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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / pharmacology*
  • Analgesics / pharmacology*
  • Animals
  • Blotting, Western
  • Calcium Channels / biosynthesis*
  • Cyclohexanecarboxylic Acids / pharmacology*
  • Disease Models, Animal
  • Down-Regulation
  • Drug Tolerance / physiology*
  • Fluorescent Antibody Technique
  • Gabapentin
  • Hyperalgesia / etiology
  • Hyperalgesia / metabolism*
  • Male
  • Neuralgia / etiology
  • Neuralgia / metabolism
  • Neurons / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Stroke / complications
  • Thalamus / metabolism
  • gamma-Aminobutyric Acid / pharmacology*


  • Amines
  • Analgesics
  • Cacna2d2 protein, rat
  • Calcium Channels
  • Cyclohexanecarboxylic Acids
  • gamma-Aminobutyric Acid
  • Gabapentin