Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A(1) receptor

Caffeine is believed to act by blocking adenosine A(1) and A(2A) receptors (A(1)R, A(2A)R), indicating that some A receptors are tonically activated. We generated mice with a targeted disruption of the second coding exon of t he A(1)R (A(1)R(-/-)). These animals bred and gained weight normally and ha d a normal heart rate, blood pressure, and body temperature. In most behavi oral tests they were similar to A(1)R(+/+) mice, but A(1)R(-/-) mice showed signs of increased anxiety. Electrophysiological recordings from hippocamp al slices revealed that both adenosine-mediated inhibition and theophylline -mediated augmentation of excitatory glutamatergic neurotransmission were a bolished in A(1)R(-/-) mice. In A(1)R(+/-) mice the potency of adenosine wa s halved, as was the number of A(1)R. In A(1)R(-/-) mice, the analgesic eff ect of intrathecal adenosine was lost, and thermal hyperalgesia was observe d, but the analgesic effect of morphine was intact. The decrease in neurona l activity upon hypoxia was reduced both in hippocampal slices and in brain stem, and functional recovery after hypoxia was attenuated. Thus A(1)Rs do not play an essential role during development, and although they significan tly influence synaptic activity, they play a nonessential role in normal ph ysiology. However, under pathophysiological conditions, including noxious s timulation and oxygen deficiency, they are important.