Fyn kinase‐mediated phosphorylation of NMDA receptor NR2B subunit at Tyr1472 is essential for maintenance of neuropathic pain

Abe, Tetsuya; Matsumura, Shinji; Katano, Tayo; Mabuchi, Tamaki; Takagi, Kunio; Xu, Li; Yamamoto, Akira; Hattori, Kotaro; Yagi, Takeshi; Watanabe, Masahiko; Nakazawa, Takahiro; Yamamoto, Tadashi; Mishina, Masayoshi; Nakai, Yousuke; Ito, Seiji

doi:10.1111/j.1460-9568.2005.04340.x

Cited by 157 publications

(161 citation statements)

References 46 publications

Supporting

Mentioning

150

Contrasting

Order By: Relevance

“…We found that after peripheral nerve injury, the cells expressing p-Src, as well as p-Lck and p-Lyn, are microglia rather than neurons or astrocytes in the dorsal horn. Furthermore, a recent report showed that phosphorylation of N-methyl-Daspartate receptors by Fyn is essential for the maintenance of neuropathic pain (Abe et al, 2005). Considering that nerve injury induces a significant increase in p-Src family expression in spinal microglia, these findings suggest that other SFKs, such as Fyn or Yes, are also activated in microglia and play a role in the generation of mechanical hypersensitivity.…”

Section: Discussionmentioning

confidence: 89%

Activation of Src-Family Kinases in Spinal Microglia Contributes to Mechanical Hypersensitivity after Nerve Injury

Katsura¹,

Obata²,

Mizushima³

et al. 2006

J. Neurosci.

136

View full text Add to dashboard Cite

Hypersensitivity to mechanical stimulation is a well documented symptom of neuropathic pain, for which there is currently no effective therapy. Src-family kinases (SFKs) are involved in proliferation and differentiation and in neuronal plasticity, including long-term potentiation, learning, and memory. Here we show that activation of SFKs induced in spinal cord microglia is crucial for mechanical hypersensitivity after peripheral nerve injury. Nerve injury induced a striking increase in SFK phosphorylation in the ipsilateral dorsal horn, and SFKs were activated in hyperactive microglia but not in neurons or astrocytes. Intrathecal administration of the Src-family tyrosine kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) suppressed nerve injury-induced mechanical hypersensitivity but not heat and cold hypersensitivity. Furthermore, PP2 reversed the activation of extracellular signalregulated protein kinase (ERK), but not p38 mitogen-activated protein kinase, in spinal microglia. In contrast, there was no change in SFK phosphorylation in primary sensory neurons, and PP2 did not decrease the induction of transient receptor potential ion channel TRPV1 and TRPA1 in sensory neurons. Together, these results demonstrate that SFK activation in spinal microglia contributes to the development of mechanical hypersensitivity through the ERK pathway. Therefore, preventing the activation of the Src/ERK signaling cascade in microglia might provide a fruitful strategy for treating neuropathic pain.

show abstract

Section: Discussionmentioning

confidence: 89%

Activation of Src-Family Kinases in Spinal Microglia Contributes to Mechanical Hypersensitivity after Nerve Injury

Katsura¹,

Obata²,

Mizushima³

et al. 2006

J. Neurosci.

136

View full text Add to dashboard Cite

show abstract

“…The kinase most closely related to Src is Fyn, and PNI-induced behaviors are suppressed in Fyn null mutant mice 40 , indicating that Fyn may also be important for these behaviors. It is known that Fyn does not interact with ND2 18 and here we found that Src40-49Tat does not affect the association of Fyn with NMDARs.…”

Section: Within the Nmdar Complex Src Enhances Nmdar Function By Incmentioning

confidence: 99%

“…Src (40)(41)(42)(43)(44)(45)(46)(47)(48)(49) or sSrc (40)(41)(42)(43)(44)(45)(46)(47)(48)(49) were added to the intracellular solution for a final concentration of 0.015 mg ml −1 . Whole-cell currents were recorded with an AxoPatch 200B amplifier (Axon Instruments), digitized (20 KHz) and analyzed offline.…”

