Ligation of mouse L4 and L5 spinal nerves produces robust allodynia without major motor function deficit

Ye, Gui-Lan; Savelieva, Katerina V.; Vogel, Peter; Baker, Kevin B.; Mason, S.E.; Lanthorn, Thomas H.; Rajan, Indrani

doi:10.1016/j.bbr.2014.04.039

Cited by 26 publications

(24 citation statements)

References 19 publications

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“…The AAK1 knockout mice and wild-type control mice were then tested in a SNL model commonly used to evaluate treatments for neuropathic pain (Kim and Chung, 1992; Ye et al, 2015). In this model, ligation of the L4 and L5 spinal nerves resulted in mechanical allodynia, a painful response to a normally benign tactile stimulus, which developed by 3 days postsurgery and persisted for at least 3 weeks in wild-type mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Both alleles exhibited similar phenotypes (data not shown), and the work described in this paper was carried out with the gene-targeted allele. Mice used for LP-935509 in vivo pharmacology studies were of the C57BL/6J albino strain (Ye et al, 2015). The formalin-paw test was used to assess acute and tonic nociceptive responses in mice.…”

Section: Methodsmentioning

confidence: 99%

“…Methods for mouse SNL were carried out according to the procedures devised by Kim and Chung (1992) with modifications, as published previously (Kim and Chung, 1992; Ye et al, 2015). At 5–7 weeks of age, male mice were anesthetized with isoflurane (2% at the oxygen flow rate of 1 ml/min).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain

Kostich

Hamman²,

Li³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

127

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To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor–induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain

Kostich

Hamman²,

Li³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

127

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“…Anatomically, 60%–70% spinal fibers that make up the sciatic nerve are derived from L5 segment in Sprague-Dawley rats [52, 53]. Furthermore, the study of nerve degeneration caused by spinal nerve ligation indicated that L5 is the primary contributor to the sural branches of the sciatic nerve [54], making L5 as the detection target of ChAT which is a transferase enzyme responsible for the synthesis of the excitatory neurotransmitter acetylcholine. As expected, the expression levels of ChAT in the TANES and EA groups were higher than those of the Sham group.…”

Section: Discussionmentioning

confidence: 99%

Tail Nerve Electrical Stimulation and Electro-Acupuncture Can Protect Spinal Motor Neurons and Alleviate Muscle Atrophy after Spinal Cord Transection in Rats

et al. 2017

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Spinal cord injury (SCI) often results in death of spinal neurons and atrophy of muscles which they govern. Thus, following SCI, reorganizing the lumbar spinal sensorimotor pathways is crucial to alleviate muscle atrophy. Tail nerve electrical stimulation (TANES) has been shown to activate the central pattern generator (CPG) and improve the locomotion recovery of spinal contused rats. Electroacupuncture (EA) is a traditional Chinese medical practice which has been proven to have a neural protective effect. Here, we examined the effects of TANES and EA on lumbar motor neurons and hindlimb muscle in spinal transected rats, respectively. From the third day postsurgery, rats in the TANES group were treated 5 times a week and those in the EA group were treated once every other day. Four weeks later, both TANES and EA showed a significant impact in promoting survival of lumbar motor neurons and expression of choline acetyltransferase (ChAT) and ameliorating atrophy of hindlimb muscle after SCI. Meanwhile, the expression of neurotrophin-3 (NT-3) in the same spinal cord segment was significantly increased. These findings suggest that TANES and EA can augment the expression of NT-3 in the lumbar spinal cord that appears to protect the motor neurons as well as alleviate muscle atrophy.

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“…To prepare mouse models of allodynia, peripheral nerve injury at the distal side of the dorsal root ganglion (DRG) was induced in six wild-type adult mice, as previously described5354. In brief, after mice were deeply anesthetized with 2–3% isoflurane (Foren; Abbott, Tokyo, Japan), a midline incision was made in the dorsal region of L6 to L4 and the transverse process at L5 was removed using forceps.…”

Section: Methodsmentioning

confidence: 99%

Functional brain mapping using specific sensory-circuit stimulation and a theoretical graph network analysis in mice with neuropathic allodynia

Komaki

Hikishima

Shibata

et al. 2016

Sci Rep

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Allodynia, a form of neuropathic pain, is defined as pain in response to a non-nociceptive stimulus. The brain regions responsible for pain, which are not normally activated, can be activated in allodynic mice by providing a suitable stimulus to Aβ-fibers, which transmit signals from tactile sensory fibers. Functional MRI (fMRI) can be used to objectively observe abnormal brain activation. In the present study, fMRI was conducted to investigate allodynia in mice; allodynia was generated by surgical injury at the L4 spinal nerve root, thus selectively stimulating sensory nerve fibers. In intact mice, only the primary somatosensory cortex (S1) was activated by stimulation of Aβ-fibers. Meanwhile, allodynic mice showed significantly higher BOLD signals in the anterior cingulate area (ACA) and thalamus. Using resting state fMRI, both degree and eigenvector centrality were significantly decreased in the contralateral S1, clustering coefficient and local efficiency were significantly increased in the ACA, and betweenness centrality was significantly higher in the ventral posterolateral nucleus of the thalamus. These results suggest that the observed abnormal BOLD activation is associated with defects in Aβ-fibers when Aβ-fibers in allodynic mice are selectively stimulated. The objective approach enabled by fMRI can improve our understanding of pathophysiological mechanisms and therapeutic efficacy.

show abstract

Ligation of mouse L4 and L5 spinal nerves produces robust allodynia without major motor function deficit

Cited by 26 publications

References 19 publications

Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain

Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain

Tail Nerve Electrical Stimulation and Electro-Acupuncture Can Protect Spinal Motor Neurons and Alleviate Muscle Atrophy after Spinal Cord Transection in Rats

Functional brain mapping using specific sensory-circuit stimulation and a theoretical graph network analysis in mice with neuropathic allodynia

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