Molecular basis for the dosing time-dependency of anti-allodynic effects of gabapentin in a mouse model of neuropathic pain.
BACKGROUND
Neuropathic pain is characterized by hypersensitivity to innocuous stimuli (tactile allodynia) that is nearly always resistant to NSAIDs or even opioids. Gabapentin, a GABA analogue, was originally developed to treat epilepsy. Accumulating clinical evidence supports the effectiveness of this drug for diverse neuropathic pain. In this study, we showed that the anti-allodynic effect of gabapentin was changed by the circadian oscillation in the expression of its target molecule, the calcium channel α2δ-1 subunit.


RESULTS
Mice were underwent partial sciatic nerve ligation (PSL) to create a model of neuropathic pain. The paw withdrawal threshold (PWT) in PSL mice significantly decreased and fluctuated with a period length about 24 h. The PWT in PSL mice was dose-dependently increased by intraperitoneal injection of gabapentin, but the anti-allodynic effects varied according to its dosing time. The protein levels of α2δ-1 subunit were up-regulated in the DRG of PSL mice, but the protein levels oscillated in a circadian time-dependent manner. The time-dependent oscillation of α2δ-1 subunit protein correlated with fluctuations in the maximal binding capacity of gabapentin. The anti-allodynic effect of gabapentin was attenuated at the times of the day when α2δ-1 subunit protein was abundant.


CONCLUSIONS
These findings suggest that the dosing time-dependent difference in the anti-allodynic effects of gabapentin is attributable to the circadian oscillation of α2δ-1 subunit expression in the DRG and indicate that the optimizing its dosing schedule helps to achieve rational pharmacotherapy for neuropathic pain.
Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Naoki
N
Kusunose
Satoru
S
Koyanagi
Kengo
K
Hamamura
Naoya
N
Matsunaga
Miyako
M
Yoshida
Takahiro
T
Uchida
Makoto
M
Tsuda
Kazuhide
K
Inoue
Shigehiro
S
Ohdo
D000588:Amines / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D002940:Circadian Rhythm / Q000502:physiology; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000077206:Gabapentin; D006930:Hyperalgesia / Q000188:drug therapy*; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy*; D021122:Protein Subunits / Q000187:drug effects; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use
D000588:Amines; D015220:Calcium Channels; D003509:Cyclohexanecarboxylic Acids; D021122:Protein Subunits; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin