Effects of intrathecal administration of newer antidepressants on mechanical allodynia in rat models of neuropathic pain

Division of Neurobiology, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan.
Neuroscience Research (Impact Factor: 2.15). 11/2008; 63(1):42-6. DOI: 10.1016/j.neures.2008.10.002
Source: PubMed

ABSTRACT Antidepressants, especially tricyclic antidepressants (TCAs) are widely used for the treatment of various types of chronic and neuropathic pain. The antinociceptive effects of TCAs are, however, complicated. Therefore, two kinds of newer antidepressants whose functions have been more fully clarified were selected, milnacipran, a serotonin and noradrenaline reuptake inhibitor (SNRI) and paroxetine and fluvoxamine, which are selective serotonin reuptake inhibitors (SSRIs). The antiallodynic effects of intrathecal administration of these newer antidepressants were examined in two rat models of neuropathic pain, chronic constriction injury (CCI) of the sciatic nerve and streptozotocin (STZ)-induced diabetic neuropathy. The antiallodynic effect of these antidepressants was evaluated using the von Frey test. The intrathecal administration of milnacipran had an antiallodynic effect in both CCI and STZ-induced diabetic rats in a dose-dependent manner. On the other hand, the intrathecal administration of either paroxetine or fluvoxamine elicited little antiallodynic effect in CCI rats, while both SSRIs had antiallodynic effects in the STZ-induced diabetic rats in a dose-dependent manner. These results indicate a considerable difference to exist in the development and/or maintenance between these two animal models of neuropathic pain and suggest that each of these three antidepressants may be effective for the treatment of diabetic neuropathic pain.

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Available from: Yasushi Ishida, Aug 15, 2015
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    • "Therefore, an increase of NA and 5-HT following administration of SNRI inhibits pain transmission at the spinal cord (Fürst, 1999; Millan, 2002; Ren and Dubner, 2002; Pertovaara, 2006; Yoshimura and Furue, 2006). Milnacipran, an SNRI, elicits an antinociceptive or antiallodynic effect in rodent models with neuropathic pain following intrathecal administration (Obata et al., 2005; King et al., 2006; Suzuki et al., 2008; Ikeda et al., 2009; Takeda et al., 2009) or systemic administration (Yokogawa et al., 2002; Önal et al., 2007; Berrocoso et al., 2011). In addition, the effect of milnacipran on patients with fibromyalgia as well as depression has been clinically evaluated (Clauw et al., 2008; Mease et al., 2009; Branco et al., 2010; Matthey et al., 2013). "
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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
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    • "Streptozotocin (STZ), an antibiotic extracted from Streptomyces achromogenes, is one of the most commonly used chemical agents to induce experimental diabetic syndrome in rodents. It is well defined that a systemic injection of STZ induces hyperalgesia to thermal, mechanical (Bishnoi et al., 2011; Christoph et al., 2010; Cunha et al., 2009; Ikeda et al., 2009) and chemical noxious stimulation of rodents hindpaw (Cunha et al., 2009; Hasanein, 2011; Pabreja et al., 2011). There is also evidence that the trigeminal nerve may be affected in diabetes mellitus (Troger et al., 1999). "
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    ABSTRACT: Peripheral neuropathy is a common complication of diabetes and is often accompanied by episodes of pain. There is evidence that diabetic neuropathy may affect the trigeminal nerve, altering the transmission of orofacial sensory information. Structural changes in the trigeminal ganglia may be involved in the development of these sensory alterations. Herein, we evaluate the development of orofacial sensory changes after streptozotocin-induced diabetes in rats, and their sensitivity to pregabalin and morphine treatments. Furthermore, stereological analysis of the trigeminal ganglia was performed. Diabetic rats showed similar responses to 1% formalin applied into the upper lip compared to normoglycemic rats on weeks 1, 2 and 4 after streptozotocin. Additionally, there was no difference in the facial mechanical threshold of normoglycemic and diabetic rats, on weeks 1 up to 5 after streptozotocin, while the paw mechanical threshold of diabetic rats was significantly reduced. In contrast, diabetic rats developed long-lasting orofacial heat and cold hyperalgesia. Moreover, stereological analyses revealed significant neuronal loss in the trigeminal ganglia of diabetic compared to normoglycemic rats. Pregabalin treatment (30mg/kg, p.o.) of diabetic rats resulted in marked and prolonged (up to 6h) reduction of heat and cold orofacial hyperalgesia. Likewise, morphine treatment (2.5mg/kg, s.c.) abolished orofacial heat and cold hyperalgesia, but its effect was significant only up to 1h after the administration. In conclusion, the results of the present study demonstrated that streptozotocin-treated rats developed long-lasting orofacial heat and cold hyperalgesia, which is more amenable to reduction by pregabalin than morphine.
    Brain research 01/2013; DOI:10.1016/j.brainres.2013.01.002
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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
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