Rac1-regulated dendritic spine remodeling contributes to neuropathic pain after peripheral nerve injury

Tan, Andrew M.; Chang, Yu-Wen; Zhao, Peng; Hains, Bryan C.; Waxman, Stephen G.

doi:10.1016/j.expneurol.2011.08.028

Cited by 73 publications

(84 citation statements)

References 51 publications

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“…Therefore, Rac1 inhibitors are potential cardioprotective agents for treatment of cardiac hypertrophy, atrial as well as ventricular fibrosis, and thus of atrial fibrillation and heart failure (Shen et al, 2009;Vettel et al, 2012;Ma et al, 2013). In addition to cardiac diseases, Rac1 inhibitors are thought to be beneficial and thus have been tested in vivo for a variety of other disorders (Müller et al, 2008;Shibata et al, 2008;Tan et al, 2011Tan et al, , 2012.…”

Section: Discussionmentioning

confidence: 99%

“…In cells, it blocks serum or platelet-derived growth factor-induced Rac1 activation and lamellipodia formation without affecting the activity of Cdc42 or RhoA (Gao et al, 2004). Therefore, NSC23766 is the most widely used small molecule to inhibit Rac1 activity in different cell types and, most importantly, in in vivo mouse models by injection, intrathecal catheter, or even implanted Alzet osmotic pump (Binker et al, 2008;Müller et al, 2008;Shibata et al, 2008;Shen et al, 2009;Colomba et al, 2011;Tan et al, 2011, Competitive Antagonism of NSC23766 at mAChRs 2012; Ma et al, 2013). From different studies in which NSC23766 was used to inhibit Rac1-dependent responses, IC 50 values of 50-100 mM were reported (Montalvo-Ortiz et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

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NSC23766, a Widely Used Inhibitor of Rac1 Activation, Additionally Acts as a Competitive Antagonist at Muscarinic Acetylcholine Receptors

Lévay

Krobert

Wittig

et al. 2013

J Pharmacol Exp Ther

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Small molecules interfering with Rac1 activation are considered as potential drugs and are already studied in animal models. A widely used inhibitor without reported attenuation of RhoA activity is NSC23766 [(. We found that NSC23766 inhibits the M 2 muscarinic acetylcholine receptor (M 2 mAChR)-induced Rac1 activation in neonatal rat cardiac myocytes. Surprisingly, NSC27366 concomitantly suppressed the carbachol-induced RhoA activation and a M 2 mAChR-induced inotropic response in isolated neonatal rat hearts requiring the activation of Rhodependent kinases. We therefore aimed to identify the mechanisms by which NSC23766 interferes with the differentially mediated, M 2 mAChR-induced responses. Interestingly, NSC23766 caused a rightward shift of the carbachol concentration response curve for the positive inotropic response without modifying carbachol efficacy. To analyze the specificity of NSC23766, we compared the carbachol and the similarly G i bg-mediated, adenosine-induced activation of G i protein-regulated potassium channel (GIRK) channels in human atrial myocytes. Application of NSC23766 blocked the carbachol-induced K 1 current but had no effect on the adenosine-induced GIRK current. Similarly, an adenosine A 1 receptor-induced positive inotropic response in neonatal rat hearts was not attenuated by NSC23766. To investigate its specificity toward the different mAChR types, we studied the carbachol-induced elevation of intracellular Ca 21 concentrations in human embryonic kidney 293 (HEK-293) cells expressing M 1 , M 2 , or M 3 mAChRs. NSC23766 caused a concentration-dependent rightward shift of the carbachol concentration response curves at all mAChRs. Thus, NSC23766 is not only an inhibitor of Rac1 activation, but it is within the same concentration range a competitive antagonist at mAChRs. Molecular docking analysis at M 2 and M 3 mAChR crystal structures confirmed this interpretation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

NSC23766, a Widely Used Inhibitor of Rac1 Activation, Additionally Acts as a Competitive Antagonist at Muscarinic Acetylcholine Receptors

