In vivo behavioral assessment of central nervous system purinergic receptors

Administered intracisternally, adenosine (ADO), 2-chloroadenosine (CADO), adenosine-5'-cyclopropylcarboxamide (ACC) and adenosine-5'-ethylcarboxamide (AEC) caused dose-related increases in hot plate reaction times in mice. The rank order of potency was AEC=ACC greater than CADO greater than ADO and ACC exerted demonstrable effects with doses as low as 10 ng/mouse. ADO itself was more potent than AMP, ADP, ATP and several other related compounds of interest. Theophylline, caffeine and 8-phenyltheophylline antagonized the antinocisponsive effect of CADO or ACC. Papaverine (an adenosine uptake blocker) and erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA: an adenosine deaminase inhibitor) potentiated the effect of ADO. EHNA did not potentiate the action of CADO in this procedure. The antinocisponsive effect of CADO was not antagonized by a host of neurally active agents including naloxone, clonidine and RO 20-1724. Time course studies indicated that the antinocisponsive effect of ADO was transient with the peak effect occurring 5 min after injection and disappearing by 60 min, whereas the effect of CADO persisted for at least 90 min. Intracisternally administered CADO also caused a pronounced hypothermia, loss of muscle tone and was active in the mouse writhing test. Taken together, these data demonstrate that purine exert potent in vivo behavioral effects and are consonant with the existence of a central purinergic P1-receptor which is amenable to selective pharmacological manipulation.