Loose ligation of the sciatic nerve in rats elicits transient up-regulation of Homer1a gene expression in the spinal dorsal horn

Miyabe, Takako; Miletić, Gordana; Miletić, Vjekoslav

doi:10.1016/j.neulet.2006.01.011

Cited by 22 publications

(32 citation statements)

References 14 publications

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“…Injury-associated plasticity in the spinal dorsal horn is thought to underlie at least in part pain behavior following peripheral nerve injury5, and we and others have previously reported an intriguing potential role for the Homer1 isoforms in pain6,7,8. In our most recent investigation7 we observed that an early but transient up-regulation of Homer1 gene expression is associated with loose ligation of the sciatic nerve.…”

Section: Introductionmentioning

confidence: 56%

Early Changes in Homer1 Proteins in the Spinal Dorsal Horn Are Associated with Loose Ligation of the Rat Sciatic Nerve

Miletić

Driver²,

Miyabe‐Nishiwaki³

et al. 2009

Anesthesia &Amp; Analgesia

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Background Plasticity in the spinal dorsal horn is thought to underlie at least in part pain behavior following peripheral nerve injury. Homer1 proteins play an important role in synaptic plasticity through an activity-dependent remodeling of the post-synaptic density (PSD). In this study we examined the early consequences of the loose ligation of the sciatic nerve on the levels of Homer1a and Homer1b/c proteins in the PSD of spinal dorsal horn neurons. Methods Male rats were randomly assigned to control, sham-operated or ligated groups. Four hours after sciatic exposure or ligation the animals were anesthetized and euthanized. Dorsal horn ipsilateral and contralateral quadrants were homogenized and centrifuged to obtain a PSD-containing LP1 fraction. Homer1 isoforms were identified in Western immunoblots. In some animals, Homer1 small interfering RNA (siRNA), non-target siRNA, MK-801 or U-01026 were injected intrathecally before surgery to assess the effects of this treatment on the levels of Homer1 isoforms and on two signs of injury-associated pain behavior, a shift in weight-bearing distribution and thermal hyperalgesia. Results In ligated animals the protein levels of Homer1a increased and those of Homer1b/c decreased in the ipsilateral LP1 fraction of the spinal dorsal horn. In contrast, no changes were detected in the contralateral LP1 fraction of ligated animals, or either the ipsilateral or contralateral LP1 fraction of sham-operated animals. Intrathecal injections of Homer1 siRNA, but not non-target siRNA, 2h before the ligation prevented the accumulation of Homer1a and loss of Homer1b/c in the ipsilateral LP1 fraction. The same pre-treatment with Homer1 siRNA also alleviated both a shift in weight-bearing behavior and thermal hyperalgesia in the ligated animals. Intrathecal injections of MK-801 or U0126 15 min before the ligation similarly prevented the injury-associated changes in Homer1 protein levels and the behavioral signs of pain. Conclusion The ligation-associated changes in the protein levels of Homer1a and Homer 1b/c in the ipsilateral PSD of spinal dorsal horn neurons may be an important early reflection of the injury-associated plasticity that in time leads to the development of persistent pain.

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Section: Introductionmentioning

confidence: 56%

Early Changes in Homer1 Proteins in the Spinal Dorsal Horn Are Associated with Loose Ligation of the Rat Sciatic Nerve

Miletić

Driver²,

Miyabe‐Nishiwaki³

et al. 2009

Anesthesia &Amp; Analgesia

Self Cite

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“…Homer1a, a short isoform of Homer1b/c that lacks the coiled-coil structure, is an immediate early gene activated on neuronal activity and participates in remodeling synapses in an activity-dependent manner 129. Homer1a is upregulated in dorsal horn neurons after the subcutaneous injection of formalin or CFA324 as well as transiently after peripheral nerve injury 208. Factors responsible for Homer1a activation include NMDAR, ERK1/2 and Src 208,324.…”

Section: Scaffolding Proteins Synaptic Plasticity and Central Sensimentioning

confidence: 99%

“…Homer1a is upregulated in dorsal horn neurons after the subcutaneous injection of formalin or CFA324 as well as transiently after peripheral nerve injury 208. Factors responsible for Homer1a activation include NMDAR, ERK1/2 and Src 208,324. Knock-down of Homer1a increases pain-like behaviors specific to central sensitization and not those associated with peripheral sensitization,324 whereas overexpression reduced inflammatory pain-like behavior without altering basal nociception 324.…”

Section: Scaffolding Proteins Synaptic Plasticity and Central Sensimentioning

confidence: 99%

Central Sensitization: A Generator of Pain Hypersensitivity by Central Neural Plasticity

