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B. B. FREDHOLM ANAL. REAL ACAD. NAL. FARM.

Ever since the pioneering work of Berne and Gerlach a role for adenosine
in mediating responses to hypoxia and ischemia has been postulated. We
have so far examined the role of A1 receptors in two such responses. In
the hippocampal slice preparation responses to hypoxia include a fast
decrease in responses to excitatory stimulation. We found that virtually all
of this decrease was lost in slices from A1R -/- mice (Johansson,
Halldner, Dunwiddie, Masino, Poelchen, Giménez-Llort, Escorihuela,
Fernández-Teruel, Wiesenfeld-Hallin, Xu, Hårdemark, Betsholtz,
Herlenius and Fredholm; 2001). Furthermore, A1R -/- slices did not fully
recover after hypoxia, as did A1R +/+ slices. These findings clearly
demonstrate that adenosine acting on A1 receptors is critically important
in regulating the responsiveness of neurons to decreased supply of
metabolizable energy, enabling the neurons to survive such energy
shortage.

A somewhat similar effect was observed when activity of respiratory
neurons in the immature brainstem was studied. The normal depression of
rate of spontaneous firing induced by hypoxia was lost or markedly
reduced in A1R -/- mice. Also in this preparation the recovery seen in
A1R +/+ mice was less complete in A1R -/- brainstem neurons
(Johansson, Halldner, Dunwiddie, Masino, Poelchen, Giménez-Llort,
Escorihuela, Fernández-Teruel, Wiesenfeld-Hallin, Xu, Hårdemark,
Betsholtz, Herlenius and Fredholm; 2001).

Body temperature was similar in all genotypes, but the temperature
lowering effect of adenosine analogues was less pronounced in A1R +/-,
and, particularly, A1R -/- mice (Johansson, Halldner, Dunwiddie, Masino,
Poelchen, Giménez-Llort, Escorihuela, Fernández-Teruel, Wiesenfeld-
Hallin, Xu, Hårdemark, Betsholtz, Herlenius and Fredholm; 2001).
It has long been known that adenosine can control pain (Sawynok and
Sweeney; 1989) and adenosine receptors, particularly A1 receptors, have
been known to be present in spinal cord (Geiger et al.; 1984, Fastbom,
Post and Fredholm; 1990). It was therefore no major surprise when we
found that the analgesic effects of intrathecal adenosine analogues were
essentially lost in A1R -/- mice (Johansson, Halldner, Dunwiddie,
Masino, Poelchen, Giménez-Llort, Escorihuela, Fernández-Teruel,
Wiesenfeld-Hallin, Xu, Hårdemark, Betsholtz, Herlenius and Fredholm;

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