Long‐term, dynamic synaptic reorganization after GABAergic precursor cell transplantation into adult mouse spinal cord

Llewellyn‐Smith, Ida J.; Basbaum, Allan I.; Bráz, Joao

doi:10.1002/cne.24346

Cited by 19 publications

(18 citation statements)

References 36 publications

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“…These medial ganglionic eminence cells integrate into the spinal cord circuitry and form GABA-A inhibitory synapses with the host, and prevent the development of nerve-injury induced mechanical hypersensitivity by synaptic release of GABA. 31,66 If these experimental results can be exported to humans, this will represent perhaps the first truly restorative treatment for neuropathic pain.…”

Section: Dorsal Horn Restorationmentioning

confidence: 99%

Contemporary concepts of pain surgery

Burchiel

Raslan

2019

Journal of Neurosurgery

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Pain surgery is one of the historic foundations of neurological surgery. The authors present a review of contemporary concepts in surgical pain management, with reference to past successes and failures, what has been learned as a subspecialty over the past 50 years, as well as a vision for current and future practice. This subspecialty confronts problems of cancer pain, nociceptive pain, and neuropathic pain. For noncancer pain, ablative procedures such as dorsal root entry zone lesions and rhizolysis for trigeminal neuralgia (TN) should continue to be practiced. Other procedures, such as medial thalamotomy, have not been proven effective and require continued study. Dorsal rhizotomy, dorsal root ganglionectomy, and neurotomy should probably be abandoned. For cancer pain, cordotomy is an important and underutilized method for pain control. Intrathecal opiate administration via an implantable system remains an important option for cancer pain management. While there are encouraging results in small case series, cingulotomy, hypophysectomy, and mesencephalotomy deserve further detailed analysis. Electrical neuromodulation is a rapidly changing discipline, and new methods such as high-frequency spinal cord stimulation (SCS), burst SCS, and dorsal root ganglion stimulation may or may not prove to be more effective than conventional SCS. Despite a history of failure, deep brain stimulation for pain may yet prove to be an effective therapy for specific pain conditions. Peripheral nerve stimulation for conditions such as occipital neuralgia and trigeminal neuropathic pain remains an option, although the quality of outcomes data is a challenge to these applications. Based on the evidence, motor cortex stimulation should be abandoned. TN is a mainstay of the surgical treatment of pain, particularly as new evidence and insights into TN emerge. Pain surgery will continue to build on this heritage, and restorative procedures will likely find a role in the armamentarium. The challenge for the future will be to acquire higher-level evidence to support the practice of surgical pain management.

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Section: Dorsal Horn Restorationmentioning

confidence: 99%

Contemporary concepts of pain surgery

Burchiel

Raslan

2019

Journal of Neurosurgery

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“…In our earlier studies, we transplanted GABAergic progenitor cells derived from the medial ganglionic eminence (MGE) into the dorsal horn of mice in which there was a profound mechanical hypersensitivity produced in different models of neuropathic pain (Braz et al , 2015 b ). The transplants not only integrated synaptically into host circuits of adult mice (Etlin et al , 2016; Llewellyn-Smith et al , 2018) in a random fashion, but also completely reversed the mechanical hypersensitivity. In the present study, we asked whether transplants into the rACC can reverse the affective component of the neuropathic pain phenotype and whether this can occur without concurrently blocking its sensory-discriminative component, namely mechanical hypersensitivity.…”

Section: Introductionmentioning

confidence: 99%

GABAergic cell transplants in the anterior cingulate cortex reduce neuropathic pain aversiveness

Juarez-Salinas¹,

Bráz²,

Etlin³

et al. 2019

Brain

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Dysfunction of inhibitory circuits in the rostral anterior cingulate cortex underlies the affective (aversive), but not the sensory-discriminative features (hypersensitivity) of the pain experience. To restore inhibitory controls, we transplanted inhibitory interneuron progenitor cells into the rostral anterior cingulate cortex in a chemotherapy-induced neuropathic pain model. The transplants integrated, exerted a GABA-A mediated inhibition of host pyramidal cells and blocked gabapentin preference (i.e. relieved ongoing pain) in a conditioned place preference paradigm. Surprisingly, pain aversiveness persisted when the transplants populated both the rostral and posterior anterior cingulate cortex. We conclude that selective and long lasting inhibition of the rostral anterior cingulate cortex, in the mouse, has a profound pain relieving effect against nerve injury-induced neuropathic pain. However, the interplay between the rostral and posterior anterior cingulate cortices must be considered when examining circuits that influence ongoing pain and pain aversiveness.

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“…Mice were perfused with phosphate-buffered 4% formaldehyde (n=3) or 4% formaldehyde plus 0.3% glutaraldehyde (n=5). Transverse or parasagittal Vibratome sections (50 μm) were processed for detection of tdTomato for either light (LM) or electron microscopic (EM) (Llewellyn-Smith, Basbaum, & Braz, 2018) examination.…”

Section: Methodsmentioning

confidence: 99%

Dorsal horn CGRP-expressing interneurons contribute to nerve injury-induced mechanical hypersensitivity

Löken¹,

Etlin²,

Bernstein³

et al. 2020

Preprint

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17 Primary sensory neurons are generally considered the only source of dorsal horn 18 calcitonin gene-related peptide (CGRP), a neuropeptide critical to the transmission of 19 pain messages. Using a tamoxifen-inducible CGRP CreER transgenic mouse, here we 20 identified a distinct population of CGRP-expressing excitatory interneurons in lamina III 21 of the spinal cord dorsal horn and trigeminal nucleus caudalis. These interneurons have 22 spine-laden, dorsally-directed, dendrites and ventrally-directed axons. Neither 23 innocuous nor noxious stimulation provoked significant Fos expression in these 24 neurons. However, synchronous, electrical non-nociceptive Aβ primary afferent 25 stimulation of dorsal roots depolarized the CGRP interneurons, consistent with their 26 receipt of a VGLUT1 innervation. In contrast, chemogenetic activation produced a 27 significant mechanical hypersensitivity. Importantly, the CGRP interneurons could be 28 activated after peripheral nerve injury, but only with concurrent innocuous, brush 29 stimulation. These findings suggest that hyperexcitability of dorsal horn CGRP

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Long‐term, dynamic synaptic reorganization after GABAergic precursor cell transplantation into adult mouse spinal cord

Cited by 19 publications

References 36 publications

Contemporary concepts of pain surgery

Contemporary concepts of pain surgery

GABAergic cell transplants in the anterior cingulate cortex reduce neuropathic pain aversiveness

Dorsal horn CGRP-expressing interneurons contribute to nerve injury-induced mechanical hypersensitivity

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