen, 2010), supporting the notion that SNRIs should be a firstline treatment for neuropathic pain (Sindrup et al., 2005). Although SNRIs exert analgesic activity when administered by various routes in neuropathic pain model animals (Iyengar et al. 2004; King et al., 2006; Suzuki et al., 2008), the spinal cord may be an important site for SNRI-induced analgesia, given that the intrathecal administration of monoamine reuptake inhibitors effectively ameliorates abnormal pain behaviours in the animal models (Shin and Eisenach, 2004; Obata et al., 2005; Honda et al., 2006; Ikeda et al., 2009). Therefore, it could be important to clarify the analgesic mechanism(s) of spinally administered SNRIs on spinal nociceptive transmission without affecting the supraspinal and peripheral regions. "
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    ABSTRACT: 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, α(2) -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.
    British Journal of Pharmacology 04/2012; 167(3):537-47. DOI:10.1111/j.1476-5381.2012.02007.x · 4.99 Impact Factor
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