Distribution of the Tetrodotoxin-Resistant Sodium Channel PN3 in Rat Sensory Neurons in Normal and Neuropathic Conditions

Novaković, Sanja D.; Tzoumaka, Elda; McGivern, Joseph G.; Haraguchi, Miki; Sangameswaran, Lakshmi; Gogas, Kathleen R.; Eglen, Richard M.; Hunter, John C.

doi:10.1523/jneurosci.18-06-02174.1998

Cited by 344 publications

(195 citation statements)

References 58 publications

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“…7) could result from the effect of cyclic GMP on TTX-R I Na rather than K ATP . However, TTX-R sodium channels are expressed in ∼80% of the small diameter sensory neurons (Novakovic et al 1998;Dib-Hajj et al 1998). If the actions of cyclic GMP were on TTX-R I Na only, then we would have expected to encounter ∼80% of the neurons to be sensitive to the inhibitory effects of cyclic GMP whereas we found that the sensitization produced by PGE 2 was reversed by 8-Br cyclic GMP in ∼50% of the small to medium diameter neurons (11 of 21).…”

Section: Discussionmentioning

confidence: 70%

“…K ATP channels, originally identified in cardiac myocytes (Noma 1983), are also present in the central nervous system (Amoroso et al 1990;Murphy and Greenfield 1991;Li and Henry 1992;Ohno-Shosaku and Yamamoto 1992). The K ATP channel is an octomeric complex composed of either the Kir6.1 or Kir6.2 channel subunits and sulphonylurea regulatory subunits (SUR) (Inagaki et al 1996;Aguilar-Bryan et al 1998;Ashcroft and Gribble 1998;Babenko et al 1998).…”

Section: Introductionmentioning

confidence: 99%

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ATP-sensitive potassium currents reduce the PGE2-mediated enhancement of excitability in adult rat sensory neurons

2007

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Behavioral studies have shown that the hyperalgesia arising from inflammatory agents, such as prostaglandin E 2 (PGE 2 ) can be antagonized by activators of the ATP-sensitive potassium current (K ATP ). This observation raises questions as to whether this suppression results from a direct action on sensory neurons and what are the cellular mechanisms giving rise to this inhibition. We found that small to medium diameter sensory neurons isolated from the L4-6 DRGs expressed the mRNAs for Kir6.1, Kir6.2, and SUR1. In perforated-patch clamp recordings from acutely dissociated sensory neurons from the young adult rat, exposure to 300 μM diazoxide, a K ATP channel agonist, significantly hyperpolarized the resting membrane potential, reduced the number of action potentials evoked by a ramp of depolarizing current, and increased the amplitude of inward K ATP currents evoked by the voltage ramp. Similar results were obtained with the protonophore FCCP, which is known to reduce the levels of intracellular ATP and lead to the activation of K ATP . Only a subpopulation of sensory neurons was sensitive to diazoxide whereas other neurons were unaffected. Treatment with 1 μM PGE 2 significantly enhanced the excitability of these small to medium diameter capsaicin-sensitive sensory neurons; this enhancement was reversed by subsequent exposure to diazoxide in a subpopulation of neurons. Similar to diazoxide, exposure to 8-Br-cyclic GMP antagonized the PGE 2 -induced increase in excitability. The effects of 8-Br-cyclic GMP could be reversed by exposure to glibenclamide, an antagonist of K ATP channels. As with diazoxide, only a subpopulation of sensory neurons were affected by 8-Br-cyclic GMP. These results demonstrate that activation of K ATP can reverse the sensitization produced by PGE 2 and may be an important means to modulate the enhanced excitability that results from inflammatory or injury conditions.

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Section: Discussionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

ATP-sensitive potassium currents reduce the PGE2-mediated enhancement of excitability in adult rat sensory neurons

2007

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“…The number of ATF3-immunoreactive (IR) neurons and total neurons were counted at 4009 magnification using a counting grid. DRG neurons were classified as small (\700 lm 2 ) and large ([700 lm 2 ) according to the measured cross-sectional area [13,14]. Positive or negative staining was blinded and observed by three orthopedic hand surgeons.…”

Section: Immunohistochemistry For Atf3 (A Marker Of Drg Neuron Activamentioning

confidence: 99%

Expression of activating transcription factor 3 (ATF3) in uninjured dorsal root ganglion neurons in a lower trunk avulsion pain model in rats

