Analgesic effect of milnacipran is associated with c-Fos expression in the anterior cingulate cortex in the rat neuropathic pain model

Takeda, Ryuichiro; Watanabe, Yûko; Ikeda, Tetsuya; Abe, Hiroshi; Ebihara, Kosuke; Matsuo, Hitoshi; Nonaka, Hiroi; Hashiguchi, Hiroyuki; Nishimori, Toshikazu; Ishida, Yoshiteru

doi:10.1016/j.neures.2009.04.010

Cited by 33 publications

(24 citation statements)

References 28 publications

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“…These differences may underlie brain region and cell type-specific effects of stress and nerve injury on Cyr61 and Dusp1 expression, or may suggest that these genes play distinct roles in neuropathic pain versus chronic stress states. Moreover, we observed decreases in Fos expression in the NAc of SNI and CUS mice, and although the antidepressants imipramine (104), and milnacipran (10) enhance c-Fos expression in the PFC of rats, homozygous Fos KO mice show reduced anxiety-like behaviors (105). Nevertheless, these observations highlight the value of network-wide analysis, and the potential detrimental effects disruptions in normal gene expression (be it enhanced or decreased) may exert on normal emotional function.…”

Section: Discussionmentioning

confidence: 82%

“…Top, mPFC: Capn11 (t (16) = −2.83, p = 0.012), Capn2 (t (10) = −0.02, p = 0.669), Capn1 (t (10) = 1.44, p = 0.168), Btg2 (t (10) = 2.35, p = 0.041), Cyr61 (t (10) = 2.48, p = 0.033), Tph2 (t (10) = 2.61, p = 0.037), Dusp1 (t (14) = 4.27, p < 0.001), F2rl1 (t (10) = −1.28, p = 0.23. Middle, NAc: Capn11 (t (10) = −3.06, p = 0.012), Capn2 (t (10) = 0.61, p = 0.558), Capn1 (t (10) = −0.15, p = 0.883), Btg2 (t (10) = 4.14, p = 0.002), Ccl3 (t (10) = −2.26, p = 0.048), Cyp2e1 (t (12) = 2.54, p = 0.026), Fos (t (10) = 4.57, p = 0.001), Oacyl (t (10) = 3.27, p = 008). Bottom, PAG: Capn11 (t (12) = −4.15, p < 0.001), Capn2( t (10) = −0.91, p = 0.383), Capn1 (t (10) = −0.36, p = 0.727), Mt1 (t (10) = −6.14, p < 0.001), Slc17a8 (t (10) = 3.12, p = 0.011), Sgk1 (t (10) = −3.03, p = 0.013), Vgf (t (14) = − 4.15, p < 0.001), Pde6g (t (10) = −0.92, p= 0.380).…”

Section: Figmentioning

confidence: 99%

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Neuropathic pain promotes adaptive changes in gene expression in brain networks involved in stress and depression

et al. 2017

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Neuropathic pain is a complex chronic condition characterized by a wide range of sensory, cognitive, and affective symptoms. A large percentage of neuropathic pain patients are also afflicted with depression and anxiety disorders – a pattern that is reliably replicated in animal models. Furthermore, clinical and preclinical studies indicate that chronic pain corresponds with adaptations in several brain networks involved in mood, motivation, and reward. Chronic stress is also a major risk factor for depression. We investigated whether chronic pain and stress affect similar mechanisms, and whether chronic pain can affect gene expression patterns known to be involved in depression. Using two mouse models for neuropathic pain and depression (spared nerve injury (SNI) and chronic unpredictable stress (CUS)) we performed next generation RNA-sequencing and pathway analysis to monitor changes in gene expression in the nucleus accumbens (NAc), the medial prefrontal cortex (mPFC), and the periaqueductal grey (PAG). These three brain regions are implicated in the pathophysiology of depression and in the modulation of pain. In addition to finding unique transcriptome profiles across the three brain regions,.we identified a substantial number of signaling pathway-associated genes with similar changes in expression in both SNI and CUS mice. Many of these genes have been implicated in depression, anxiety and chronic pain in patients. Our study provides a resource of the changes in gene expression induced by long-term neuropathic pain in three distinct brain regions and reveals molecular connections between pain and chronic stress.

