Intraspinal transplantation of GABAergic neural progenitors attenuates neuropathic pain in rats: A pharmacologic and neurophysiological evaluation

Jergová, Stanislava; Hentall, Ian D.; Gajavelli, Shyam; Varghese, Mathew S.; Sagen, Jacqueline

doi:10.1016/j.expneurol.2011.12.005

Cited by 45 publications

(56 citation statements)

References 61 publications

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“…In the spinal cord, local interneurons and descending inhibitory circuits modulate pain sensations that are processed in the superficial layers of the dorsal horn. The neurotransmitter GABA released by these interneurons plays a major role in pain modulation, as pharmacological blockade of GABA-ergic neurotransmission or deletion of specific subunits of GABA receptors in the spinal cord leads to hyperalgesia (exacerbated pain) and allodynia (Gwak et al, 2006;Jergova et al, 2012). Allodynia is a state of increased response of neurons to repetitive painful stimulation, and pain response to stimulus from skin that typically does not elicit pain (e.g.…”

Section: Gaba-ergic Cell Therapy For Relieving Neuropathic Painmentioning

confidence: 99%

“…LGE cells into the ipsilateral lumbar gray matter of the spinal cord a week after nerve constriction (Jergova et al, 2012, Table 2). Grafting into the dorsal horn of the spinal cord decreased hypersensitivity, heat hyperalgesia, cold allodynia and exaggerated neuronal firing at 1-3 weeks post-grafting.…”

Section: Gaba-ergic Cell Therapy For Relieving Neuropathic Painmentioning

confidence: 99%

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Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases

Shetty

Bates

2016

Brain Research

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Several neurological and psychiatric disorders present hyperexcitability of neurons in specific regions of the brain or spinal cord, partly because of some loss and/or dysfunction of gammaamino butyric acid positive (GABA-ergic) inhibitory interneurons. Strategies that enhance inhibitory neurotransmission in the affected brain regions may therefore ease several or most deficits linked to these disorders. This perception has incited a huge interest in testing the efficacy of GABA-ergic interneuron cell grafting into regions of the brain or spinal cord exhibiting hyperexcitability, dearth of GABA-ergic interneurons or impaired inhibitory neurotransmission, using preclinical models of neurological and psychiatric disorders. Interneuron progenitors from the embryonic ventral telencephalon capable of differentiating into diverse subclasses of interneurons have particularly received much consideration because of their ability for dispersion, migration and integration with the host neural circuitry after grafting. The goal of this review is to discuss the premise, scope and advancement of GABA-ergic cell therapy for easing neurological deficits in preclinical models of schizophrenia, chronic neuropathic pain, Alzheimer's disease and Parkinson's disease. As grafting studies in these prototypes have so far utilized either primary cells from the embryonic medial and lateral ganglionic eminences or neural progenitor cells expanded from these eminences as donor material, the proficiency of these cell types is highlighted. Moreover, future studies that are essential prior to considering the possible clinical application of these cells for the above neurological conditions are proposed. Particularly, the need for grafting studies utilizing medial ganglionic eminence-like progenitors generated from human pluripotent stem cells via directed differentiation approaches or somatic cells through direct reprogramming methods are emphasized.

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Section: Gaba-ergic Cell Therapy For Relieving Neuropathic Painmentioning

confidence: 99%

Section: Gaba-ergic Cell Therapy For Relieving Neuropathic Painmentioning

confidence: 99%

Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases

Shetty

Bates

2016

Brain Research

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“…Not surprisingly, therefore, the most common therapies for neuropathic pain rely on anti-convulsants with proven efficacy in the management of epilepsy, another condition associated with hyperexcitability. An alternative is to take a disease-modifying therapeutic approach, namely one that restores inhibitory tone by rewiring inhibitory circuits in the spinal cord [22]. Following upon the studies of Baraban et al [2] in a mouse model of epilepsy, w demonstrated that intraspinal transplantation of precursors of cortical GABAergic interneurons derived from the mouse medial ganglionic eminence (MGE) can completely reverse the mechanical hypersensitivity produced in a peripheral nerve injury model of neuropathic pain [7].…”

Section: Introductionmentioning

confidence: 99%

Transplant-mediated enhancement of spinal cord GABAergic inhibition reverses paclitaxel-induced mechanical and heat hypersensitivity

