title: 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.
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.
authors.affiliation: Institute for Biomedical Sciences of Pain, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Yang
authors.affiliation: Institute for Biomedical Sciences of Pain, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
authors.forename: Chun-Li
authors.initials: CL
authors.lastname: Li
authors.affiliation: Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Lu
authors.affiliation: Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
authors.forename: Yao-Qing
authors.initials: YQ
authors.lastname: Yu
authors.affiliation: Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
authors.forename: Han
authors.initials: H
authors.lastname: Fu
authors.affiliation: Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
authors.forename: Ting
authors.initials: T
authors.lastname: He
authors.affiliation: Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
authors.forename: Rui-Rui
authors.initials: RR
authors.lastname: Wang
authors.affiliation: Institute for Biomedical Sciences of Pain, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China. junchen@fmmu.edu.cn.|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.|Key Laboratory of Brain Stress and Behavior, PLA, Xi'an, 710038, China. junchen@fmmu.edu.cn.|Beijing Institute for Brain Disorders, Beijing, 100069, China. junchen@fmmu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000588:Amines / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D015220:Calcium Channels / Q000096:biosynthesis*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D004361:Drug Tolerance / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D000077206:Gabapentin; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism*; D008297:Male; D009437:Neuralgia / Q000209:etiology / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000150:complications; D013788:Thalamus / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D000588:Amines; D000700:Analgesics; C478374:Cacna2d2 protein, rat; D015220:Calcium Channels; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin
keywords: Calcium channel α2δ subunit; Central post-stroke pain; Gabapentinoid; Spinal dorsal horn; Thalamic hemorrhagic stroke; Thalamus