Dosing Time-Dependent Changes in the Analgesic Effect of Pregabalin on Diabetic Neuropathy in Mice
Abstract
Patients with diabetes often develop peripheral nerve complications, including numbness and pain in the extremities. Diabetes-induced peripheral neuropathic pain is characterized by hypersensitivity to innocuous stimuli, known as tactile allodynia. Pregabalin (PGN) is currently used to treat diabetes-induced peripheral neuropathy and alleviates allodynia. In the present study, we demonstrated that the antiallodynic effect of PGN on diabetic mice was modulated by circadian changes in its intestinal absorption. A single intraperitoneal administration of 200 mg/kg streptozotocin (STZ) to mice induced type I diabetic pathologic changes that were accompanied by tactile allodynia. The intensity of tactile allodynia in STZ-induced diabetic mice was alleviated by the oral administration of PGN; however, the antiallodynic effect varied according to its dosing time. The analgesic effect of PGN was enhanced by its administration at the times of day when its intestinal absorption was accelerated. Organic cation transporter novel type 1 (Octn1) mediated the uptake of PGN into intestinal epithelial cells. The expression of Octn1 in the small intestine of STZ-induced diabetic mice oscillated in a circadian time-dependent manner. This oscillation in Octn1 appeared to cause the time of day-dependent changes in the intestinal absorption of PGN. Similar dosing time dependencies of the antiallodynic effect of PGN and oscillation in Octn1 expression were also detected in type II diabetic db/db mice. These results suggested that the dosing time-dependent differences in the analgesic effect of PGN were attributable to circadian oscillations in the intestinal expression of Octn1 and also that optimizing its dosing schedule may assist in achieving rational pharmacotherapy for diabetes-induced peripheral neuropathic pain.
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SLC22A4 and its homologues have significant specificity for ERG and weak activity for various drugs.
“Subsequent work(87,169–172) has confirmed and reinforced this view of SLC22A4 and its homologues(173) as having significant specificity for ERG, and weak activity for various drugs(174–177).”
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Cites
Quantitative assessment of tactile allodynia in the rat paw
Chaplan, S. R., Bach, F. W., Pogrel, J. W., Chung, J. M., & Yaksh, T. L. (1994) · Journal of Neuroscience Methods · doi:10.1016/0165-0270(94)90144-9 · Cited by 7,740 · see citing works
Rosenstock, J., Tuchman, M. M., LaMoreaux, L., & Sharma, U. (2004) · Pain · doi:10.1016/j.pain.2004.05.001 · Cited by 722 · see citing works
Lévi, F. A., Zidani, R., & Misset, J. L. (1997) · The Lancet · doi:10.1016/s0140-6736(97)03358-8 · Cited by 702 · see citing works
Discovery of the ergothioneine transporter
Gründemann, D., Harlfinger, S., Gölz, S., Geerts, A., Lazar, A., Berkels, R., Jung, N., RUBBERT, A., & Schömig, E. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0408624102 · Cited by 613 · see citing works
Inhibition of neuronal Ca2+ influx by gabapentin and pregabalin in the human neocortex
Fink, K., Dooley, D. J., Meder, W. P., Suman‐Chauhan, N., Duffy, S., Clusmann, H., & Göthert, M. (2002) · Neuropharmacology · doi:10.1016/s0028-3908(01)00172-1 · Cited by 496 · see citing works
Carrier-Mediated Intestinal Transport of Drugs
Tsuji, A., & Tamai, I. (1996) · Pharmaceutical Research · doi:10.1023/a:1016086003070 · Cited by 392 · see citing works
The mammalian circadian timing system: from gene expression to physiology
Gachon, F., Nagoshi, E., Brown, S., Ripperger, J. A., & Schibler, U. (2004) · Chromosoma · doi:10.1007/s00412-004-0296-2 · Cited by 382 · see citing works
Molecular and Functional Characterization of Organic Cation/Carnitine Transporter Family in Mice
Tamai, I., Ohashi, R., Nezu, J., Sai, Y., Kobayashi, D., Oku, A., Shimane, M., & Tsuji, A. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005340200 · Cited by 292 · see citing works
Bleasby, K., Castle, J. C., Roberts, C. J., Cheng, C., Bailey, W. J., Sina, J. F., Kulkarni, A., Hafey, M., Evers, R., Johnson, J. M., et al. (2006) · Xenobiotica · doi:10.1080/00498250600861751 · Cited by 269 · see citing works
Changing the dosing schedule minimizes the disruptive effects of interferon on clock function
Ohdo, S., Koyanagi, S., Suyama, H., Higuchi, S., & Aramaki, H. (2001) · Nature Medicine · doi:10.1038/85507 · Cited by 205 · see citing works
Self-citationDooley, D. J., Donovan, C. M., Meder, W. P., & Whetzel, S. Z. (2002) · Synapse · doi:10.1002/syn.10094 · Cited by 180 · see citing works
Pregabalin: From molecule to medicine
Kavoussi, R. J. (2006) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2006.04.005 · Cited by 146 · see citing works
Laposky, A. D., Bradley, M. A., Williams, D. L., Bass, J., & Turek, F. W. (2008) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00026.2008 · Cited by 135 · see citing works
Circadian Clock-Controlled Intestinal Expression of the Multidrug-Resistance Gene mdr1a in Mice
Murakami, Y., Higashi, Y., Matsunaga, N., Koyanagi, S., & Ohdo, S. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.07.073 · Cited by 118 · see citing works
Self-citationVermeij, T. A. C., & Edelbroek, P. M. (2004) · Journal of Chromatography B · doi:10.1016/j.jchromb.2004.08.018 · Cited by 115 · see citing works
Diurnal Rhythmicity in the Transcription of Jejunal Drug Transporters
Stearns, A. T., Balakrishnan, A., Rhoads, D. B., Ashley, S. W., & Tavakkolizadeh, A. (2008) · Journal of Pharmacological Sciences · doi:10.1254/jphs.08100sc · Cited by 83 · see citing works
Kusunose, N., Koyanagi, S., Hamamura, K., Matsunaga, N., Yoshida, M., Uchida, T., Tsuda, M., Inoue, K., & Ohdo, S. (2010) · Molecular Pain · doi:10.1186/1744-8069-6-83 · Cited by 74 · see citing works
Self-citationThe molecular mechanism regulating 24‐hour rhythm of CYP2E1 expression in the mouse liver†
Matsunaga, N., Ikeda, M., Takiguchi, T., Koyanagi, S., & Ohdo, S. (2008) · Hepatology · doi:10.1002/hep.22304 · Cited by 73 · see citing works
Self-citationLamhonwah, A., Skaug, J., Scherer, S. W., & Tein, I. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)02946-7 · Cited by 70 · see citing works
Methotrexate Chronotherapy is Effective Against Rheumatoid Arthritis
To, H., Yoshimatsu, H., Tomonari, M., Ida, H., Tsurumoto, T., Tsuji, Y., Sonemoto, E., Shimasaki, N., Koyanagi, S., Sasaki, H., et al. (2011) · Chronobiology International · doi:10.3109/07420528.2011.553017 · Cited by 69 · see citing works
Self-citationHamdan, A. M., Koyanagi, S., Wada, E., Kusunose, N., Murakami, Y., Matsunaga, N., & Ohdo, S. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.333377 · Cited by 58 · see citing works
Self-citationChronopharmacology and controlled drug release
Lemmer, B. (2005) · Expert Opinion on Drug Delivery · doi:10.1517/17425247.2.4.667 · Cited by 57 · see citing works
Mucosal Uptake of Gabapentin (Neurontin) vs. Pregabalin in the Small Intestine
Piyapolrungroj, N., Li, C., Bockbrader, H. N., Liu, G., & Fleisher, D. (2001) · Pharmaceutical Research · doi:10.1023/a:1010970809090 · Cited by 53 · see citing works
Okamura, A., Koyanagi, S., Dilxiat, A., Kusunose, N., Chen, J. J., Matsunaga, N., Shibata, S., & Ohdo, S. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.577023 · Cited by 51 · see citing works
Self-citationWada, E., Koyanagi, S., Kusunose, N., Akamine, T., Masui, H., Hashimoto, H., Matsunaga, N., & Ohdo, S. (2014) · Molecular Pharmacology · doi:10.1124/mol.114.094979 · Cited by 45 · see citing works
Self-citationTransport of Pregabalin in Rat Intestine and Caco-2 Monolayers
Jezyk, N., Li, C., Stewart, B. H., Wu, X., Bockbrader, H. N., & Fleisher, D. (1999) · Pharmaceutical Research · doi:10.1023/a:1018866928335 · Cited by 35 · see citing works
Bostwick, J., Nguyen, D. D. T., Cornélissen, G., Franz Halberg, A., & Hoogerwerf, W. A. (2009) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-009-0354-4 · Cited by 23 · see citing works
Establishment of Intestinal Epithelial Cell Lines from Adult Mouse Small and Large Intestinal Crypts
Iwamoto, T., YAMADA, K., Shimizu, M., & Totsuka, M. (2011) · Bioscience Biotechnology and Biochemistry · doi:10.1271/bbb.100887 · Cited by 15 · see citing works
Blay, R., Bigley, N. J., & Giron, D. J. (1985) · Diabetes · doi:10.2337/diab.34.12.1288 · Cited by 14 · see citing works
A Systematic Review of Pharmacoeconomic Studies for Pregabalin
Parker, L., Huelin, R., Khankhel, Z., Wasiak, R., & Mould, J. F. (2014) · Pain Practice · doi:10.1111/papr.12193 · Cited by 8 · see citing works
Flagged first, then by citations
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The biology of ergothioneine, an antioxidant nutraceutical
Borodina, I., Kenny, L. C., McCarthy, C. M., Paramasivan, K., Pretorius, E., Roberts, T. J., van der Hoek, S. A., & Kell, D. B. (2020) · Nutrition Research Reviews · doi:10.1017/s0954422419000301 · Cited by 296 · see citing works
“Interestingly, it is up-regulated chronobiologi-cally just before meal times (175) .”
BackgroundCircadian rhythm in pharmacokinetics and its relevance to chronotherapy
Dong, D., Yang, D., Lin, L., Wang, S., & Wu, B. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.114045 · Cited by 146 · see citing works
Timing in drug absorption and disposition: The past, present, and future of chronopharmacokinetics
Bicker, J., Alves, G., Falcão, A. C., & Fortuna, A. C. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15017 · Cited by 98 · see citing works
Pochini, L., Galluccio, M., Scalise, M., Console, L., & Indiveri, C. (2018) · SLAS DISCOVERY · doi:10.1177/2472555218812821 · Cited by 83 · see citing works
The ergothioneine transporter (ETT): substrates and locations, an inventory
Gründemann, D., Hartmann, L., & Flögel, S. (2021) · FEBS Letters · doi:10.1002/1873-3468.14269 · Cited by 81 · see citing works
The circadian clock at the intercept of sleep and pain
Palada, V., Gilron, I., Canlon, B., Svensson, C. I., & Kalso, E. A. (2019) · Pain · doi:10.1097/j.pain.0000000000001786 · Cited by 70 · see citing works
Chronopharmacological strategies focused on chrono-drug discovery
Ohdo, S., Koyanagi, S., & Matsunaga, N. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.05.018 · Cited by 65 · see citing works
Self-citationCircadian Clock–Controlled Drug Metabolism: Implications for Chronotherapeutics
Lu, D., Zhao, M., Chen, M., & Wu, B. (2020) · Drug Metabolism and Disposition · doi:10.1124/dmd.120.090472 · Cited by 64 · see citing works
Takahashi, Y., Nishimura, T., Higuchi, K., Noguchi, S., Tega, Y., Kurosawa, T., Deguchi, Y., & Tomi, M. (2018) · Pharmaceutical Research · doi:10.1007/s11095-018-2532-0 · Cited by 61 · see citing works
Bali, K. K., & Kuner, R. (2017) · Pain · doi:10.1097/j.pain.0000000000001032 · Cited by 34 · see citing works
McDonnell, C., Leánez, S., & Pol, O. (2017) · PLoS ONE · doi:10.1371/journal.pone.0180998 · Cited by 32 · see citing works
Recent advances in circadian-regulated pharmacokinetics and its implications for chronotherapy
Yu, F., Liu, Y., Zhang, R., Zhu, L., Zhang, T., & Shi, Y. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115185 · Cited by 29 · see citing works
McDonnell, C., Leánez, S., & Pol, O. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18112268 · Cited by 25 · see citing works
Circadian regulation of transporter expression and implications for drug disposition
Pácha, J., Balounová, K., & Soták, M. (2020) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2021.1868438 · Cited by 22 · see citing works
Ohdo, S. (2021) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b21-00277 · Cited by 20 · see citing works
Self-citationAkamine, T., Kusunose, N., Matsunaga, N., Koyanagi, S., & Ohdo, S. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.05.209 · Cited by 18 · see citing works
Self-citationPharmacokinetics and Efficacy of a Long-lasting, Highly Concentrated Buprenorphine Solution in Mice
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Kato, M. S., Tsurudome, Y., Kanemitsu, T., Yasukochi, S., Kanado, Y., Ogino, T., Matsunaga, N., Koyanagi, S., & Ohdo, S. (2020) · Scientific Reports · doi:10.1038/s41598-020-70321-6 · Cited by 13 · see citing works
Self-citationChen, F., Li, D.-Y., Zhang, B., Sun, J., Sun, F., Ji, X., Qiu, J., Parker, R. B., Laizure, S. C., & Xu, J. (2018) · Drug Metabolism Reviews · doi:10.1080/03602532.2018.1497645 · Cited by 12 · see citing works
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Self-citationAkashi, T., Noguchi, S., Takahashi, Y., Nishimura, T., & Tomi, M. (2023) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2022.12.028 · Cited by 8 · see citing works
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Beers, J. L., Hébert, M. F., & Wang, J. (2025) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2025.2461479 · Cited by 7 · see citing works
Sato, A., Yasukochi, S., Iwanaka, N., Yamauchi, T., Tsuruta, A., Koyanagi, S., & Ohdo, S. (2024) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.123.001856 · Cited by 7 · see citing works
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Seto, Y., Yoshihashi, T., Tomonari, M., & To, H. (2020) · Chronobiology International · doi:10.1080/07420528.2020.1784189 · Cited by 5 · see citing works
Shaheen, A., Alam, S. M., Azam, F., Saleem, S. A., Khan, M., HASAN, S. S., & Liaquat, A. (2022) · PLoS ONE · doi:10.1371/journal.pone.0266559 · Cited by 3 · see citing works
Liu, D., Wang, W., Hong Li, A., Khan, S., Wang, Q., Xia, C., Nasır, A., Wang, Z., & Bai, Q. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.146097 · Cited by 2 · see citing works
Yoshikawa, N., Naito, T., Yagi, T., & Kawakami, J. (2019) · Therapeutic Drug Monitoring · doi:10.1097/ftd.0000000000000634 · Cited by 2 · see citing works
Sato, A., Iwanaka, N., Yamauchi, T., Tsuruta, A., Ohdo, S., & Koyanagi, S. (2025) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b25-00524 · Cited by 1 · see citing works
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Wang, S., Lin, Y., Gao, L., Yang, Z., & Dong, D. (2020) · Springer eBooks · doi:10.1007/978-981-15-8807-5_10
Sales, J. E. D. S., Veloso, E. V. L., da Silva, R. C. M., Araújo, P. P. B., Machado, J. L. D. S., de Souza, J. G., Caldeira, M. E. C., Machado, R. A. D. S., de Menezes, D. J. A., & de Sousa, O. B. (2022) · Research Society and Development · doi:10.33448/rsd-v11i3.26407
Brimblecombe, K. R., Harris, A. L., Bengoa‐Vergniory, N., O’Connor, B., Duquenoy, L., Anand, R., Lopes, E. F., Roberts, B. M., Burgeno, L. M., Walton, M. E., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.16.675586
- Authors
- Akamine, T., Koyanagi, S., Kusunose, N., Hashimoto, H., Taniguchi, M., Matsunaga, N., & Ohdo, S.
- Affiliations
- Kyushu University (JP)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 354
- Issue
- 1
- Pages
- 65-72
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2249226713
- Cited by
- 33
- References
- 30
- Citations by year
- 2025: 4 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 9 · 2019: 3 · 2018: 4 · 2017: 3
- FWCI
- 1.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (26861456)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- pregabalin, diabetic neuropathic pain, mechanical allodynia, circadian rhythm, timing of drug administration, intestinal absorption, OCTN1, organic cation transporters, streptozotocin-induced diabetes, db/db mice
- MeSH terms
- Pregabalin, Analgesics, Animals, Carrier Proteins, Circadian Rhythm, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Diabetic Neuropathies, Epithelial Cells, gamma-Aminobutyric Acid, Humans, Hyperalgesia, Intestinal Absorption, Jejunum, Membrane Proteins, Mice, Inbred ICR, Spinal Cord, Time Factors, Touch, Calcium Channels, Organic Cation Transport Proteins, Symporters
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