Bráz¹,

Wang²,

Guan³

et al. 2015

Pain

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Decreased spinal cord GABAergic inhibition is a major contributor to the persistent neuropathic pain that can follow peripheral nerve injury. Recently, we reported that restoring spinal cord GABAergic signaling by intraspinal transplantation of cortical precursors of GABAergic interneurons from the embryonic medial ganglionic eminence (MGE) can reverse the mechanical hypersensitivity (allodynia) that characterizes a neuropathic pain model in the mouse. Here we show that MGE cell transplants are also effective against both the mechanical allodynia and the heat hyperalgesia produced in a paclitaxel-induced, chemotherapy model of neuropathic pain. To test the necessity of GABA release by the transplants, we also studied the utility of transplanting MGE cells from mice with a deletion of VGAT, the vesicular GABA transporter. Transplants from these mice, in which GABA is synthesized but cannot be stored or released, had no effect on mechanical hypersensitivity or heat hyperalgesia in the paclitaxel model. Taken together, these results demonstrate the therapeutic potential of GABAergic precursor cell transplantation in diverse neuropathic pain models and support our contention that restoration of inhibitory controls through release of GABA from the transplants is their mode of action.

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“…Furthermore, knockout of inhibitory neurons or blockade of these neurons receptors induce allodynia and hyperalgesia (32,36). But ablating of apoptotic GABAergic interneurons or transplantation of GABAergic neural progenitors attenuates neuropathic pain in rats (32,37,38). These data suggested that inhibitory interneurons play a key role in neuropathic pain processing.…”

Section: Disinhibition Of Spinal Gabaergic Interneurons and Neuro-patmentioning

confidence: 98%

“…Several possible mechanisms have been proposed for the disinhibition of inhibitory interneurons in spinal dorsal cord after nerve injury. These mechanisms include loss of spinal interneurons, reduction of transmitter release, diminished activity of these cells and decreased effectiveness of inhibitory interneurons (38).…”

Section: Disinhibition Of Spinal Gabaergic Interneurons and Neuro-patmentioning

confidence: 99%

The Inhibitory Neuronal Circuit of Spinal Cord in Neuropathic Pain

Fu¹,

Wang²

2016

J Anesth Perioper Med

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Aim of review:Inhibitory interneurons, including GABAergic neurons and glycine neurons, regulate nociceptive information and non-nociceptive information in spinal dorsal horn. Emerging evidence showed that disinhibition of inhibitory interneurons of neuronal circuit in spinal dorsal horn is a pivotal mechanism of neuropathic pain after nerve injury. Method: In this view, we summarized the recent researches of the structure of inhibitory neurons in spinal dorsal horn and disinhibition of inhibitory interneurons after nerve injury and discussed the primary mechanism. Recent findings: Much progress has been made with the construction of inhibitory neuronal network in spinal dorsal horn and the dysfunction of inhibitory interneurons in these networks since inhibitory interneurons in spinal dorsal horn firstly integrate nociceptive information and non-nociceptive information from primary afferent fiber and separate non-nociceptive stimuli from nociceptive information. Disinhibitory of inhibitory interneurons underlies hyperalgesia and allodynia after nerve injury. Summary: Loss of inhibitory function of neurons in inhibitory network in the dorsal horn contributes to hyperalgesia and allodynia. The findings of these inhibitory networks provide a new evidence for preventing and curing neuropathic pain.ABSTRACT N europathic pain is a challenge for clinicians because the treatment of neuropathic pain is still unsatisfactory. Therefore, increasing understanding of the mechanisms that underlie neuropathic pain will be beneficial for the discovery of new molecular therapy targets. The gate control theory of pain is one of important mechanisms of pain. The theory is the idea that physical pain is modulated by interaction between different neurons. According to the postulate of Melzack and Wall (1), the nerve fibers project to the substantia gelatinosa (SG) of the dorsal horn and the first central transmission cells of the spinal cord. Inhibitory interneurons in the SG act as the gate and determine which signals should reach the T cells and then go further through the spinothalamic tract to reach the brain. Thus, spinal inhibitory interneurons play an important role in maintaining normal pain. Spinal dorsal horn is the first site of integration of nociceptive and nonnociceptive information within the central nervous system (CNS). Under normal physiological conditions, spinal inhibitory interneurons, including gammaaminobutyric acid (GABA) neurons and glycine neurons, form axo-axonic contacts with the termination of primary afferent fiber (PAF), exerting presynaptic inhibition control over sensory transmission. Meanwhile, these inhibitory interneurons generate postsynaptic inhibi-

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Intraspinal transplantation of GABAergic neural progenitors attenuates neuropathic pain in rats: A pharmacologic and neurophysiological evaluation

Cited by 45 publications

References 61 publications

Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases

Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases

Transplant-mediated enhancement of spinal cord GABAergic inhibition reverses paclitaxel-induced mechanical and heat hypersensitivity

The Inhibitory Neuronal Circuit of Spinal Cord in Neuropathic Pain

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