Spinal mechanism of standard analgesics: Evaluation using mouse models of allodynia

Tsukamoto, Mina; Kiso, Tetsuo; Shimoshige, Yukinori; Aoki, Toshiaki; Matsuoka, Naoki

doi:10.1016/j.ejphar.2010.02.025

Cited by 21 publications

(10 citation statements)

References 25 publications

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“…1A). These data supported the notion that activation of spinal NMDARs by NMDA was able to evoke pain hypersensitivity in naive animals (Sato et al,2003; Shimoyama et al,2005; Kim et al,2008; Tsukamoto et al,2010).…”

Section: Resultssupporting

confidence: 82%

“…3). The doses of NMDA, KN‐93, PP2, and ifenprodil were chosen based on previous reports (Garry et al,2003; Gabra et al,2007; Slack et al,2008; Tsukamoto et al,2010) and modified according to our preliminary experiments. Before and after intrathecal drug application, 50% paw withdrawal threshold (PWT) of mice in response to von Frey filament stimulation (Stoelting, Wood Dale, IL) was measured by using the up‐down method as described previously (Chaplan et al,1994).…”

Section: Methodsmentioning

confidence: 99%

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NR2B phosphorylation at tyrosine 1472 in spinal dorsal horn contributed to N‐methyl‐D‐aspartate‐induced pain hypersensitivity in mice

Cao

Yang

et al. 2011

J of Neuroscience Research

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Calcium influx via N-methyl-D-aspartate (NMDA)-subtype glutamate receptors (NMDARs) regulates the intracellular trafficking of NMDARs, leading to long-lasting modification of NMDAR-mediated synaptic transmission that is involved in development, learning, and synaptic plasticity. The present study investigated the contribution of such NMDAR-dependent synaptic trafficking in spinal dorsal horn to the induction of pain hypersensitivity. Our data showed that direct activation of NMDARs by intrathecal NMDA application elicited pronounced mechanical allodynia in intact mice, which was concurrent with a specific increase in the abundance of NMDAR subunits NR1 and NR2B at the postsynaptic density (PSD)-enriched fraction. Selective inhibition of NR2B-containing NMDARs (NR2BR) by ifenprodil dose dependently attenuated the mechanical allodynia in NMDA-injected mice, suggesting the importance of NR2BR synaptic accumulation in NMDA-induced pain sensitization. The NR2BR redistribution at synapses after NMDA challenge was associated with a significant increase in NR2B phosphorylation at Tyr1472, a catalytic site by Src family protein tyrosine kinases (SFKs) that has been shown to prevent NR2B endocytosis. Intrathecal injection of a specific SFKs inhibitor, PP2, to block NR2B tyrosine phosphorylation eliminated NMDA-induced NR2BR synaptic expression and also attenuated the mechanical allodynia. These data suggested that activation of spinal NMDARs was able to accumulate NR2BR at synapses via SFK signaling, which might exaggerate NMDAR-dependent nociceptive transmission and contribute to NMDA-induced nociceptive behavioral hyperresponsiveness.

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Section: Resultssupporting

confidence: 82%

Section: Methodsmentioning

confidence: 99%

NR2B phosphorylation at tyrosine 1472 in spinal dorsal horn contributed to N‐methyl‐D‐aspartate‐induced pain hypersensitivity in mice

Cao

Yang

et al. 2011

J of Neuroscience Research

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“…An additional support for the minor role of noradrenaline, but a major role of 5‐HT and 5‐HT 2A receptors in both diabetic painful neuropathy and the mechanism of action of duloxetine, is the rapid and complete reversal of the anti‐allodynic effect by the 5‐HT 2A receptor antagonists. In contrast, in normal rats, duloxetine suppressed spinal hyperactivity triggered by prostaglandin E 2 , and that effect was blocked by a combination of 5‐HT 1B/1D and α 2 ‐adrenoceptor antagonists (Tsukamoto et al ., 2010), implying a role for these receptors in the antinociceptive effect of duloxetine. Although we cannot totally exclude noradrenaline or other possible mechanisms, such as blockade of Na + currents (Wang et al ., 2010), 5‐HT 1B/1D and α 2 ‐adrenoceptors (Tsukamoto et al ., 2010), from playing a role in the anti‐allodynic effect of duloxetine, our data suggest that duloxetine alleviated allodynia in diabetic rat model mainly via the indirect activation of 5‐HT 2A receptors in the spinal cord.…”

Section: Discussionmentioning

confidence: 99%

A spinal mechanism of action for duloxetine in a rat model of painful diabetic neuropathy

