The β-lactam clavulanic acid mediates glutamate transport-sensitive pain relief in a rat model of neuropathic pain

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The β-lactam clavulanic acid mediates glutamate transport-sensitive pain relief in a rat model of neuropathic pain. / Kristensen, P J; Gegelashvili, G; Munro, G; Heegaard, A M; Bjerrum, O J.

In: European Journal of Pain, Vol. 22, No. 2, 02.2018, p. 282-294.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Kristensen, PJ, Gegelashvili, G, Munro, G, Heegaard, AM & Bjerrum, OJ 2018, 'The β-lactam clavulanic acid mediates glutamate transport-sensitive pain relief in a rat model of neuropathic pain', European Journal of Pain, vol. 22, no. 2, pp. 282-294. https://doi.org/10.1002/ejp.1117

APA

Kristensen, P. J., Gegelashvili, G., Munro, G., Heegaard, A. M., & Bjerrum, O. J. (2018). The β-lactam clavulanic acid mediates glutamate transport-sensitive pain relief in a rat model of neuropathic pain. European Journal of Pain, 22(2), 282-294. https://doi.org/10.1002/ejp.1117

Vancouver

Kristensen PJ, Gegelashvili G, Munro G, Heegaard AM, Bjerrum OJ. The β-lactam clavulanic acid mediates glutamate transport-sensitive pain relief in a rat model of neuropathic pain. European Journal of Pain. 2018 Feb;22(2):282-294. https://doi.org/10.1002/ejp.1117

Author

Kristensen, P J ; Gegelashvili, G ; Munro, G ; Heegaard, A M ; Bjerrum, O J. / The β-lactam clavulanic acid mediates glutamate transport-sensitive pain relief in a rat model of neuropathic pain. In: European Journal of Pain. 2018 ; Vol. 22, No. 2. pp. 282-294.

Bibtex

@article{2d0d9db3f364491aa5eb12eac6b46a61,
title = "The β-lactam clavulanic acid mediates glutamate transport-sensitive pain relief in a rat model of neuropathic pain",
abstract = "BACKGROUND: Following nerve injury, down-regulation of astroglial glutamate transporters (GluTs) with subsequent extracellular glutamate accumulation is a key factor contributing to hyperexcitability within the spinal dorsal horn. Some β-lactam antibiotics can up-regulate GluTs, one of which, ceftriaxone, displays analgesic effects in rodent chronic pain models.METHODS: Here, the antinociceptive actions of another β-lactam clavulanic acid, which possesses negligible antibiotic activity, were compared with ceftriaxone in rats with chronic constriction injury (CCI)-induced neuropathic pain. In addition, the protein expression of glutamate transporter-1 (GLT1), its splice variant GLT1b and glutamate-aspartate transporter (GLAST) was measured in the spinal cord of CCI rats. Finally, protein expression of the same GluTs was evaluated in cultured astrocytes obtained from rodents and humans.RESULTS: Repeated injection of ceftriaxone or clavulanic acid over 10 days alleviated CCI-induced mechanical hypersensitivity, whilst clavulanic acid was additionally able to affect the thermal hypersensitivity. In addition, clavulanic acid up-regulated expression of GLT1b within the spinal cord of CCI rats, whereas ceftriaxone failed to modulate expression of any GluTs in this model. However, both clavulanic acid and ceftriaxone up-regulated GLT1 expression in rat cortical and human spinal astrocyte cultures. Furthermore, clavulanic acid increased expression of GLT1b and GLAST in rat astrocytes in a dose-dependent manner.CONCLUSIONS: Thus, clavulanic acid up-regulates GluTs in cultured rodent- and human astroglia and alleviates CCI-induced hypersensitivity, most likely through up-regulation of GLT1b in spinal dorsal horn.SIGNIFICANCE: Chronic dosing of clavulanic acid alleviates neuropathic pain in rats and up-regulates glutamate transporters both in vitro and in vivo. Crucially, a similar up-regulation of glutamate transporters in human spinal astrocytes by clavulanic acid supports the development of novel β-lactam-based analgesics, devoid of antibacterial activity, for the clinical treatment of chronic pain.",
keywords = "Journal Article",
author = "Kristensen, {P J} and G Gegelashvili and G Munro and Heegaard, {A M} and Bjerrum, {O J}",
note = "{\circledC} 2017 European Pain Federation - EFIC{\circledR}.",
year = "2018",
month = "2",
doi = "10.1002/ejp.1117",
language = "English",
volume = "22",
pages = "282--294",
journal = "European Journal of Pain",
issn = "1090-3801",
publisher = "JohnWiley & Sons Ltd",
number = "2",

}

RIS

TY - JOUR

T1 - The β-lactam clavulanic acid mediates glutamate transport-sensitive pain relief in a rat model of neuropathic pain

AU - Kristensen, P J

AU - Gegelashvili, G

AU - Munro, G

AU - Heegaard, A M

AU - Bjerrum, O J

N1 - © 2017 European Pain Federation - EFIC®.

