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First and second generation H₁ histamine receptor antagonists produce different sleep-inducing profiles in rats.
Eur J Pharmacol. 2012 May 15; 683(1-3):179-85.EJ

Abstract

First generation H₁ histamine receptor antagonists, such as d-chlorpheniramine (d-CPA) and diphenhydramine, produce drowsiness in humans. They are currently used as over-the-counter sleep aids. However, the mechanisms underlying drowsiness induced by these H₁ histamine receptor antagonists remain obscure because they produce heterogeneous receptor-independent actions. Ketotifen is a second generation H₁ histamine receptor antagonist which is more permeable to the brain than newer H₁ histamine receptor antagonists. Therefore, to access sleep-inducing profiles by H₁ histamine receptor blocking actions, the present study compared the dose-dependent effects of diphenhydramine and ketotifen (1-40 mg/kg, intraperitoneal injection at dark onset time) on daily sleep-wake patterns in rats. Ketotifen dose-dependently decreased rapid-eye-movement (REM) sleep and increased non-REM sleep by amplifying slow-wave electroencephalogram powers. Diphenhydramine at 4 mg/kg transiently increased non-REM sleep and reduced REM sleep similar to the effects of ketotifen. The larger injections of diphenhydramine (10-40 mg/kg), however, reduced non-REM sleep, abolished slow-wave enhancements and facilitated wakefulness. The bi-directional action of diphenhydramine on sleep is similar to our former results using d-CPA. Taken together, the arousal effects caused by over-dose administrations of the first generation H₁ histamine receptor antagonists may be mediated by H₁ histamine receptor-independent actions. To further examine the tolerance of ketotifen-induced sleep, 3 mg/kg ketotifen was injected daily for 5 days 3 h before light onset time. These experiments consistently enhanced non-REM-sleep at the end of the active phase of rats, suggesting that ketotifen may function as a desirable sleep aid although the coincidental REM sleep reduction requires attention.

Authors+Show Affiliations

Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

22449385

Citation

Unno, Katsuya, et al. "First and Second Generation H₁ Histamine Receptor Antagonists Produce Different Sleep-inducing Profiles in Rats." European Journal of Pharmacology, vol. 683, no. 1-3, 2012, pp. 179-85.
Unno K, Ozaki T, Mohammad S, et al. First and second generation H₁ histamine receptor antagonists produce different sleep-inducing profiles in rats. Eur J Pharmacol. 2012;683(1-3):179-85.
Unno, K., Ozaki, T., Mohammad, S., Tsuno, S., Ikeda-Sagara, M., Honda, K., & Ikeda, M. (2012). First and second generation H₁ histamine receptor antagonists produce different sleep-inducing profiles in rats. European Journal of Pharmacology, 683(1-3), 179-85. https://doi.org/10.1016/j.ejphar.2012.03.017
Unno K, et al. First and Second Generation H₁ Histamine Receptor Antagonists Produce Different Sleep-inducing Profiles in Rats. Eur J Pharmacol. 2012 May 15;683(1-3):179-85. PubMed PMID: 22449385.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - First and second generation H₁ histamine receptor antagonists produce different sleep-inducing profiles in rats. AU - Unno,Katsuya, AU - Ozaki,Tomoya, AU - Mohammad,Shahid, AU - Tsuno,Saki, AU - Ikeda-Sagara,Masami, AU - Honda,Kazuki, AU - Ikeda,Masayuki, Y1 - 2012/03/16/ PY - 2011/11/10/received PY - 2012/03/01/revised PY - 2012/03/07/accepted PY - 2012/3/28/entrez PY - 2012/3/28/pubmed PY - 2012/9/14/medline SP - 179 EP - 85 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 683 IS - 1-3 N2 - First generation H₁ histamine receptor antagonists, such as d-chlorpheniramine (d-CPA) and diphenhydramine, produce drowsiness in humans. They are currently used as over-the-counter sleep aids. However, the mechanisms underlying drowsiness induced by these H₁ histamine receptor antagonists remain obscure because they produce heterogeneous receptor-independent actions. Ketotifen is a second generation H₁ histamine receptor antagonist which is more permeable to the brain than newer H₁ histamine receptor antagonists. Therefore, to access sleep-inducing profiles by H₁ histamine receptor blocking actions, the present study compared the dose-dependent effects of diphenhydramine and ketotifen (1-40 mg/kg, intraperitoneal injection at dark onset time) on daily sleep-wake patterns in rats. Ketotifen dose-dependently decreased rapid-eye-movement (REM) sleep and increased non-REM sleep by amplifying slow-wave electroencephalogram powers. Diphenhydramine at 4 mg/kg transiently increased non-REM sleep and reduced REM sleep similar to the effects of ketotifen. The larger injections of diphenhydramine (10-40 mg/kg), however, reduced non-REM sleep, abolished slow-wave enhancements and facilitated wakefulness. The bi-directional action of diphenhydramine on sleep is similar to our former results using d-CPA. Taken together, the arousal effects caused by over-dose administrations of the first generation H₁ histamine receptor antagonists may be mediated by H₁ histamine receptor-independent actions. To further examine the tolerance of ketotifen-induced sleep, 3 mg/kg ketotifen was injected daily for 5 days 3 h before light onset time. These experiments consistently enhanced non-REM-sleep at the end of the active phase of rats, suggesting that ketotifen may function as a desirable sleep aid although the coincidental REM sleep reduction requires attention. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/22449385/First_and_second_generation_H₁_histamine_receptor_antagonists_produce_different_sleep_inducing_profiles_in_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(12)00257-9 DB - PRIME DP - Unbound Medicine ER -