et al. 2013

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Purpose Clinically, neuropathic pain is frequent and intense following brachial plexus injury. It is thought that brachial plexus pain is not generated by avulsed roots, but rather by non-avulsed roots, since the avulsed root could not possibly transmit action potentials to central nerves. The aim of this study was to evaluate pain behavior and activation of sensory neurons in a brachial plexus avulsion (BPA) model in rats. Methods Fifteen male Wistar rats were used. In the BPA group, the C8-T1 roots were avulsed from the spinal cord with forceps at the lower trunk level (n = 5). In the naïve group, rats did not receive any procedures (n = 5). In the sham-operated group, the lower trunk was simply exposed (n = 5). Mechanical hyperalgesia of forelimbs corresponding to C6 and C7 dermatomes was measured using von Frey filaments every third day for 3 weeks. Activation of DRG neurons was immunohistochemically examined using anti-ATF3 (a marker for neuron activation) antibodies 21 days after surgery. Von Frey and immunohistochemical data between groups were analyzed using a Kruskal-Wallis test, followed by Mann-Whitney U tests. Bonferroni corrections were performed. Results Animals in the BPA group displayed significant mechanical hyperalgesia at the dermatome innervated by uninjured nerves continuing through day 21 compared with animals in the sham-operated group. ATF3-immunoreactive small and large DRG neurons were significantly activated in the BPA group (10.6 ± 9.5 and 5.2 ± 4.1 %, 39.7 ± 6.7 and 25.2 ± 10.3 %, 78.0 ± 9.1 and 53.7 ± 29.3 %) compared with the sham-operated group (0.7 ± 0.9 and 0 ± 0 %, 2.8 ± 2.0 and 1.0 ± 2.0 %, 3.9 ± 2.7 and 8.6 ± 10.1 %) at every level of C5, 6, and 7. In the naïve group, no DRG neurons were activated. ATF3-immunoreactive small and large DRG neurons were significantly activated at the level of C7 compared with C6 and C5, and significantly activated at the level of C6 compared with C5 in the BPA group. Conclusions Expression of ATF3 in uninjured DRG neurons may contribute to pain following brachial plexus avulsion injury. Consequently, spared spinal sensory nerves may represent therapeutic targets for treatment of this pain.

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“…The development of hyperalgesia and allodynia in nerve ligation models is reduced with Na v 1.8 antisense treatment (Porreca et al, 1999;Lai et al, 2002;Joshi et al, 2006), while ectopic firing of neurons is related to Na v 1.8 protein expression (Novakovic et al, 1998;Gold et al, 2003). Evidence of a direct role of Na v 1.9 in the development of thermal and mechanical hyperalgesia is lacking in rats with neuropathic pain states (Porecca et al, 1999;Priest et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Reported alterations in the expression of both Na v 1.8 and Na v 1.9 in response to chronic constriction injury (CCI) are conflicting (Novakovic et al, 1998;Dib-Hajj et al, 1999;Decosterd et al, 2002), and the channels respond differently to inflammation (Tanaka et al, 1998;Black et al, 2004;Gould et al, 2004). This may be due to the complexity of the CCI model which produces preferential axotomy of large sized DRG neurons and exposure of the remaining intact axons to an inflammatory environment (Bennett and Xie, 1988;Kajander and Bennett, 1992) with increased levels of nerve growth factor (NGF) that increase injury-induced expression of these channels Fjell et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Neurotrophin-3 significantly reduces sodium channel expression linked to neuropathic pain states

Wilson-Gerwing

Stucky

McComb

et al. 2008

Experimental Neurology

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Neuropathic pain resulting from chronic constriction injury (CCI) is critically linked to sensitization of peripheral nociceptors. Voltage gated sodium channels are major contributors to this state and their expression can be upregulated by nerve growth factor (NGF). We have previously demonstrated that neurotrophin-3 (NT-3) acts antagonistically to NGF in modulation of aspects of CCI-induced changes in trkA-associated nociceptor phenotype and thermal hyperalgesia. Thus, we hypothesized that exposure of neurons to increased levels of NT-3 would reduce expression of Na v 1.8 and Na v 1.9 in DRG neurons subject to CCI. In adult male rats, Na v 1.8 and Na v 1.9 mRNAs are expressed at high levels in predominantly small to medium size neurons. One week following CCI, there is reduced incidence of neurons expressing detectable Na v 1.8 and Na v 1.9 mRNA, but without a significant decline in mean level of neuronal expression, and similar findings observed immunohistochemically. There is also increased accumulation/redistribution of channel protein in the nerve most apparent proximal to the first constriction site. Intrathecal infusion of NT-3 significantly attenuates neuronal expression of Na v 1.8 and Na v 1.9 mRNA contralateral and most notably, ipsilateral to CCI, with a similar impact on relative protein expression at the level of the neuron and constricted nerve. We also observe reduced expression of the common neurotrophin receptor p75 in response to CCI that is not reversed by NT-3 in small to medium sized neurons and may confer an enhanced ability of NT-3 to signal via trkA, as has been previously shown in other cell types. These findings are consistent with an analgesic role for NT-3.

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Distribution of the Tetrodotoxin-Resistant Sodium Channel PN3 in Rat Sensory Neurons in Normal and Neuropathic Conditions

Cited by 344 publications

References 58 publications

ATP-sensitive potassium currents reduce the PGE2-mediated enhancement of excitability in adult rat sensory neurons

ATP-sensitive potassium currents reduce the PGE2-mediated enhancement of excitability in adult rat sensory neurons

Expression of activating transcription factor 3 (ATF3) in uninjured dorsal root ganglion neurons in a lower trunk avulsion pain model in rats

Neurotrophin-3 significantly reduces sodium channel expression linked to neuropathic pain states

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