Involvement of spinal tyrosine kinase in inflammatory and N-methyl-d-aspartate-induced hyperalgesia in rats

Sato, Eiru; Takano, Yoshito; Kuno, Y; Takano, Manami; Satō, Isao

doi:10.1016/s0014-2999(03)01718-7

Cited by 16 publications

(13 citation statements)

References 42 publications

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“…In contrast to the neuropathic pain model, neither SFK activation nor Lyn upregulation in spinal microglia was observed in the inflammatory pain model caused by CFA. However, studies have shown that inhibitors of SFKs reduce inflammatory pain behaviors (Guo et al, 2002;Sato et al, 2003). Considering our evidence of a lack of any change in the CFA-induced inflammatory pain in lyn 2/2 mice compared with wild-type mice, it is conceivable that SFKs other than Lyn might be involved in inflammatory pain.…”

Section: Discussionmentioning

confidence: 74%

Lyn tyrosine kinase is required for P2X₄ receptor upregulation and neuropathic pain after peripheral nerve injury

Tsuda

Tozaki‐Saitoh

Masuda

et al. 2007

Glia

102

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Neuropathic pain, a debilitating chronic pain following nerve damage, is a reflection of the aberrant functioning of a pathologically altered nervous system. One hallmark is abnormal pain hypersensitivity to innocuous stimuli (tactile allodynia), for which effective therapy is lacking, and the underlying mechanisms of which remain to be determined. Here we show that Lyn, a member of the Src family kinases (SFKs), plays an important role in the pathogenesis of neuropathic pain. Nerve injury, but not peripheral inflammation, increased immunoreactivity for active SFKs that were autophosphorylated in the kinase domain (phospho-SFK-IR) in spinal microglia. In spinally derived microglial cells, we identified Lyn as the predominant SFK among the five members (Src, Fyn, Yes, Lck, and Lyn) known to be expressed in the CNS. Lyn expression in the spinal cord was highly restricted to microglia, and its level was increased after nerve injury. We found that mice lacking lyn (lyn(-/-)) exhibit a striking reduction in the levels of phospho-SFK-IR and tactile allodynia after nerve injury, without any change in basal mechanical sensitivity or inflammatory pain. Importantly, lyn(-/-) mice displayed impaired upregulation of the ionotropic ATP receptor subtype P2X(4) receptors (P2X(4)R) in the spinal cord after nerve injury, which is crucial for tactile allodynia. Microglial cells from lyn(-/-) mice showed a deficit in their ability to increase P2X(4)R expression in response to fibronectin, a factor implicated as a microglial P2X(4)R upregulator in allodynia. Together, our findings suggest that Lyn may be a critical kinase mediating nerve injury-induced P2X(4)R upregulation and neuropathic pain.

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Section: Discussionmentioning

confidence: 74%

Lyn tyrosine kinase is required for P2X₄ receptor upregulation and neuropathic pain after peripheral nerve injury

Tsuda

Tozaki‐Saitoh

Masuda

et al. 2007

Glia

102

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“…Central sensitization by formalin is known to require activation of spinal NMDA receptors (Haley et al, 1990; Dickenson and Sullivan, 1991). In addition, direct intrathecal delivery of NMDA ligand (5–50 mM) sensitizes dorsal horn neurons and produces spontaneous nociceptive behaviors in intact rats (Raigorodsky and Urca, 1987; Dougherty et al, 1992; Bjorkman et al, 1994; Menendez et al, 1997; Alvarez-Vega et al, 2000; Sato et al, 2003; Kim et al, 2008; Roh et al, 2009). …”

Section: Resultsmentioning

confidence: 99%

Central nociceptive sensitization vs. spinal cord training: opposing forms of plasticity that dictate function after complete spinal cord injury

Ferguson¹,

Huie²,

Crown³

et al. 2012

Front. Physio.

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The spinal cord demonstrates several forms of plasticity that resemble brain-dependent learning and memory. Among the most studied form of spinal plasticity is spinal memory for noxious (nociceptive) stimulation. Numerous papers have described central pain as a spinally-stored memory that enhances future responses to cutaneous stimulation. This phenomenon, known as central sensitization, has broad relevance to a range of pathological conditions. Work from the spinal cord injury (SCI) field indicates that the lumbar spinal cord demonstrates several other forms of plasticity, including formal learning and memory. After complete thoracic SCI, the lumbar spinal cord can be trained by delivering stimulation to the hindleg when the leg is extended. In the presence of this response-contingent stimulation the spinal cord rapidly learns to hold the leg in a flexed position, a centrally mediated effect that meets the formal criteria for instrumental (response-outcome) learning. Instrumental flexion training produces a central change in spinal plasticity that enables future spinal learning on both the ipsilateral and contralateral leg. However, if stimulation is given in a response-independent manner, the spinal cord develops central maladaptive plasticity that undermines future spinal learning on both legs. The present paper tests for interactions between spinal cord training and central nociceptive sensitization after complete spinal cord transection. We found that spinal training alters future central sensitization by intradermal formalin (24 h post-training). Conversely intradermal formalin impaired future spinal learning (24 h post-injection). Because formalin-induced central sensitization has been shown to involve NMDA receptor activation, we tested whether pre-treatment with NMDA would also affect spinal learning in manner similar to formalin. We found intrathecal NMDA impaired learning in a dose-dependent fashion, and that this effect endures for at least 24 h. These data provide strong evidence for an opposing relationship between nociceptive plasticity and use-dependent learning in the spinal cord. The present work has clinical implications given recent findings that adaptive spinal training improves recovery in humans with SCI. Nociception below the SCI may undermine this rehabilitation potential.

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“…147 As in CA1, NMDARs in dorsal horn neurons are regulated by CAK Src signaling balanced by STEP activity in vitro. 1 Inhibition of SFKs in vivo delays the onset of inflammatory hyperalgesia 106 and inhibition of SFKs, PKC or group I mGluRs prevents the increase in NR2B tyrosine phosphorylation. 1 Inhibition of SFKs in vivo delays the onset of inflammatory hyperalgesia 106 and inhibition of SFKs, PKC or group I mGluRs prevents the increase in NR2B tyrosine phosphorylation.…”

Section: Painmentioning

confidence: 99%

Regulation of NMDA Receptors by Kinases and Phosphatases

Pitcher¹,

Kalia²,

Liu³

et al. 2008

Biology of the NMDA Receptor

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Involvement of spinal tyrosine kinase in inflammatory and N-methyl-d-aspartate-induced hyperalgesia in rats

Cited by 16 publications

References 42 publications

Lyn tyrosine kinase is required for P2X₄ receptor upregulation and neuropathic pain after peripheral nerve injury

Lyn tyrosine kinase is required for P2X₄ receptor upregulation and neuropathic pain after peripheral nerve injury

Central nociceptive sensitization vs. spinal cord training: opposing forms of plasticity that dictate function after complete spinal cord injury

Regulation of NMDA Receptors by Kinases and Phosphatases

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Involvement of spinal tyrosine kinase in inflammatory and N-methyl-d-aspartate-induced hyperalgesia in rats

Cited by 16 publications

References 42 publications

Lyn tyrosine kinase is required for P2X4 receptor upregulation and neuropathic pain after peripheral nerve injury

Lyn tyrosine kinase is required for P2X4 receptor upregulation and neuropathic pain after peripheral nerve injury

Central nociceptive sensitization vs. spinal cord training: opposing forms of plasticity that dictate function after complete spinal cord injury

Regulation of NMDA Receptors by Kinases and Phosphatases

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Lyn tyrosine kinase is required for P2X₄ receptor upregulation and neuropathic pain after peripheral nerve injury

Lyn tyrosine kinase is required for P2X₄ receptor upregulation and neuropathic pain after peripheral nerve injury