Lévay

Krobert

Wittig

et al. 2013

J Pharmacol Exp Ther

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“…We identified WDR neurons by their response to both low-and highthreshold peripheral stimuli applied to their cutaneous receptive fields (1,27). In diabetic animals, peripheral stimulus consisting of PB, press, and pinch produced mean spike frequencies between 35 and 40 Hz (PB, 33.9 ± 10.7 Hz; press, 25.6 ± 10.0 Hz; pinch, 35.8 ± 13.4 Hz) ( Figure 3A).…”

Section: Nav13 Knockdown Reduces Nociceptive Hyperexcitability Assocmentioning

confidence: 99%

Virus-Mediated Knockdown of Nav1.3 in Dorsal Root Ganglia of STZ-Induced Diabetic Rats Alleviates Tactile Allodynia

Tan

Samad

Dib‐Hajj

et al. 2015

Mol Med

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Diabetic neuropathic pain affects a substantial number of people and represents a major public health problem. Available clinical treatments for diabetic neuropathic pain remain only partially effective and many of these treatments carry the burden of side effects or the risk of dependence. The misexpression of sodium channels within nociceptive neurons contributes to abnormal electrical activity associated with neuropathic pain. Voltage-gated sodium channel Nav1.3 produces tetrodotoxin-sensitive sodium currents with rapid repriming kinetics and has been shown to contribute to neuronal hyperexcitability and ectopic firing in injured neurons. Suppression of Nav1.3 activity can attenuate neuropathic pain induced by peripheral nerve injury. Previous studies have shown that expression of Nav1.3 is upregulated in dorsal root ganglion (DRG) neurons of diabetic rats that exhibit neuropathic pain. Here, we hypothesized that viral-mediated knockdown of Nav1.3 in painful diabetic neuropathy would reduce neuropathic pain. We used a validated recombinant adeno-associated virus (AAV)-shRNA-Nav1.3 vector to knockdown expression of Nav1.3, via a clinically applicable intrathecal injection method. Three weeks following vector administration, we observed a significant rate of transduction in DRGs of diabetic rats that concomitantly reduced neuronal excitability of dorsal horn neurons and reduced behavioral evidence of tactile allodynia. Taken together, these findings offer a novel gene therapy approach for addressing chronic diabetic neuropathic pain.

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“…[85][86][87] In adult rats, ipsilateral WDR neurons exhibited increased dendritic spine density and altered spine distribution 10 days following a chronic constriction injury of the sciatic nerve. Dendritic spine length and head diameter also increased.…”

Section: Peripheral Nerve Injurymentioning

confidence: 99%

“…Nerve-injured animals with abnormal dendritic spines also exhibited behavioral evidence of neuropathic mechanical allodynia and heat hyperalgesia. 85 Interestingly, in FMR1 knockout mice in which dendritic spine development and maturation is impaired, 88,89 peripheral nerve injury fails to increase nociceptive sensitization to the same extent as control wild-type mice. 90 The finding of dendritic spine remodeling after nerve injury suggests the existence of a putative peripheral nervous system (PNS)-to-CNS signal that chronically and adversely changes the central sensory circuit system.…”

Section: Peripheral Nerve Injurymentioning

confidence: 99%

Dendritic Spine Dysgenesis in Neuropathic Pain

Tan¹

2015

Progress in Molecular Biology and Translational Science

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Rac1-regulated dendritic spine remodeling contributes to neuropathic pain after peripheral nerve injury

Cited by 73 publications

References 51 publications

NSC23766, a Widely Used Inhibitor of Rac1 Activation, Additionally Acts as a Competitive Antagonist at Muscarinic Acetylcholine Receptors

NSC23766, a Widely Used Inhibitor of Rac1 Activation, Additionally Acts as a Competitive Antagonist at Muscarinic Acetylcholine Receptors

Virus-Mediated Knockdown of Nav1.3 in Dorsal Root Ganglia of STZ-Induced Diabetic Rats Alleviates Tactile Allodynia

Dendritic Spine Dysgenesis in Neuropathic Pain

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