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Neurosci Bull. 2016 Feb;32(1):41-50. doi: 10.1007/s12264-015-0008-3. Epub 2016 Jan 19.

Gabapentinoid Insensitivity after Repeated Administration is Associated with Down-Regulation of the α(2)δ-1 Subunit in Rats with Central Post-Stroke Pain Hypersensitivity.

Author information

1
Institute for Biomedical Sciences of Pain, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
2
Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
3
Institute for Biomedical Sciences of Pain, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China. junchen@fmmu.edu.cn.
4
Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China. junchen@fmmu.edu.cn.
5
Key Laboratory of Brain Stress and Behavior, PLA, Xi'an, 710038, China. junchen@fmmu.edu.cn.
6
Beijing Institute for Brain Disorders, Beijing, 100069, China. junchen@fmmu.edu.cn.

Abstract

The α2δ-1 subunit of the voltage-gated Ca(2+) channel (VGCC) is a molecular target of gabapentin (GBP), which has been used as a first-line drug for the relief of neuropathic pain. GBP exerts its anti-nociceptive effects by disrupting trafficking of the α2δ-1 subunit to the presynaptic membrane, resulting in decreased neurotransmitter release. We previously showed that GBP has an anti-allodynic effect in the first two weeks; but this is followed by insensitivity in the later stage after repeated administration in a rat model of central post-stroke pain (CPSP) hypersensitivity induced by intra-thalamic hemorrhage. To explore the mechanisms underlying GBP insensitivity, the cellular localization and time-course of expression of the α2δ-1 subunit in both the thalamus and spinal dorsal horn were studied in the same model. We found that the α2δ-1 subunit was mostly localized in neurons, but not astrocytes and microglia. The level of α2δ-1 protein increased in the first two weeks after injury but then decreased in the third week, when GBP insensitivity occurred. Furthermore, the α2δ-1 down-regulation was likely caused by later neuronal loss in the injured thalamus through a mechanism other than apoptosis. In summary, the present results suggest that the GBP receptor α2δ-1 is mainly expressed in thalamic neurons in which it is up-regulated in the early stage of CPSP but this is followed by dramatic down-regulation, which is likely associated with GBP insensitivity after long-term use.

KEYWORDS:

Calcium channel α2δ subunit; Central post-stroke pain; Gabapentinoid; Spinal dorsal horn; Thalamic hemorrhagic stroke; Thalamus

PMID:
26781878
PMCID:
PMC5563753
DOI:
10.1007/s12264-015-0008-3
[Indexed for MEDLINE]
Free PMC Article

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