Blocking the <scp>GABA</scp> transporter <scp>GAT</scp>‐1 ameliorates spinal <scp>GABA</scp>ergic disinhibition and neuropathic pain induced by paclitaxel

Yadav, Ruchi; Yan, Xisheng; Maixner, Dylan W.; Gao, Mei; Weng, Han‐Rong

doi:10.1111/jnc.13103

Cited by 44 publications

(64 citation statements)

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“…GAT-1 is responsible for most of the GABA uptake from the synaptic cleft in the brain (Borden, 1996; Conti et al, 1998; Jensen et al, 2003). In the same year (2015) another group also reported increased expression of GAT-1 in the spinal cord of an animal model of PINP (Yadav et al, 2015). In addition, they observed that intrathecal injection of a GAT-1 inhibitor ameliorates PINP (Yadav et al, 2015).…”

Section: Introductionmentioning

confidence: 93%

Preventative and therapeutic effects of a GABA transporter 1 inhibitor administered systemically in a mouse model of paclitaxel-induced neuropathic pain

Masocha

Parvathy

2016

PeerJ

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BackgroundThere is a dearth of drugs to manage a dose-limiting painful peripheral neuropathy induced by paclitaxel in some patients during the treatment of cancer. Gamma-aminobutyric acid transporter-1 (GAT-1) whose expression is increased in the brain and spinal cord during paclitaxel-induced neuropathic pain (PINP) might be a potential therapeutic target for managing PINP. Thus, our aim was to evaluate if systemic administration of a GAT-1 inhibitor ameliorates PINP.MethodsThe reaction latency to thermal stimuli (hot plate test; at 55 °C) and cold stimuli (cold plate test; at 4 °C) of female BALB/c mice was recorded before and after intraperitoneal treatment with paclitaxel, its vehicle, and/or a selective GAT-1 inhibitor NO-711. The effects of NO-711 on motor coordination were evaluated using the rotarod test at a constant speed of 4 rpm or accelerating mode from 4 rpm to 40 rpm over 5 min.ResultsThe coadministration of paclitaxel with NO-711 3 mg/kg prevented the development of paclitaxel-induced thermal hyperalgesia and cold allodynia at day 7 after drug treatment. NO-711 at 3 mg/kg produced antihyperalgesic activity up to 1 h and antiallodynic activity up to 2 h in mice with established paclitaxel-induced thermal hyperalgesia and cold allodynia. No motor deficits were observed with NO-711 at a dose of 3 mg/kg, whereas a higher dose 5 mg/kg caused motor impairment and reduced mean time spent on the rotarod at a constant speed of 4 rpm. However, at a rotarod accelerating mode from 4 rpm to 40 rpm over 5 min, NO-711 3 mg/kg caused motor impairment up to 1 h, but had recovered by 2 h.ConclusionsThese results show that systemic administration of the GAT-1 inhibitor NO-711 has preventative and therapeutic activity against paclitaxel-induced thermal hyperalgesia and cold allodynia. NO-711’s antiallodynic effects, but not antihyperalgesic effects, were independent of its motor impairment/sedation properties. Thus, low doses of GAT-1 inhibitors could be useful for the prevention and treatment of PINP with proper dose titration to reduce motor impairment/sedation side effects.

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Section: Introductionmentioning

confidence: 93%

Preventative and therapeutic effects of a GABA transporter 1 inhibitor administered systemically in a mouse model of paclitaxel-induced neuropathic pain

Masocha

Parvathy

2016

PeerJ

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“…Furthermore, astrocytes express GABAA and GABAB receptors (41). With expression of GABA transport, astrocytes involve in GABA uptake to regulate extracellular concentrations of GABA (42). In spare nerve injury model of neuropathic pain, GABA uptake increase with upregulation of the GABA transport 1 (GAT-1) in activated spinal astrocytes (42).…”

Section: Disinhibition Of Spinal Gabaergic Interneurons and Neuro-patmentioning

confidence: 99%

“…With expression of GABA transport, astrocytes involve in GABA uptake to regulate extracellular concentrations of GABA (42). In spare nerve injury model of neuropathic pain, GABA uptake increase with upregulation of the GABA transport 1 (GAT-1) in activated spinal astrocytes (42). In ischemic injury, activated astrocytes up-regulate the expression of GAD and GABA (43).…”