Mixcoatl-Zecuatl

Jolivalt²

2011

British Journal of Pharmacology

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BACKGROUND AND PURPOSEThis study was designed to clarify mechanisms responsible for the anti-allodynic effects of duloxetine in diabetes. EXPERIMENTAL APPROACHThe streptozotocin-induced diabetic rat model was used to compare the efficacy of duloxetine, 5-HT, the 5-HT2A receptor agonist [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI)] and two antagonists (ketanserin and pruvanserin) on tactile allodynia. KEY RESULTSSystemic or intrathecal injection of duloxetine alleviated tactile allodynia in diabetic rats. The effect of systemic duloxetine was reduced by intrathecal administration of ketanserin or pruvanserin, indicating participation of spinal 5-HT2A receptors in the mechanism of action of duloxetine. In contrast to spinal delivery, systemic and local peripheral injections of ketanserin or pruvanserin alleviated tactile allodynia in diabetic rats. This effect was reversed immediately after systemic or local DOI injection. CONCLUSIONS AND IMPLICATIONSThese results support the involvement of spinal 5-HT2A receptors in the ability of duloxetine to ameliorate painful diabetic neuropathy. Our data also suggest that the role of 5-HT2A receptors depends on the level of the neuraxis at which activation takes place, with peripheral activation contributing to tactile allodynia in diabetic rats, whereas spinal activation of this receptor alleviates tactile allodynia. The development of selective peripheral 5-HT2A receptor antagonists may offer a novel approach for the treatment of diabetic neuropathic pain. AbbreviationsAUC, area under the 50% PWT time curve; ECL, enhanced chemiluminescence; DOI, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride; DRG, dorsal root ganglia; i.t., intrathecal; PBS, phosphate buffered saline buffer; PWT, paw withdrawal threshold IntroductionDiabetes mellitus is an increasingly common chronic medical condition, affecting over 100 million people worldwide. Up to 60% of diabetic patients develop some form of peripheral neuropathy and around 20% will develop neuropathic pain, including spontaneous pain, paresthesia, dysethesia, hyperalgesia and allodynia (Boulton et al., 1983;Partanen et al., 1995). The current first-line treatments for painful diabetic neuropathy include anticonvulsants, tricyclic antidepressants, opioids and serotonin (5-HT) and noradrenaline reuptake inhibitors (Ziegler, 2009). Duloxetine (Cymbalta) is a 5-HT-noradrenaline reuptake inhibitor used to treat depression that also alleviates allodynia in several inflammatory and neuropathic pain models (Iyengar et al., 2004 Piesla et al., 2009;Vranken et al., 2011). Clinical studies have confirmed the efficacy of duloxetine against pain in diabetic patients (Goldstein et al., 2005;Raskin et al., 2005;Wernicke et al., 2006), and the drug has been approved by the US Food and Drug Administration for management of painful diabetic neuropathy. The sites and mechanisms of action responsible for the pain-relieving effects of duloxetine in diabetes remain unclear. Duloxetine inhibits transporters of 5-HT and n...

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“…In articular chondrocytes, ATP could stimulate the release of PGE2 via P2Y2 receptors (Berenbaum et al, 2003). And PGE2 could produce hyperalgesia and allodynia in conscious mice (Okuda-Ashitaka et al, 2006;Tsukamoto et al, 2010). Moreover, PGE2 could stimulate the intracellular Ca 21 concentration ([Ca 21 ] i ) in osteoblasts, but this [Ca 21 ] i signaling pathway was attenuated by cytokines, such as TNF-a and IL-1 (Tam et al, 1998).…”

Section: Introductionmentioning

confidence: 97%

Signaling pathways of ATP‐induced PGE2 release in spinal cord astrocytes are EGFR transactivation‐dependent

Xia

Zhu

2011

Glia

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Traumatic spinal cord injury is characterized by an immediate, irreversible loss of tissue at the lesion site, as well as a secondary expansion of tissue damage over time. Although secondary injury should, in principle, be preventable, no effective treatment options currently exist for patients with acute spinal cord injury (SCI). Excessive release of ATP by the traumatized tissue, triggers the rapid release of arachidonic acid (AA) and prostaglandin E2 (PGE2), and has beenimplicated in acute and chronic neuropathic pain and inflammation. But the intracellular pathways between ATP and PGE2 remain largely unknown. We have explored the signaling events involved in this synthesis by primarily culturing spinal cord astrocytes: (1) we determined significant PGE2 production increased by ATP is mainly via Subtype 1 of P2 purinoceptors (P2Y1) but not P2Y2; (2) we found that ATP strongly increased the level of intracellular Ca(2+) via P2Y1 receptor; (3) we indicated that ATP stimulates the definitely release of AA and PGE2 which involved the transactivation of epidermal growth factor (EGF) receptor, the phosphorylation of extracellular-regulated protein kinases 1 and 2 (ERK(1/2) ) and the activation of cytosolic phospholipase A(2) (cPLA(2) ); (4) we examined ATP could increase the phosphorylation of Akt via P2Y1 receptor which also depend on the transactivation of EGFR, but the activation of Akt has no effect on the downstream of cPLA(2) phosphorylation. ATP induced by SCI could mobilize the release of AA and PGE2. And inhibition of PGE2 release reduces behavioral signs of pain after SCI and peripheral nerve injury.

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Spinal mechanism of standard analgesics: Evaluation using mouse models of allodynia

Cited by 21 publications

References 25 publications

NR2B phosphorylation at tyrosine 1472 in spinal dorsal horn contributed to N‐methyl‐D‐aspartate‐induced pain hypersensitivity in mice

NR2B phosphorylation at tyrosine 1472 in spinal dorsal horn contributed to N‐methyl‐D‐aspartate‐induced pain hypersensitivity in mice

A spinal mechanism of action for duloxetine in a rat model of painful diabetic neuropathy

Signaling pathways of ATP‐induced PGE2 release in spinal cord astrocytes are EGFR transactivation‐dependent

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