Latrémolière

Woolf

2009

The Journal of Pain

2,898

2,457

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Central sensitization represents an enhancement in the function of neurons and circuits in nociceptive pathways caused by increases in membrane excitability and synaptic efficacy as well as to reduced inhibition and is a manifestation of the remarkable plasticity of the somatosensory nervous system in response to activity, inflammation, and neural injury. The net effect of central sensitization is to recruit previously subthreshold synaptic inputs to nociceptive neurons, generating an increased or augmented action potential output: a state of facilitation, potentiation, augmentation, or amplification. Central sensitization is responsible for many of the temporal, spatial, and threshold changes in pain sensibility in acute and chronic clinical pain settings and exemplifies the fundamental contribution of the central nervous system to the generation of pain hypersensitivity. Because central sensitization results from changes in the properties of neurons in the central nervous system, the pain is no longer coupled, as acute nociceptive pain is, to the presence, intensity, or duration of noxious peripheral stimuli. Instead, central sensitization produces pain hypersensitivity by changing the sensory response elicited by normal inputs, including those that usually evoke innocuous sensations.Perspective-In this article, we review the major triggers that initiate and maintain central sensitization in healthy individuals in response to nociceptor input and in patients with inflammatory and neuropathic pain, emphasizing the fundamental contribution and multiple mechanisms of synaptic plasticity caused by changes in the density, nature, and properties of ionotropic and metabotropic glutamate receptors. KeywordsCentral sensitization; inflammatory pain; neuropathic pain; scaffolding protein; heterosynaptic facilitation Acute nociceptive pain is that physiological sensation of hurt that results from the activation of nociceptive pathways by peripheral stimuli of sufficient intensity to lead to or to threaten tissue damage (noxious stimuli). 374 Nociception, the detection of noxious stimuli, 282 is a protective process that helps prevent injury by generating both a reflex withdrawal from the stimulus and as a sensation so unpleasant that it results in complex behavioral strategies to avoid further contact with such stimuli. An additional important phenomenon that further enhances this protective function is the sensitization of the nociceptive system that occurs after repeated or particularly intense noxious stimuli, so that the threshold for its activation falls and responses to subsequent inputs are amplified. 132,376,380 In the absence of ongoing tissue injury, NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript this state of heightened sensitivity returns over time to the normal baseline, where highintensity stimuli are again required to initiate nociceptive pain; the phenomenon is long lasting but not permanent. The nociceptor-induced sensitization of the somatosensory system is adaptive in...

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“…Presynaptic functional changes after peripheral nerve injury that increase synaptic strength include alterations in the synthesis of transmitters and neuromodulators (Obata et al 2003) and in calcium channel density (Hendrich et al 2008, Li et al 2004). Postsynaptic changes involve phosphorylation of N-methyl-D-aspartate (NMDA) subunits (Ultenius et al 2006) and increased receptor density due to trafficking and enhanced synthesis of ion channels and scaffold proteins (Cheng et al 2008, Iwata et al 2007, Miyabe et al 2006, Takasusuki et al 2007, Tao et al 2003). Drugs that attenuate central sensitization by acting on calcium channel subunits to decrease transmitter release and on NMDA channels to reduce transmitter action (Chizh et al 2007; Jorum et al 2003) are effective treatment options in neuropathic pain (Dworkin et al 2007).…”

Section: Mechanisms Of Neuropathic Painmentioning

confidence: 99%

Neuropathic Pain: A Maladaptive Response of the Nervous System to Damage

Costigan

Scholz

Woolf

2009

Annu. Rev. Neurosci.

1,657

1,533

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Neuropathic pain is triggered by lesions to the somatosensory nervous system that alter its structure and function so that pain occurs spontaneously and responses to noxious and innocuous stimuli are pathologically amplified. The pain is an expression of maladaptive plasticity within the nociceptive system, a series of changes that constitute a neural disease state. Multiple alterations distributed widely across the nervous system contribute to complex pain phenotypes. These alterations include ectopic generation of action potentials, facilitation and disinhibition of synaptic transmission, loss of synaptic connectivity and formation of new synaptic circuits, and neuroimmune interactions. Although neural lesions are necessary, they are not sufficient to generate neuropathic pain; genetic polymorphisms, gender, and age all influence the risk of developing persistent pain. Treatment needs to move from merely suppressing symptoms to a disease-modifying strategy aimed at both preventing maladaptive plasticity and reducing intrinsic risk.

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Loose ligation of the sciatic nerve in rats elicits transient up-regulation of Homer1a gene expression in the spinal dorsal horn

Cited by 22 publications

References 14 publications

Early Changes in Homer1 Proteins in the Spinal Dorsal Horn Are Associated with Loose Ligation of the Rat Sciatic Nerve

Early Changes in Homer1 Proteins in the Spinal Dorsal Horn Are Associated with Loose Ligation of the Rat Sciatic Nerve

Central Sensitization: A Generator of Pain Hypersensitivity by Central Neural Plasticity

Neuropathic Pain: A Maladaptive Response of the Nervous System to Damage

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