Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A<inf>1</inf> receptor

Björn Johansson, Linda Halldner, Thomas V. Dunwiddie, Susan A. Masino, Wolfgang Poelchen, Lydia Giménez-Llort, Rosa M. Escorihuela, Alberto Fernández-Teruel, Zsuzsanna Wiesenfeld-Hallin, Xiao Jun Xu, Anna Hårdemark, Christer Betsholtz, Eric Herlenius, Bertil B. Fredholm

Research output: Contribution to journalArticleResearchpeer-review

409 Citations (Scopus)

Abstract

Caffeine is believed to act by blocking adenosine A1 and A2A receptors (A1R, A2AR), indicating that some A1 receptors are tonically activated. We generated mice with a targeted disruption of the second coding exon of the A1R (A1R-/-). These animals bred and gained weight normally and had a normal heart rate, blood pressure, and body temperature. In most behavioral tests they were similar to A1R+/+ mice, but A1R-/- mice showed signs of increased anxiety. Electrophysiological recordings from hippocampal slices revealed that both adenosine-mediated inhibition and theophylline-mediated augmentation of excitatory glutamatergic neurotransmission were abolished in A1R-/- mice. In A1R+/- mice the potency of adenosine was halved, as was the number of A1R. In A1R-/- mice, the analgesic effect of intrathecal adenosine was lost, and thermal hyperalgesia was observed, but the analgesic effect of morphine was intact. The decrease in neuronal activity upon hypoxia was reduced both in hippocampal slices and in brainstem, and functional recovery after hypoxia was attenuated. Thus A1Rs do not play an essential role during development, and although they significantly influence synaptic activity, they play a nonessential role in normal physiology. However, under pathophysiological conditions, including noxious stimulation and oxygen deficiency, they are important.
Original languageEnglish
Pages (from-to)9407-9412
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
DOIs
Publication statusPublished - 31 Jul 2001

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