PY - 2018/2

Y1 - 2018/2

N2 - BACKGROUND: Following nerve injury, down-regulation of astroglial glutamate transporters (GluTs) with subsequent extracellular glutamate accumulation is a key factor contributing to hyperexcitability within the spinal dorsal horn. Some β-lactam antibiotics can up-regulate GluTs, one of which, ceftriaxone, displays analgesic effects in rodent chronic pain models.METHODS: Here, the antinociceptive actions of another β-lactam clavulanic acid, which possesses negligible antibiotic activity, were compared with ceftriaxone in rats with chronic constriction injury (CCI)-induced neuropathic pain. In addition, the protein expression of glutamate transporter-1 (GLT1), its splice variant GLT1b and glutamate-aspartate transporter (GLAST) was measured in the spinal cord of CCI rats. Finally, protein expression of the same GluTs was evaluated in cultured astrocytes obtained from rodents and humans.RESULTS: Repeated injection of ceftriaxone or clavulanic acid over 10 days alleviated CCI-induced mechanical hypersensitivity, whilst clavulanic acid was additionally able to affect the thermal hypersensitivity. In addition, clavulanic acid up-regulated expression of GLT1b within the spinal cord of CCI rats, whereas ceftriaxone failed to modulate expression of any GluTs in this model. However, both clavulanic acid and ceftriaxone up-regulated GLT1 expression in rat cortical and human spinal astrocyte cultures. Furthermore, clavulanic acid increased expression of GLT1b and GLAST in rat astrocytes in a dose-dependent manner.CONCLUSIONS: Thus, clavulanic acid up-regulates GluTs in cultured rodent- and human astroglia and alleviates CCI-induced hypersensitivity, most likely through up-regulation of GLT1b in spinal dorsal horn.SIGNIFICANCE: Chronic dosing of clavulanic acid alleviates neuropathic pain in rats and up-regulates glutamate transporters both in vitro and in vivo. Crucially, a similar up-regulation of glutamate transporters in human spinal astrocytes by clavulanic acid supports the development of novel β-lactam-based analgesics, devoid of antibacterial activity, for the clinical treatment of chronic pain.

AB - BACKGROUND: Following nerve injury, down-regulation of astroglial glutamate transporters (GluTs) with subsequent extracellular glutamate accumulation is a key factor contributing to hyperexcitability within the spinal dorsal horn. Some β-lactam antibiotics can up-regulate GluTs, one of which, ceftriaxone, displays analgesic effects in rodent chronic pain models.METHODS: Here, the antinociceptive actions of another β-lactam clavulanic acid, which possesses negligible antibiotic activity, were compared with ceftriaxone in rats with chronic constriction injury (CCI)-induced neuropathic pain. In addition, the protein expression of glutamate transporter-1 (GLT1), its splice variant GLT1b and glutamate-aspartate transporter (GLAST) was measured in the spinal cord of CCI rats. Finally, protein expression of the same GluTs was evaluated in cultured astrocytes obtained from rodents and humans.RESULTS: Repeated injection of ceftriaxone or clavulanic acid over 10 days alleviated CCI-induced mechanical hypersensitivity, whilst clavulanic acid was additionally able to affect the thermal hypersensitivity. In addition, clavulanic acid up-regulated expression of GLT1b within the spinal cord of CCI rats, whereas ceftriaxone failed to modulate expression of any GluTs in this model. However, both clavulanic acid and ceftriaxone up-regulated GLT1 expression in rat cortical and human spinal astrocyte cultures. Furthermore, clavulanic acid increased expression of GLT1b and GLAST in rat astrocytes in a dose-dependent manner.CONCLUSIONS: Thus, clavulanic acid up-regulates GluTs in cultured rodent- and human astroglia and alleviates CCI-induced hypersensitivity, most likely through up-regulation of GLT1b in spinal dorsal horn.SIGNIFICANCE: Chronic dosing of clavulanic acid alleviates neuropathic pain in rats and up-regulates glutamate transporters both in vitro and in vivo. Crucially, a similar up-regulation of glutamate transporters in human spinal astrocytes by clavulanic acid supports the development of novel β-lactam-based analgesics, devoid of antibacterial activity, for the clinical treatment of chronic pain.

KW - Journal Article

U2 - 10.1002/ejp.1117

DO - 10.1002/ejp.1117

M3 - Journal article

VL - 22

SP - 282

EP - 294

JO - European Journal of Pain

JF - European Journal of Pain

SN - 1090-3801

IS - 2

ER -

ID: 186876461