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Molecular basis for the dosing time-dependency of anti-allodynic effects of gabapentin in a mouse model of neuropathic pain.
Mol Pain. 2010 Nov 26; 6:83.MP

Abstract

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.

Authors+Show Affiliations

Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21108841

Citation

Kusunose, Naoki, et al. "Molecular Basis for the Dosing Time-dependency of Anti-allodynic Effects of Gabapentin in a Mouse Model of Neuropathic Pain." Molecular Pain, vol. 6, 2010, p. 83.
Kusunose N, Koyanagi S, Hamamura K, et al. Molecular basis for the dosing time-dependency of anti-allodynic effects of gabapentin in a mouse model of neuropathic pain. Mol Pain. 2010;6:83.
Kusunose, N., Koyanagi, S., Hamamura, K., Matsunaga, N., Yoshida, M., Uchida, T., Tsuda, M., Inoue, K., & Ohdo, S. (2010). Molecular basis for the dosing time-dependency of anti-allodynic effects of gabapentin in a mouse model of neuropathic pain. Molecular Pain, 6, 83. https://doi.org/10.1186/1744-8069-6-83
Kusunose N, et al. Molecular Basis for the Dosing Time-dependency of Anti-allodynic Effects of Gabapentin in a Mouse Model of Neuropathic Pain. Mol Pain. 2010 Nov 26;6:83. PubMed PMID: 21108841.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular basis for the dosing time-dependency of anti-allodynic effects of gabapentin in a mouse model of neuropathic pain. AU - Kusunose,Naoki, AU - Koyanagi,Satoru, AU - Hamamura,Kengo, AU - Matsunaga,Naoya, AU - Yoshida,Miyako, AU - Uchida,Takahiro, AU - Tsuda,Makoto, AU - Inoue,Kazuhide, AU - Ohdo,Shigehiro, Y1 - 2010/11/26/ PY - 2010/08/31/received PY - 2010/11/26/accepted PY - 2010/11/27/entrez PY - 2010/11/27/pubmed PY - 2011/4/5/medline SP - 83 EP - 83 JF - Molecular pain JO - Mol Pain VL - 6 N2 - 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. SN - 1744-8069 UR - https://www.unboundmedicine.com/medline/citation/21108841/Molecular_basis_for_the_dosing_time_dependency_of_anti_allodynic_effects_of_gabapentin_in_a_mouse_model_of_neuropathic_pain_ L2 - https://journals.sagepub.com/doi/10.1186/1744-8069-6-83?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -