d-Aspartate drinking solution alleviates pain and cognitive impairment in neuropathic mice
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d-Aspartate (d-Asp) is a free d-amino acid detected in multiple brain regions and putative precursor of endogenous N-methyl-d-aspartate (NMDA) acting as agonist at NMDA receptors. In this study, we investigated whether d-Asp (20 mM) in drinking solution for 1 month affects pain responses and pain-related emotional, and cognitive behaviour in a model of neuropathic pain induced by the spared nerve injury (SNI) of the sciatic nerve in mice. SNI mice developed mechanical allodynia and motor coordination impairment 30 days after SNI surgery. SNI mice showed cognitive impairment, anxiety and depression-like behaviour, reduced sociability in the three chamber sociability paradigm, increased expression of NR2B subunit of NMDA receptor and Homer 1a in the medial prefrontal cortex (mPFC). The expression of (post synaptic density) PSD-95 and Shank 1was instead unaffected in the mPFC of the SNI mice. Treatment with d-Asp drinking solution, started right after the SNI (day 0), alleviated mechanical allodynia, improved cognition and motor coordination and increased social interaction. d-Asp also restored the levels of extracellular d-Asp, Homer 1a and NR2B subunit of the NMDA receptor to physiological levels and reduced Shank1 and PSD-95 protein levels in the mPFC. Amitriptyline, a tricyclic antidepressant used also to alleviate neuropathic pain in humans, reverted mechanical allodynia and cognitive impairment, and unlike d-Asp, was effective in reducing depression and anxiety-like behaviour in the SNI mice and increased PSD protein level. Altogether these findings demonstrate that d-Asp improves sensorial, motor and cognitive-like symptoms related to chronic pain possibly through glutamate neurotransmission normalization in neuropathic mice.
Keywordsd-Aspartate Spared nerve injury Mechanical allodynia Pain-related affective and cognitive behaviour NMDA receptor Mice
This work was financially supported by the Ministero Istruzione, Università e Ricerca, Project n° PRIN 2012WBSSY4_001.
Compliance with ethical standards
Conflict of interest
All the authors who took part in this study declare that they have nothing to disclose regarding competing interests or funding with respect to this manuscript.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed (Animal Ethics Committee of the Second University of Naples in compliance with the IASP and European Community (E.C. L358/1 18/12/86). All procedures were in accordance with the Animal Ethics Committee of the Second University of Naples. This article does not contain any studies with human participants performed by any of the authors.
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