Painful Nerve Injury Shortens the Intracellular Ca2+ Signal in Axotomized Sensory Neurons of Rats

Fuchs, Andreas; Rigaud, Marcel; Hogan, Quinn H.

doi:10.1097/01.anes.0000267538.72900.68

Cited by 43 publications

(56 citation statements)

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“…Interruption of sensory activity by axotomy leads to loss of normal afferent neuronal traffic, particularly the low-threshold input into large myelinated somata. The loss of depolarization events decreases Ca 2ϩ influx through VGCC and diminishes release from intracellular stores (3,4). This is confirmed by our present results that indicate depressed [Ca 2ϩ ] i levels in SNL-H neurons both at rest and after ionomycin administration (Fig.…”

Section: Single-channel Properties Are Not Altered By Painful Nerve Isupporting

confidence: 90%

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Suppressed Ca ²⁺ /CaM/CaMKII-dependent K _ATP channel activity in primary afferent neurons mediates hyperalgesia after axotomy

Kawano

Zoga

Gemes

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Painful axotomy decreases KATP channel current (IKATP) in primary afferent neurons. Because cytosolic Ca 2؉ signaling is depressed in injured dorsal root ganglia (DRG) neurons, we investigated whether Ca 2؉ -calmodulin (CaM)-Ca 2؉ /CaM-dependent kinase II (CaMKII) regulates IK ATP in large DRG neurons. Immunohistochemistry identified the presence of K ATP channel subunits SUR1, SUR2, and Kir6.2 but not Kir6.1, and pCaMKII in neurofilament 200 -positive DRG somata. Single-channel recordings from cell-attached patches revealed that basal and evoked IK ATP by ionomycin, a Ca 2؉ ionophore, is activated by CaMKII. In axotomized neurons from rats made hyperalgesic by spinal nerve ligation (SNL), basal K ATP channel activity was decreased, and sensitivity to ionomycin was abolished. Basal and Ca 2؉ -evoked K ATP channel activity correlated inversely with the degree of hyperalgesia induced by SNL in the rats from which the neurons were isolated. Inhibition of IK ATP by glybenclamide, a selective KATP channel inhibitor, depolarized resting membrane potential (RMP) recorded in perforated whole-cell patches and enhanced neurotransmitter release measured by amperometry. The selective K ATP channel opener diazoxide hyperpolarized the RMP and attenuated neurotransmitter release. Axotomized neurons from rats made hyperalgesic by SNL lost sensitivity to the myristoylated form of autocamtide-2-related inhibitory peptide (AIPm), a pseudosubstrate blocker of CaMKII, whereas axotomized neurons from SNL animals that failed to develop hyperalgesia showed normal IK ATP inhibition by AIPm. AIPm also depolarized RMP in control neurons via K ATP channel inhibition. Unitary current conductance and sensitivity of K ATP channels to cytosolic ATP and ligands were preserved even after painful nerve injury, thus providing opportunities for selective therapeutic targeting against neuropathic pain.calcium ͉ calmodulin ͉ potassium channels ͉ dorsal root ganglia ͉ neuropathic pain A fter peripheral nerve injury, phenotypic changes in axons and the corresponding somata in the dorsal root ganglia (DRG) lead to membrane hyperexcitability, which results in neuropathic pain (1, 2). These alterations include decreased Ca 2ϩ influx via voltage-gated calcium channels (VGCC), reduced [Ca 2ϩ ] i , and diminished Ca 2ϩ -induced Ca 2ϩ release (3, 4). Additionally, ATPsensitive potassium (K ATP ) channels in large axotomized DRG neurons from rats with hyperalgesia exhibit decreased opening (5, 6). K ATP channels in cardiac myocytes and pancreatic ␤-cells are modulated by cytosolic Ca 2ϩ (7,8), but it remains unknown whether Ca 2ϩ affects neuronal K ATP channels.Cytosolic Ca 2ϩ regulates neuronal channels and other targets via multiple mechanisms (9), including the Ca 2ϩ -calmodulin (CaM)-Ca 2ϩ /CaM-dependent kinase II (CaMKII) pathway (10). CaMKII, which is abundant in neurons (11), assembles into a dodecameric holoenzymatic structure (12, 13). Ca 2ϩ /CaM activates CaMKII subunits, triggering autophosphorylation at T286 residues (14) that increase the affinit...

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Section: Single-channel Properties Are Not Altered By Painful Nerve Isupporting

confidence: 90%

“…These alterations include decreased Ca 2ϩ influx via voltage-gated calcium channels (VGCC), reduced [Ca 2ϩ ] i , and diminished Ca 2ϩ -induced Ca 2ϩ release (3,4). Additionally, ATPsensitive potassium (K ATP ) channels in large axotomized DRG neurons from rats with hyperalgesia exhibit decreased opening (5,6).…”

mentioning

confidence: 99%

Suppressed Ca ²⁺ /CaM/CaMKII-dependent K _ATP channel activity in primary afferent neurons mediates hyperalgesia after axotomy

Kawano

Zoga

Gemes

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Indeed, the loss of I h might be considered a compensatory measure in the context of injury. While the present experiments do not indicate a mechanism by which I h in decreased after axotomy, it is possible that axotomy-induced depression of both resting levels of cytosolic Ca 2+ as well as the transient rises of Ca 2+ that accompany neuronal activation (Fuchs et al, 2005;Fuchs et al, 2007) may result in lowered activity of Ca 2+ /calmodulindependent protein kinase II, which is a regulator of I h activity (Fan et al, 2005;Rigg et al, 2003).…”

Section: Discussioncontrasting

confidence: 72%

Hyperpolarization-activated current (Ih) contributes to excitability of primary sensory neurons in rats

Hogan

Poroli

2008

Brain Research

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In various excitable tissues, the hyperpolarization-activated, cyclic nucleotide-gated current (I h ) contributes to burst firing by depolarizing the membrane after a period of hyperpolarization. Alternatively, conductance through open channels I h channels of the resting membrane may impede excitability. Since primary sensory neurons of the dorsal root ganglion show both loss of I h and elevated excitability after peripheral axonal injury, we examined the contribution of I h to excitability of these neurons. We used a sharp electrode intracellular technique to record from neurons in nondissociated ganglia to avoid potential artefacts due to tissue dissociation and cytosolic dialysis. Neurons were categorized by conduction velocity. I h induced by hyperpolarizing voltage steps was completely blocked by ZD7288 (approximately 10μM), which concurrently eliminated the depolarizing sag of transmembrane potential during hyperpolarizing current injection. I h was most prominent in rapidly conducting Aα/β neurons, in which ZD7288 produced resting membrane hyperpolarization, slowed conduction velocity, prolonged action potential (AP) duration, and elevated input resistance. The rheobase current necessary to trigger an AP was elevated and repetitive firing was inhibited by ZD7288, indicating an excitatory influence of I h . Less I h was evident in more slowly conducting Aδ neurons, resulting in diminished effects of ZD7288 on AP parameters. Repetitive firing in these neurons was also inhibited by ZD7288, and the peak frequency of AP transmission during tetanic bursts was diminished by ZD7288. Slowly conducting C-type neurons showed minimal I h , and no effect of ZD7288 on excitability was seen. After spinal nerve ligation, axotomized neurons had less I h compared to control neurons and showed minimal effects of ZD7288 application. We conclude that I h supports sensory neuron excitability, and loss of I h is not a factor contributing to increased neuronal excitability after peripheral axonal injury.

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“…The changes occurred in lesioned animals only. It is known that peripheral axonal lesion induces ectopic discharges in the primary neuron, which is related to changes of ionic channels [50,51]. In cat spinal cord, the high frequency stimulation of sciatic nerve evoked increase in monoamines concentrations [52].…”

Section: Discussionmentioning

confidence: 99%

Effect of Treadmill Exercise on Serotonin Immunoreactivity in Medullary Raphe Nuclei and Spinal Cord Following Sciatic Nerve Transection in Rats

et al. 2009

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The serotoninergic system modulates nociceptive and locomotor spinal cord circuits. Exercise improves motor function and changes dopaminergic, noradrenergic, and serotonergic central systems. However, the direct relationship between serotonin, peripheral nerve lesion and aerobic treadmill exercise has not been studied. Using immunohistochemistry and optic densitometry, this study showed that the sciatic nerve transection increased the serotoninergic immunoreactivity in neuronal cytoplasm of the magnus raphe nuclei of trained and sedentary rats. In the dorsal raphe nucleus the increase only occurred in sedentary-sham-operated rats. In the spinal cord of trained, transected rats, the ventral horn showed significant changes, while the change in dorsal horn was insignificant. Von Frey's test indicated analgesia in all exercise-trained rats. The sciatic nerve functional index indicated recovery in the trained group. Thus, both the aerobic treadmill exercise training and the nervous lesion appear to contribute to changes in serotonin immunoreactivity.

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Painful Nerve Injury Shortens the Intracellular Ca2+ Signal in Axotomized Sensory Neurons of Rats

Cited by 43 publications

References 42 publications

Suppressed Ca ²⁺ /CaM/CaMKII-dependent K _ATP channel activity in primary afferent neurons mediates hyperalgesia after axotomy

Suppressed Ca ²⁺ /CaM/CaMKII-dependent K _ATP channel activity in primary afferent neurons mediates hyperalgesia after axotomy

Hyperpolarization-activated current (Ih) contributes to excitability of primary sensory neurons in rats

Effect of Treadmill Exercise on Serotonin Immunoreactivity in Medullary Raphe Nuclei and Spinal Cord Following Sciatic Nerve Transection in Rats

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Painful Nerve Injury Shortens the Intracellular Ca2+ Signal in Axotomized Sensory Neurons of Rats

Cited by 43 publications

References 42 publications

Suppressed Ca 2+ /CaM/CaMKII-dependent K ATP channel activity in primary afferent neurons mediates hyperalgesia after axotomy

Suppressed Ca 2+ /CaM/CaMKII-dependent K ATP channel activity in primary afferent neurons mediates hyperalgesia after axotomy

Hyperpolarization-activated current (Ih) contributes to excitability of primary sensory neurons in rats

Effect of Treadmill Exercise on Serotonin Immunoreactivity in Medullary Raphe Nuclei and Spinal Cord Following Sciatic Nerve Transection in Rats

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Suppressed Ca ²⁺ /CaM/CaMKII-dependent K _ATP channel activity in primary afferent neurons mediates hyperalgesia after axotomy

Suppressed Ca ²⁺ /CaM/CaMKII-dependent K _ATP channel activity in primary afferent neurons mediates hyperalgesia after axotomy