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: 1.94). 11/2008; 63(1):42-6. DOI: 10.1016/j.neures.2008.10.002
Source: PubMed


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
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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.
    Full-text · Article · May 2014 · European Journal of Pharmacology
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    • "Our protocol for DRN 5-HT neuron photostimulation in behaving mice (20 Hz for 12 seconds) evoked robust decreases in behavioral responses to hind paw stimulation. Previous observations have shown that chronic elevation of 5-HT levels can increase response thresholds in rodent models of mechanical allodynia [35]–[37]. Our result extends this observation by showing that a similar effect can be reversibly induced on a faster timescale in non-pathological conditions by recruiting DRN 5-HT neurons. "
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    ABSTRACT: The inhibition of sensory responsivity is considered a core serotonin function, yet this hypothesis lacks direct support due to methodological obstacles. We adapted an optogenetic approach to induce acute, robust and specific firing of dorsal raphe serotonergic neurons. In vitro, the responsiveness of individual dorsal raphe serotonergic neurons to trains of light pulses varied with frequency and intensity as well as between cells, and the photostimulation protocol was therefore adjusted to maximize their overall output rate. In vivo, the photoactivation of dorsal raphe serotonergic neurons gave rise to a prominent light-evoked field response that displayed some sensitivity to a 5-HT1A agonist, consistent with autoreceptor inhibition of raphe neurons. In behaving mice, the photostimulation of dorsal raphe serotonergic neurons produced a rapid and reversible decrease in the animals' responses to plantar stimulation, providing a new level of evidence that serotonin gates sensory-driven responses.
    Full-text · Article · Aug 2013 · PLoS ONE
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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.
    Full-text · Article · Jan 2013 · Brain research
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