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Section: Discussionmentioning

confidence: 82%

Section: Figmentioning

confidence: 99%

Neuropathic pain promotes adaptive changes in gene expression in brain networks involved in stress and depression

et al. 2017

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“…These changes occur through both presynaptic glutamate and postsynaptic AMPA alterations, mediated by adenyl cyclase [104]. Increased expression of the c-Fos gene (a marker for noxious stimuli activated neurons) has been correlated with persistent pain, which is blocked by SNRI medications [105]. Persistent pain models also demonstrate a decrease in ACC cannabinoid 1 receptor sensitivity rather than a decrease in number of receptors [106].…”

Section: Cingulate Cortexmentioning

confidence: 99%

The Neurobiology of Pain Perception in Normal and Persistent Pain

2015

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Pain is a significant national burden in terms of patient suffering, expenditure and lost productivity. Understanding pain is fundamental to improving evaluation, treatment and innovation in the management of acute and persistent pain syndromes. Pain perception begins in the periphery, and then ascends in several tracts, relaying at different levels. Pain signals arrive in the thalamus and midbrain structures which form the pain neuromatrix, a constantly shifting set of networks and connections that determine conscious perception. Several cortical regions become active simultaneously during pain perception; activity in the cortical pain matrix evolves over time to produce a complex pain perception network. Dysfunction at any level has the potential to produce unregulated, persistent pain.

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“…Normalisation of ACC hyperperfusion following treatment could be explained by activation of the endogenous opioid system. In terms of duloxetine-specific factors, in ACC, the expression of c-Fos, a useful parameter of pain,37 38 was found to be inhibited by administering serotonin-norepinephrine reuptake inhibitor (SNRI) milnacipran 39. SNRI administration was also associated with a reduction in pain scores and decrease in the functional connectivity between the rostral ACC and insula in patients with fibromyalgia 40.…”

Section: Discussionmentioning

confidence: 99%

Altered cerebral blood flow in the anterior cingulate cortex is associated with neuropathic pain

Watanabe

Hirano

Kojima

et al. 2018

J Neurol Neurosurg Psychiatry

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ObjectiveTo assess the cerebral blood flow (CBF) in patients with diabetic neuropathic pain, and its changes after duloxetine therapy.MethodsUsing iodine-123-N-isopropyl-p-iodoamphetamine single-photon emission computed tomography (IMP-SPECT), we performed a cross-sectional study of 44 patients with diabetes, and compared CBF in those with (n = 24) and without neuropathic pain (n = 20). In patients with neuropathic pain, we also longitudinally assessed changes in CBF 3 months after treatment with duloxetine.ResultsIMP-SPECT with voxel-based analyses showed a significant increase in cerebral blood flow in the right anterior cingulate cortex and a decrease in the left ventral striatum in patients with neuropathic pain, compared with those without pain. After duloxetine treatment, volume of interest analyses revealed a decrease in cerebral blood flow in the anterior cingulate cortex in patients with significant pain relief but not in non-responders. Furthermore, voxel-based whole brain correlation analyses demonstrated that greater baseline CBF in the anterior cingulate cortex was associated with better pain relief on the numerical rating scale.ConclusionsOur results suggest that the development of neuropathic pain is associated with increased activity in the anterior cingulate cortex, and greater baseline activation of this region may predict treatment responsiveness to pharmacological intervention.Trial registration numberUMIN000017130;Results.

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Analgesic effect of milnacipran is associated with c-Fos expression in the anterior cingulate cortex in the rat neuropathic pain model

Cited by 33 publications

References 28 publications

Neuropathic pain promotes adaptive changes in gene expression in brain networks involved in stress and depression

Neuropathic pain promotes adaptive changes in gene expression in brain networks involved in stress and depression

The Neurobiology of Pain Perception in Normal and Persistent Pain

Altered cerebral blood flow in the anterior cingulate cortex is associated with neuropathic pain

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