Section: Disinhibition Of Spinal Gabaergic Interneurons and Neuro-patmentioning

confidence: 99%

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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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“…However, the mechanisms underlying the increased activity of superficial dorsal horn neurons in the paclitaxel-treated mice remain unclear. Yadav et al 20) reported that paclitaxel induces the expression of γ-aminobutyric acid (GABA) transporter-1 and increases the uptake of GABA. This results in decreases in GABA levels in the synaptic clefts of spinal dorsal horn neurons.…”

Section: )mentioning

confidence: 99%

Prophylactic Administration of Aucubin Inhibits Paclitaxel-Induced Mechanical Allodynia <i>via</i> the Inhibition of Endoplasmic Reticulum Stress in Peripheral Schwann Cells

Andoh

Uta

Kato

et al. 2017

Biological & Pharmaceutical Bulletin

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Paclitaxel is a chemotherapeutic agent that causes peripheral neuropathy as its major dose-limiting side effect. However, the peripheral neuropathy is difficult to manage. A study we recently conducted showed that repetitive administration of aucubin as a prophylactic inhibits paclitaxel-induced mechanical allodynia. However, the mechanisms underlying the anti-allodynic activity of aucubin, which is a major component of Plantaginis Semen, was unclear. In addition to mechanical allodynia, aucubin inhibited spontaneous and mechanical stimuli-induced firing in spinal dorsal horn neurons; however, catalpol, a metabolite of aucubin, did not show these effects. Furthermore, paclitaxel induced the expression of CCAAT/enhancer-binding protein homologous protein, a marker of endoplasmic reticulum (ER) stress, in the sciatic nerve and a Schwann cell line (LY-PPB6 cells); however, this effect was inhibited by aucubin. These results suggest that aucubin inhibits paclitaxel-induced mechanical allodynia through the inhibition of ER stress in peripheral Schwann cells. Key words paclitaxel; mechanical allodynia; aucubin; firing; Schwann cell; stressPaclitaxel is an anti-microtubule agent originally isolated from the bark of the Pacific yew tree (Taxus brevifolia) and is wildly used to treat solid neoplasms such as breast, ovarian, and lung cancers.1,2) However, in spite of its useful anticancer effect, paclitaxel causes peripheral neuropathy, which is characterized by mechanical allodynia, spontaneous pain, shooting and burning pain, tingling, and numbness, with a stocking-and-glove distribution.3) The peripheral neuropathy is a major dose-limiting side effect, which disturbs cancer treatment with paclitaxel. Therefore, relief of the neuropathy is very important for improving both the QOL and cancer treatment with paclitaxel. Several drugs, including gabapentin and amifostine, have failed to relieve paclitaxel-induced peripheral neuropathy [4][5][6] ; therefore, alternative therapeutic agents are need.Goshajinkigan is a traditional herbal formulation that consists of 10 herbal medicines (Rehmanniae Radix, Achyranthis Radix, Corni Fructus, Dioscoreae Rhizoma, Plantaginis Semen, Alismatis Rhizoma, Poria, Moutan Cortex, Cinnamoni Cortex, and Processi Aconiti Radix). It has been shown to attenuate the progression of peripheral neuropathy induced by docetaxel and paclitaxel/carboplatin treatments in cancer patients.7,8) Our previous study has been shown that repetitive administration of goshajinkigan extract as a prophylactic inhibits the exacerbation of paclitaxel-induced mechanical allodynia in mice.9) We also showed that aucubin, which is an iridoid glycoside and the main component of Plantaginis Semen, plays an important role in the anti-allodynic action of goshajinkigan.10) However, the mechanisms underlying the anti-allodynic activity of aucubin are not understood completely. It was reported in a previous study that paclitaxel decreased peripheral blood flow and induced mechanical allodynia in mice.11) The study also demonstra...

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Blocking the GABA transporter GAT‐1 ameliorates spinal GABAergic disinhibition and neuropathic pain induced by paclitaxel

Cited by 44 publications

References 83 publications

Preventative and therapeutic effects of a GABA transporter 1 inhibitor administered systemically in a mouse model of paclitaxel-induced neuropathic pain

Preventative and therapeutic effects of a GABA transporter 1 inhibitor administered systemically in a mouse model of paclitaxel-induced neuropathic pain

The Inhibitory Neuronal Circuit of Spinal Cord in Neuropathic Pain

Prophylactic Administration of Aucubin Inhibits Paclitaxel-Induced Mechanical Allodynia <i>via</i> the Inhibition of Endoplasmic Reticulum Stress in Peripheral Schwann Cells

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