1Institute for Biomedical Sciences of Pain, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
2Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi’an 710038, China
3Key Laboratory of Brain Stress and Behavior, PLA, Xi’an 710038, China

Abstract 

The α2δ-1 subunit of the voltage-gated Ca2+ 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 antiallodynic 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

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

[SpringerLink]