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The β‐lactam clavulanic acid mediates glutamate transport‐sensitive pain relief in a rat model of neuropathic pain
Author(s) -
Kristensen P.J.,
Gegelashvili G.,
Munro G.,
Heegaard A.M.,
Bjerrum O.J.
Publication year - 2018
Publication title -
european journal of pain
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.305
H-Index - 109
eISSN - 1532-2149
pISSN - 1090-3801
DOI - 10.1002/ejp.1117
Subject(s) - ceftriaxone , neuropathic pain , pharmacology , clavulanic acid , glutamate receptor , medicine , anesthesia , visceral pain , chronic pain , chemistry , antibiotics , nociception , amoxicillin , biochemistry , receptor , psychiatry
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 ( GLT 1), its splice variant GLT 1b 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 GLT 1b 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 GLT 1 expression in rat cortical and human spinal astrocyte cultures. Furthermore, clavulanic acid increased expression of GLT 1b 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 GLT 1b 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 viv o. 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.