Section: Electrophysiological Recordingsmentioning

confidence: 99%

Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex

Liu

Gingrich

Vargas‐Caballero

et al. 2008

Nat Med

196

205

View full text Add to dashboard Cite

Chronic pain hypersensitivity depends upon N-methyl-D-aspartate receptors (NMDARs). However, clinical use of NMDAR blockers is limited by side effects from suppressing physiological functions of these receptors. Here we report a means to suppress pain hypersensitivity without blocking NMDARs but rather by inhibiting the binding of a key enhancer of NMDAR function, the protein tyrosine kinase Src. We show that a peptide consisting of amino acids 40-49 of Src fused to the protein transduction domain of the HIV Tat protein (Src40-49Tat) prevented pain behaviors induced by intraplantar formalin and reversed pain hypersensitivity produced by intraplantar injection of complete Freund's adjuvant or by peripheral nerve injury. Src40-49Tat had no effect on basal sensory thresholds, acute nociceptive responses, or cardiovascular, respiratory, locomotor or cognitive functions. Thus, by targeting Src-mediated enhancement of NMDARs, inflammatory and neuropathic pain are suppressed without deleterious consequences of directly blocking NMDARs, an approach that may be of broad relevance to managing chronic pain.Chronic pain is categorized as inflammatory or neuropathic, each involving neuroplastic changes leading to hypersensitivity in peripheral and central nociceptive systems 1,2 . Multiple mechanisms including increased primary afferent excitability 3 , enhanced transmission in the dorsal horn 1 , changes in gene expression 4 , aberrant neuron-glia interactions 5,6 and neuronal apoptosis 7 are implicated in hypersensitivity in chronic pain models. Abundant pre-clinical evidence indicates that N-methyl-D-aspartate receptor (NMDARs) 8 are critically involved in pain hypersensitivity 9-11 . However, pharmacological blockade of these receptors in humans is deleterious because the activity of NMDARs is essential for many important physiological functions including breathing and locomotion 9,12,13 . A crucial signaling event for NMDAR-dependent neuroplasticity, including pain hypersensitivity 1,14 , is upregulation of NMDAR currents by mechanisms including relieving Mg 2+ blockade and receptor phosphorylation 15,16 . Thus, preferentially inhibiting mechanisms which upregulate NMDARs without affecting basal channel activity represents a strategy that may suppress pain hypersensitivity without impairing key physiological functions.

show abstract

“…This ectopic activity might be driving mechanisms of central sensitization such as involving NMDA receptor phosphorylation (Abe et al, 2005;Gao et al, 2005;Ultenius et al, 2006), altered signal transduction mechanisms such as increased CaMKII activity (Dai et al, 2005), tyrosine kinases (Yang et al, 2004), a shift in the anion gradient (Coull et al, 2003;Keller et al, 2007), microglial activation (Coull et al, 2005), apoptosis (Scholz et al, 2005), decreased inhibitory mechanisms (Back et al, 2006;Idanpaan-Heikkila and Guilbaud, 1999;Kohno et al, 2005;Moore et al, 2002;Porreca et al, 1998;Scholz et al, 2005;Toda et al, 1998), and others. It is thought that this enhanced responsivity of sensory neurons in the spinal dorsal horn, termed central sensitization (Ji and Woolf, 2001;Sotgiu and Biella, 2000) or long term potentiation (Ji et al, 2003;Sandkuhler and Liu, 1998), contributes to neuropathic pain by facilitating and prolonging transmission of nociceptive information to supraspinal pain networks Sun et al, 2001).…”

Section: Contribution Of Peripheral Drive To Spontaneous Activity Of mentioning

confidence: 99%

Governing role of primary afferent drive in increased excitation of spinal nociceptive neurons in a model of sciatic neuropathy

Pitcher

Henry

2008

Experimental Neurology

View full text Add to dashboard Cite

Previously we reported that the cuff model of peripheral neuropathy, in which a 2 mm polyethylene tube is implanted around the sciatic nerve, exhibits aspects of neuropathic pain behavior in rats similar to those in humans and causes robust hyperexcitation of spinal nociceptive dorsal horn neurons. The mechanisms mediating this increased excitation are not known and remain a key unresolved question in models of peripheral neuropathy. In anesthetized adult male Sprague-Dawley rats 2-6 weeks after cuff implantation we found that elevated discharge rate of single lumbar (L 3-4 ) wide dynamic range (WDR) neurons persists despite acute spinal transection (T9) but is reversed by local conduction block of the cuff-implanted sciatic nerve; lidocaine applied distal to the cuff (i.e. between the cuff and the cutaneous receptive field) decreased spontaneous baseline discharge of WDR dorsal horn neurons ~40% (n=18) and when applied subsequently proximal to the cuff, i.e. between the cuff and the spinal cord, it further reduced spontaneous discharge by ~60% (n=19; P<0.05 proximal vs. distal) to a level that was not significantly different from that of naive rats. Furthermore, in cuff-implanted rats WDR neurons (n=5) responded to mechanical cutaneous stimulation with an exaggerated afterdischarge which was reversed entirely by proximal nerve conduction block. These results demonstrate that the hyperexcited state of spinal dorsal horn neurons observed in this model of peripheral neuropathy is not maintained by tonic descending facilitatory mechanisms. Rather, on-going afferent discharges originating from the sciatic nerve distal to, at, and proximal to the cuff maintain the synapticallymediated gain in discharge of spinal dorsal horn WDR neurons and hyperresponsiveness of these neurons to cutaneous stimulation. Our findings reveal that ectopic afferent activity from multiple regions along peripheral nerves may drive CNS changes and the symptoms of pain associated with peripheral neuropathy.

show abstract

Fyn kinase‐mediated phosphorylation of NMDA receptor NR2B subunit at Tyr1472 is essential for maintenance of neuropathic pain

Cited by 157 publications

References 46 publications

Activation of Src-Family Kinases in Spinal Microglia Contributes to Mechanical Hypersensitivity after Nerve Injury

Activation of Src-Family Kinases in Spinal Microglia Contributes to Mechanical Hypersensitivity after Nerve Injury

Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex

Governing role of primary afferent drive in increased excitation of spinal nociceptive neurons in a model of sciatic neuropathy

Contact Info

Product

Resources

About